CLINICAL GASTROENTEROLOGY

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George Y. Wu
University of Connecticut Health Center, Farmington, CT, USA

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Christophe Faure • Carlo Di Lorenzo
Nikhil Thapar
Editors

Pediatric
Neurogastroenterology
Gastrointestinal Motility and
Functional Disorders in Children
Editors
Christophe Faure Carlo Di Lorenzo
Division of Pediatric Gastroenterology Division of Pediatric Gastroenterology
Sainte-Justine University Health Center Nationwide Children’s Hospital
Department of Pediatrics The Ohio State University
Université de Montréal Columbus, OH, USA
Montréal, QC, Canada

Nikhil Thapar
Gastroenterology Unit
University College London
Institute of Child Health
Department of Paediatric
Gastroenterology,
Neurogastroenterology, and Motility
Great Ormond Street Hospital
for Children
London, UK

ISBN 978-1-60761-708-2 ISBN 978-1-60761-709-9 (eBook)

DOI 10.1007/978-1-60761-709-9
Springer New York Heidelberg Dordrecht London

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To my parents with love.
Christophe Faure

To my parents for their unconditioned

support and love.
Carlo Di Lorenzo

To my beloved father Baldev Sahai

Thapar—blessed by your and mum’s
unending love, forever my guiding light
and inspiration.
Nikhil Thapar

To our patients and all the children

afflicted by motility and sensory digestive
disorders.
Christophe Faure
Carlo Di Lorenzo
Nikhil Thapar
Foreword

Welcome to the first comprehensive textbook of pediatric neurogastroenterol-

ogy and motility. Thirty years have passed since the first stirrings of interest
in this field. A number of factors coalesced to facilitate its evolution from
oddity and anecdote to mainstream basic science, epidemiology, and clinical
trials. First, there has been an increase in the number of pediatric gastroenter-
ologists, providing a reservoir of intellectual curiosity. Second, medical tech-
nology has advanced, so that we measure more, both in the basic science
laboratory and in pediatric practice. Third, medical care has improved, so that
infants who were dying before diagnosis now live, for example, on parenteral
nutrition, so that their pseudo-obstruction can be characterized. Fourth, the
1999 publication of pediatric Rome criteria, symptom-based criteria for the
diagnosis of functional gastrointestinal disorders, inspired new investigations
into mind–body pediatric medicine. Motility themed advances dominated the
first 10 years. During the second 10 years the emphasis shifted to understand-
ing visceral pain and other afferent sensory sensations and reflexes. In the
past 10 years the focus has been on brain–gut interactions and the functional
gastrointestinal disorders. This text admirably covers all three areas of empha-
sis. The publication of this volume marks the end of the beginning for pediat-
ric neurogastroenterology and motility.

New Orleans, LA, USA Paul Hyman

vii
Preface

In the past 20 years, major advances have been achieved in the care of chil-
dren with pediatric gastrointestinal motility and sensitivity disorders. This is
a reflection of the progress that has been made understanding such conditions
at the developmental and molecular level as well as the development of novel
tools to investigate and treat them. These progresses have led to the birth of a
new “Science”, namely Neurogastroenterology, which is devoted to “study
the interface of all aspects of the digestive system with the different branches
of the nervous system” and which has now established itself as a major area
of clinical practice and research. In the past two decades, there has been an
almost exponential increase in publications of scientific papers in the field, a
plethora of international fora for the discussion of such conditions and cre-
ation of dedicated journals with respectable citation indices. Pediatric neuro-
gastroenterology and motility has not lagged behind and arguably is fast
becoming a major and popular subspecialty in its own right.
With this book we aimed to draw upon an extensive international expertise
to provide a contemporary state-of-the-art reference textbook for pediatric
neurogastroenterology and motility that both specialists and generalists alike
will find helpful.

Overview of the Book

The first chapters are dedicated to some of the success stories of the field.
Utilizing a range of animal models and studies in the human itself we now
have a remarkable understanding of the mechanisms involved in the forma-
tion of a functional enteric neuromusculature. It is clear that development is
a complex spatiotemporal process involving the coordinated interplay of a
number of genes regulating cellular properties and organogenesis. This com-
plexity is reflected in one of the most commonly recognized gut motility
disorders, Hirschsprung’s disease, a condition caused by a failure of devel-
opment of the enteric nervous system. The ontogeny of motility patterns
within the GI tract is now understood in great detail. Utilizing new technolo-
gies, animal models, and some studies in humans, researchers have been
able to show that GI motility is regulated by a number of mechanisms that
vary in relation to stage of development, maturity, and region within the GI
tract. It is very likely that the coming years will see an increasing recognition

ix
x Preface

of the developmental and related functional pathogenic mechanisms under-

lying a range of disorders involving enteric nerves, muscles and interstitial
cells of Cajal. The rich sensory innervation that not only underlies the nor-
mal functioning of the GI tract but has increasingly been implicated in a
range of functional GI disorders is thoroughly described. This sensory inner-
vation and its processing appear to be plastic and influenced by a number of
disease mechanisms and clinical states including infection, inflammation,
and psychological stress. How visceral sensation is modulated by the inter-
play among the CNS, neurogastrointestinal system, inflammation, and gut
microbial ecosystem especially in relation to irritable bowel syndrome is
addressed in a subsequent chapter. This theme is further developed with the
discussion of the bio-psycho-social influences on enteric neuromuscular
function and how the social and cultural settings of patients act to modify
physiologic responses.
The belly of the book summarizes the practical investigations that are
available in the pediatric neurogastroenterologist’s armamentarium. In many
respects this is where much of the recent strides of the field have taken place,
moving it into the realms of a high-tech futuristic specialty. Major highlights
have been the advent of impedance and high-resolution manometry technolo-
gies, which did not exist when the first textbook on pediatric gastrointestinal
motility was published, and are now well accepted and standardized diagnos-
tic techniques. The role of sensitivity tests, namely barostat and satiety drink-
ing tests, in recognizing altered gut sensation as a key pathophysiologic
component of functional gastrointestinal disorders, is discussed. The applica-
tion to clinical investigation of radionucleotide scintigraphy tests which have
seen in recent years a wider application given their improved tolerability,
cost, and safety profile is described in detail. Older and newer technologies
ranging from electrogastrography and transit studies to 3D-ultrasonography
and the wireless motility capsule are presented. Finally, there is a discussion
of autonomic function testing as indirect measure of gastrointestinal function.
The subsequent chapters deal with the practical approach to and description
of the pathology of disorders of enteric neuromusculature and the genetic
underpinning of motility disorders.
The next section of the book focuses on a journey through the GI tract
detailing motility disorders that occur in each region. Feeding and swallow-
ing disorders in a range of GI and systemic diseases are discussed. Pediatric
esophageal and gastric motor disorders are summarized, and intestinal
pseudo-obstruction syndrome and Hirschsprung’s diseases, the most severe
forms of GI dysmotility, are discussed in great detail. The book then focuses
on secondary (malformative) and postsurgical motor disorders.
The book then transitions from more classic motility disorders to func-
tional GI disorders, arguably one of the most common and challenging group
of conditions encountered by primary care providers and subspecialists. The
role of the Rome criteria in developing the field of pediatric functional
disorders is highlighted. Infant regurgitation and gastroesophageal reflux
disease, infantile colic, functional dyspepsia, irritable bowel syndrome, cyclic
vomiting syndrome, aerophagia, adolescent rumination syndrome, and func-
tional constipation are discussed.
Preface xi

The final section of the book is dedicated to therapy, including pharmaco-

therapy, cognitive behavioral therapy, gastric electrical stimulation, intestinal
transplantation, and the potential use of stem cells.

Montreal, QC, Canada Christophe Faure

Columbus, OH, USA Carlo Di Lorenzo
London, UK Nikhil Thapar
Acknowledgments

To our wives (Sophie, Daniela, and Catherine) and children (Alexandre,

Timothé, Clémentine, Gaspar, Mario, Cristina, Francesca, Valentina, Sachin,
Nayan, and Kira) for all their love, support, and patience throughout the prep-
aration of this book.

Montreal, QC, Canada Christophe Faure

Columbus, OH, USA Carlo Di Lorenzo
London, UK Nikhil Thapar

xiii
Contents

Part I Physiology and Development of the Enteric Neuromuscular

System and Gastrointestinal Motility

1 Introduction to Gut Motility and Sensitivity ............................ 3

Nikhil Thapar, Christophe Faure, and Carlo Di Lorenzo
2 Development of the Enteric Neuromuscular System ............... 9
Tiffany A. Heanue and Alan J. Burns
3 Development of Gut Motility ..................................................... 23
Heather M. Young, Elizabeth A. Beckett, Joel C. Bornstein,
and Sudarshan R. Jadcherla
4 Visceral Sensitivity ...................................................................... 37
Christophe Faure
5 Inflammation, Microflora, Motility,
and Visceral Sensitivity............................................................... 49
Sonia Michail and Mun-Wah Ng
6 Integration of Biomedical and Psychosocial
Issues in Pediatric Functional Gastrointestinal
and Motility Disorders................................................................ 59
Miranda A.L. van Tilburg
7 Functional Gastrointestinal Disorders:
An Anthropological Perspective ................................................ 71
Sylvie Fortin, Liliana Gomez, and Annie Gauthier

Part II Motility and Sensory Testing

8 Esophageal Manometry .............................................................. 79

Roberta Buonavolontà, Marina Russo, Rossella Turco,
and Annamaria Staiano
9 Antroduodenal Manometry ....................................................... 91
Osvaldo Borrelli, Valentina Giorgio, and Nikhil Thapar
10 Colonic Manometry .................................................................... 107
Brian P. Regan, Alejandro Flores, and Carlo Di Lorenzo

xv
xvi Contents

11 Anorectal Manometry................................................................. 119

Minou Le-Carlson and William Berquist
12 Esophageal pH and Impedance Monitoring ............................. 129
Rachel Rosen and Eric Chiou
13 Barostat and Other Sensitivity Tests ......................................... 143
Christophe Faure
14 Radionuclide Transit Tests ......................................................... 149
Lorenzo Biassoni, Keith J. Lindley, and Osvaldo Borrelli
15 Electrogastrography, Breath Tests, Ultrasonography,
Transit Tests, and SmartPill ....................................................... 163
Leonel Rodriguez
16 Autonomic Nervous System Testing .......................................... 177
Gisela Chelimsky and Thomas C. Chelimsky

Part III Disorders of Digestive Motility: Developmental

and Acquired Anomalies of the Enteric
Neuromuscular System

17 Pathology of Enteric Neuromusculature................................... 187

Virpi Vanamo Smith
18 Genetics of Motility Disorder: Gastroesophageal
Reflux, Triple A Syndrome, Hirschsprung Disease,
and Chronic Intestinal Pseudo-Obstruction ............................. 203
Jonathan M. Gisser and Cheryl E. Gariepy
19 Feeding and Swallowing Disorders ........................................... 217
Nathalie Rommel and Taher Omari
20 Esophageal Motor Disorders: Achalasia,
Diffuse Esophageal Spasm, Nonspecific
Motor Disorders, Eosinophilic Esophagitis .............................. 227
Hayat Mousa and Ann Aspirot
21 Gastric Motor Disorders: Gastroparesis
and Dumping Syndrome............................................................. 247
Miguel Saps and Ashish Chogle
22 Chronic Intestinal Pseudo-Obstruction .................................... 257
Paul E. Hyman and Nikhil Thapar
23 Hirschsprung Disease ................................................................. 271
Robert O. Heuckeroth
Contents xvii

24 Motility Problems in Developmental Disorders:

Cerebral Palsy, Down Syndrome, William Syndrome,
Familial Dysautonomia, and Mitochondrial Disorders ........... 285
Annamaria Staiano and Massimo Martinelli

Part IV Motility Disorders after Surgery and Developmental

Anomalies of the Enteric Neuromuscular System
Secondary to Anatomical Malformations

25 Esophageal Atresia...................................................................... 295

Julie Castilloux and Christophe Faure
26 Anorectal Malformations ........................................................... 301
Jose M. Garza and Ajay Kaul
27 Small Bowel and Colonic Dysfunction After Surgery ............. 307
Roberto Gomez, H. Nicole Lopez, and John E. Fortunato
28 Gastric Function After Fundoplication .................................... 317
Samuel Nurko

Part V Functional Gastrointestinal Disorders

29 History and Definition of the Rome Criteria ............................ 325

Andrée Rasquin
30 Infant Regurgitation and Pediatric Gastroesophageal
Reflux Disease .............................................................................. 331
Yvan Vandenplas, Bruno Hauser, Thierry Devreker,
and Silvia Salvatore
31 Infant Colic .................................................................................. 347
David R. Fleisher
32 Functional Diarrhea in Toddlers (Chronic Nonspecific
Diarrhea)...................................................................................... 355
Ernesto Guiraldes and José Luis Roessler
33 Functional Dyspepsia .................................................................. 359
Alycia Leiby and Denesh K. Chitkara
34 Irritable Bowel Syndrome .......................................................... 367
Bella Zeisler and Jeffrey S. Hyams
35 Functional Abdominal Pain ....................................................... 377
Manu R. Sood
36 Cyclic Vomiting Syndrome: Comorbidities
and Treatment ............................................................................. 391
Bhanu Sunku and B.U.K. Li
37 Aerophagia................................................................................... 401
Oren Koslowe and Denesh K. Chitkara
xviii Contents

38 Adolescent Rumination Syndrome ............................................ 405

Anthony Alioto and Carlo Di Lorenzo
39 Constipation................................................................................. 413
Vera Loening-Baucke and Alexander Swidsinski
40 Functional Fecal Incontinence ................................................... 429
Rosa Burgers and Marc A. Benninga

Part VI Treatments

41 Drugs Acting on the Gut: Prokinetics, Antispasmodics,

Laxatives ...................................................................................... 441
Aileen F. Har and Joseph M.B. Croffie
42 Gastric Electrical Stimulation ................................................... 465
Carlo Di Lorenzo, Hayat Mousa, and Steven Teich
43 Cognitive Behavioral Therapy for Children
with Functional Abdominal Pain ............................................... 471
Nader N. Youssef and Miranda A.L. van Tilburg
44 Complementary and Alternative Treatments
for Motility and Sensory Disorders ........................................... 481
Arine M. Vlieger and Marc A. Benninga
45 Cellular-Based Therapies for Pediatric GI
Motility Disorders ....................................................................... 493
Ryo Hotta, Dipa Natarajan, Alan J. Burns, and Nikhil Thapar
46 Chronic Intestinal Pseudo-obstruction Syndrome:
Surgical Approach and Intestinal Transplantation ................. 507
Olivier Goulet and Sabine Irtan
Index ..................................................................................................... 515
Contributors

Anthony Alioto, PhD Department of Psychology, Nationwide Children’s

Hospital, Columbus, OH, USA
Ann Aspirot, MD Department of Surgery, Pediatric Surgery Division,
Sainte-Justine University Health Center, University of Montreal, Montreal,
QC, Canada
Elizabeth A. Beckett, PhD Discipline of Physiology, School of Medical
Sciences, University of Adelaide, Adelaide, SA, Australia
Marc A. Benninga, MD, PhD Department of Pediatric Gastroenterology,
Emma Children’s Hospital/Academic Medical Centre, Amsterdam, The
Netherlands
William Berquist, MD Pediatrics Department, Gastroenterology Division,
Lucile Packard Children’s Hospital, Stanford University, Stanford, CA, USA
Lorenzo Biassoni, MSc, FRCP Nuclear Medicine, Department of Radiology,
Great Ormond Street Hospital for Children, London, UK
Joel C. Bornstein, PhD Department of Physiology, University of
Melbourne, Melbourne, VIC, Australia
Osvaldo Borrelli, MD, PhD Division of Neurogastroenterology & Motility,
Department of Paediatric Gastroenterology, Great Ormond Street Hospital for
Children, London, UK
Roberta Buonavolontà, MD Department of Pediatrics, University of Naples,
Naples, Italy
Rosa Burgers, MD Department of Pediatric Gastroenterology, Emma
Children’s Hospital/Academic Medical Centre, Amsterdam, The Netherlands
Alan J. Burns, PhD Neural Development Unit, UCL Institute of Child
Health, London, UK
Julie Castilloux, MD Pediatric Department, Gastroenterology Division,
Centre Hospitalier Universitaire Laval, Quebec City, QC, Canada

xix
xx Contributors

Gisela Chelimsky, MD Pediatric Gastroenterology Division, Pediatrics

Department, Medical College of Wisconsin, Milwaukee, WI, USA
Thomas C. Chelimsky, MD Neurology Department, Medical College of
Wisconsin, Milwaukee, WI, USA
Eric Chiou, MD Center for Motility and Functional Gastrointestinal
Disorders, Children’s Hospital Boston, Boston, MA, USA
Denesh K. Chitkara, MD Pediatric Gastroenterology and Nutrition,
Goryeb Children’s Hospital, Atlantic Health, Morristown, NJ, USA
Ashish Chogle, MD, MPH Pediatric Gastroenterology, Hepatology and
Nutrition Division, Pediatrics Department, Children’s Memorial Hospital,
Northwestern University, Chicago, IL, USA
Joseph M.B. Croffie, MD, MPH Division of Gastroenterology, Pediatrics
Department, James Whitcomb Riley Hospital for Children, Indianapolis,
IN, USA
Thierry Devreker, MD Pediatric Gastroenterology Department, Universitair
Kinderziekenhuis Brussel, Brussels, Belgium
Carlo Di Lorenzo, MD Division of Pediatric Gastroenterology, Nationwide
Children’s Hospital, The Ohio State University, Columbus, OH, USA
Christophe Faure, MD Division of Pediatric Gastroenterology, Department
of Pediatrics, Sainte-Justine University Health Center, Université de Montréal,
Montréal, QC, Canada
David R. Fleisher, MD Pediatric Gastroenterolgy Division, Department of
Child Health, University of Missouri School of Medicine, Columbia, MO, USA
Alejandro Flores, MD Pediatric Gastroenterology, Tufts Medical Center,
Boston, MA, USA
Sylvie Fortin, PhD Anthropology Department, Université de Montréal,
Montréal, QC, Canada
John E. Fortunato, MD Department of Pediatrics, Gastroenterology Division,
Wake Forest University, Winston-Salem, NC, USA
Cheryl E. Gariepy, MD Center for Molecular and Human Genetics, The
Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
Pediatric Gastroenterology, Hepatology and Nutrition Division, Pediatrics
Department, The Ohio State University College of Medicine, Columbus,
OH, USA
Jose M. Garza, MD, MS Gastroenterology, Heptaology and Nutrition
Division, Pediatrics Department, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
Annie Gauthier, PhD Research Center, Sainte-Justine University Health
Center, Montreal, QC, Canada
Contributors xxi

Valentina Giorgio Division of Neurogastroenterology & Motility, Department

of Paediatric Gastroenterology, Great Ormond Street Hospital for Children,
London, UK
Jonathan M. Gisser, MD MSc Center for Molecular and Human Genetics,
The Research Institute at Nationwide Children’s Hospital, Columbus,
OH, USA
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatrics
Department, The Ohio State University College of Medicine, Columbus,
OH, USA
Liliana Gomez, MSc Research Center, Sainte-Justine University Hospital,
Montreal, QC, Canada
Roberto Gomez, MD Pediatric Gastroenterology Department, Wake Forest
University, Winston-Salem, NC, USA
Olivier Goulet, MD, PhD Pediatrics Department, Hôpital Necker-Enfants
Malades at the University of Paris 5 René Descartes, Paris, France
Pediatric Gastroenterology-Hepatology and Nutrition and Reference Center
for Rare Digestive Diseases, Intestinal Failure Rehabilitation Center, Paris,
France
Ernesto Guiraldes, MD Pontificia Universidad Católica de Chile and
Universidad Mayor, Santiago, Chile
Aileen F. Har, MB, BCh Division of Gastroenterology, Pediatrics
Department, James Whitcomb Riley Hospital for Children, Indianapolis, IN,
USA
Bruno Hauser, MD Paediatric Gastroenterology Hepatology and Nutrition
Division, Paediatrics Department, Universitair Kinderziekenhuis Brussel,
Brussels, Belgium
Tiffany A. Heanue, PhD Division of Molecular Neurobiology, National
Institute for Medical Research, Mill Hill, London, UK
Robert O. Heuckeroth, MD, PhD Pediatric Gastroenterology Division,
Pediatrics Department, Washington University School of Medicine in St.
Louis, St. Louis, MO, USA
Developmental Biology, St. Louis Children’s Hospital, St. Louis, MO, USA
Ryo Hotta, MD, PhD Department of Anatomy and Neuroscience, The
University of Melbourne, Melbourne, AustraliaDepartment of Pediatric
Surgery, Keio University School of Medicine, Tokyo, Japan
Jeffrey S. Hyams, MD Digestive Diseases, Connecticut Childrens Medical
Center, University of Connecticut School of Medicine, Hartford, CT, USA
Paul E. Hyman, MD Gastroenterology Division, Children’s Hospital, Louisiana
State University, New Orleans, LA, USA
Sabine Irtan, MD Pediatric Surgery, Hôpital Necker-Enfants Malades,
University of Paris, Paris, France
xxii Contributors

Sudarshan R. Jadcherla, MD, FRCPI, DCH, AGAF Department of

Pediatrics, Division of Neonatology, Pediatric Gastroenterology and Nutrition,
The Ohio State University College of Medicine and Public Health
Section of Neonatology, Nationwide Children’s Hospital, Columbus, OH, USA
Ajay Kaul, MD Division of Gastroenterology, Pediatrics Department,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Oren Koslowe, MD Gastroenterology and Nutrition, Pediatrics
Department, Goryeb Children’s Hospital/Atlantic Health System,
Morristown, NJ, USA
Minou Le-Carlson, MD Pediatric Gastroenterology, Hepatology and
Nutrition, Pediatrics Department, Stanford University Medical Center, Lucile
Packard Children’s Hospital, Palo Alto, CA, USA
Alycia Leiby, MD Pediatric Gastroenterology and Nutrition, Goryeb
Children’s Hospital, Atlantic Health, Morristown, NJ, USA
B.U.K. Li, MD Division of Gastroenterology, Hepatology and Nutrition,
Pediatrics Department, Medical College of Wisconsin, Milwaukee, WI, USA
Keith J. Lindley, MD, PhD Division of Neurogastroenterology & Motility,
Department of Paediatric Gastroenterology, Great Ormond Street Hospital
for Children, London, UK
Vera Loening-Baucke, MD General Pediatric Division, Pediatrics
Department, University of Iowa, Iowa City, IA, USA
Medizinische Klinik und Poliklinik, Gastroenterologie, Hepatologie and
Endokrinologie, Charité Universitätsmedizin, Berlin, Germany
H. Nicole Lopez, MD Pediatrics Department, Wake Forest University
School of Medicine, Winston-Salem, NC, USA
Massimo Martinelli, MD Pediatric Gastroenterology Division, Pediatrics
Department, University of Naples “Federico II”, Naples, Italy
Sonia Michail, MD The Children’s Medical Center, Gastroenterology, One
Children’s Plaza, Dayton, OH, USA
Hayat Mousa, MD Pediatric Gastroenterology Hepatology and Nutrition,
Department of Pediatrics, Nationwide Children Hospital, Ohio State
University, Columbus, OH, USA
Dipa Natarajan, MSc, MPhil, PhD Neural Development Unit, UCL,
Institute of Child Health, London, UK
Mun-Wah Ng, MD Pediatrics Department, Pediatrics Department,
Gastroenterology & Nutrition Division, Children’s, Hospital Los Angeles,
Los Angeles, CA, USA
Samuel Nurko, MD, MPH Center for Motility and Functional Gastrointestinal
Disorders, Children’s Hospital, Boston, MA, USA
Contributors xxiii

Taher Omari, PhD Gastroenterology Unit, Child, Youth and Women’s

Health Service, School of Paediatrics and Reproductive Health University of
Adelaide, Adelaide, SA, Australia
Andrée Rasquin, MD Gastroenterology Division, Pediatrics Department,
Hospital Ste Justine, University of Montreal, Montreal, QC, Canada
Brian P. Regan DO Pediatric Gastroenterology, Tufts Medical Center,
Boston, MA, USA
Leonel Rodriguez, MD, MS Department of Medicine, Gastroenterology
Division, Children’s Hospital Boston, Harvard Medical School, Boston,
MA, USA
José Luis Roessler, MD Pediatric Gastroenterology Division, Pediatrics
Department, Hospital Félix Bulnes, Santiago de, Chile
Nathalie Rommel, MSc, PhD Department Neurosciences, Faculty of Medicine,
Experimental Otorhinolaryngology, University of Leuven, Leuven, Belgium
Rachel Rosen, MD, MPH Harvard Medical School, Center for Motility
and Functional Gastrointestinal Disorders Children’s Hospital Boston,
Boston, MA, USA
Marina Russo, MD Department of Pediatrics, University of Naples Federico
II, Naples, Italy
Silvia Salvatore, MD Pediatric Department, University of Insubria,
Ospedale “F. Del Ponte”, Varese, Italy
Miguel Saps, MD Pediatric Gastroenterology, Hepatology and Nutrition
Division, Pediatrics Department, Children’s Memorial Hospital, Northwestern
University, Chicago, IL, USA
Virpi Vanamo Smith, PhD, MRCPath Paediatric Surgery Unit, Institute of
Child Head, University College London, London, UK
Manu R. Sood, MD(UK), FRCPCH Pediatric Gastroenterology Division,
Medical College of Wisconsin, Children’s Hopsital of Wisconsin, Milwaukee,
WI, USA
Annamaria Staiano, MD Pediatric Gastoenterology Division, Pediatrics
Department, University of Naples “Federico II”, Naples, Italy
Bhanu Sunku, MD Mount Kisco Medical Group, Mount Kisco, NY, USA
Alexander Swidsinski, MD, PhD Gastroenterologie, Hepatologie and
Endokrinologie, Medizinische Klinik und Poliklinik, Charité Universitätsmedizin,
Berlin, Germany
Steven Teich, MD Pediatric Surgery, Nationwide Children’s Hospital, Columbus,
OH, USA Clinical Surgery, Pediatric Surgery, The Ohio State University,
Columbus, OH, USA
xxiv Contributors

Nikhil Thapar, BSc(Hon), BM(Hon), MRCP, MRCPCH, PhD

Gastroenterology Unit, University College London, Institute of Child Health,
Division of Neurogastroenterology and Motility, London, UK
Department of Paediatric Gastroenterology, Great Ormond Street Hospital
for Children, London, UK
Rossella Turco, MD Department of Pediatrics, University of Naples
Federico II, Naples, Italy
Miranda A.L. van Tilburg, PhD UNC Center for Functional GI and
Motility Disorders, Chapel Hill, NC, USA
Department of Medicine, Division of Gastroenterology and Hepatology,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Yvan Vandenplas, MD, PhD Pediatrics, Universitair Ziekenhuis Brussel,
Vrye Universiteit Brussel, Brussels, Belgium
Arine M. Vlieger, MD, PhD Department of Pediatrics, St. Antonius
Hospital, Nieuwegein, The Netherlands
Heather M. Young, PhD Department of Anatomy & Neuroscience,
University of Melbourne, Parkville, VIC, Australia
Nader N. Youssef, MD, FAAP, FACG Adolescent Gastroenterology,
Digestive Health Care Center, Hillsborough, NJ, USA
Bella Zeisler, MD Division of Digestive Diseases, Hepatology, and
Nutrition, Connecticut Children’s Medical Center, Hartford, CT, USA
 Part I
Physiology and Development of the
Enteric Neuromuscular System and
Gastrointestinal Motility
 Introduction to Gut Motility
and Sensitivity 1
Nikhil Thapar, Christophe Faure,
and Carlo Di Lorenzo

The gastrointestinal tract represents one of the interactions among the components of the gut
most complex and diverse organ of the human neuromusculature. These components comprise
body, being capable of a vast array of activities the intrinsic nervous system of the gut (enteric
from digestion, absorption and excretion to nervous system—ENS), the smooth muscle
endocrine and immune functions. Most of these coats and interstitial cells of Cajal (Fig. 1.1).
functions are dependent on highly coordinated Each of them is extensive in terms of size and
sensory and effector mechanisms which moni- numbers and has an inherent complexity in
tor the GI lumen and wall and respond to specific structure, organization and function. Apart from
cues. In conjunction with a drive to maintain genetics, further key influences on these ele-
homeostasis within the body, the effector mech- ments come from the central and autonomic
anisms regulate blood flow, adjust the balance nervous systems, endocrine system, immune
between absorption and secretion, and coordi- system, intestinal microbiota, and connective
nate mixing and propulsion of luminal contents tissue. In children, this process is further com-
along the length of the bowel. This latter “motil- plicated by ongoing development and growth of
ity” activity is executed by region specific peri- the gut and its neuromusculature, changes in
staltic contractions and emptying mechanisms, environment and diet, and adaptation to postna-
which are dependent on highly coordinated tal life. It follows, therefore, that there are an
enormous range of potential etiopathogenic fac-
tors that could result in gut motility disorders.
Sensory functions of the GI tract are similarly
N. Thapar, B.Sc. (Hon), B.M. (Hon), M.R.C.P., important in the understanding of functional dis-
M.R.C.P.C.H., Ph.D. (*) orders. Normally, most of the information origi-
Division of Neurogastroenterology, and Motility, nating from the GI tract does not reach the level
Department of Gastroenterology, Great Ormond Street
Hospital, London WC1N 3JH, UK of conscious perception and is processed in the
e-mail: [email protected] brainstem. Other sensations such as hunger, full-
C. Faure, M.D. ness, satiety, bloating, and need to defecate that
Division of Pediatric Gastroenterology, Department of involve adapted behaviors reach the cortex.
Pediatrics, Sainte-Justine University Health Center, Extrinsic innervation of the GI tract is composed
Université de Montréal, 3175 Côte Sainte-Catherine, of vagal, spinal visceral (sympathetic) and sacral
Montréal, H3T1C5, QC, Canada
nerves. These nerves contain afferent (or sensory)
C. Di Lorenzo, M.D. fibers that transmit information from the viscera
Division of Pediatric Gastroenterology, Nationwide
Children’s Hospital, The Ohio State University, to the CNS and efferent fibers that transmit infor-
Columbus, OH, USA mation from the CNS to the gut. At the level of

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 3

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_1, © Springer Science+Business Media New York 2013
4 N. Thapar et al.

Fig. 1.1 The organization of the ENS of human and Innervation of gastroenteropancreatic endocrine cells and
medium–large mammals. The ENS has ganglionated gut-associated lymphoid tissue is also present, which is
plexuses, the myenteric plexus between the longitudinal not illustrated here. Abbreviations: ENS enteric nervous
and circular layers of the external musculature and the system, SMP submucosal plexus. From Furness JB. The
SMP that has outer and inner components. Nerve fiber enteric nervous system and neurogastroenterology. Nat
bundles connect the ganglia and also form plexuses Rev Gastroenterol Hepatol. 2012;9(5):286–94. Reprinted
that innervate the longitudinal muscle, circular muscle, with permission from Nature Publishing Group
muscularis mucosae, intrinsic arteries and the mucosa.

the gastrointestinal tract, sensory neurons and The Enteric Nervous System
entero-endocrine cells serve as transducers.
Central processing of visceral sensitivity is The enteric nervous system (ENS) represents the
complex and involves somatosensory cortex intrinsic nervous system of the GI tract and is
which provides information about intensity and present along its entire length. It is part of the
localization of the stimulus, the anterior cingulate peripheral nervous system and, although it
cortex which mainly processes pain characteris- receives inputs from both the CNS and autonomic
tics and cognitive aspects of the pain experience, nervous systems, it is capable of functioning
insula which integrates internal state of the organ- independently from them.
ism and the prefrontal cortex which is believed to The ENS is one of the largest and more com-
play a key role in the integration of sensory infor- plex components of the peripheral nervous sys-
mation and in the affective aspect of the sensa- tem. It contains as many neurons as the spinal
tion. Therefore, it appears that, similar to motor cord and the enteric glial cells share their proper-
disorders, visceral sensory disorders may result ties with those in the central nervous system
from multiple factors and are prone to be (CNS) [1]. Its complexity in terms of neuronal
influenced by complex interactions with cogni- diversity is similar to that of the CNS [1, 2]. The
tive and behavioral components. ENS is organized as plexuses of interconnected
1 Introduction to Gut Motility and Sensitivity 5

Fig. 1.2 Whole-mount preparation of rat myenteric (a) submucosal plexuses. The neuronal cells of the plexuses
and submucosal (b) plexuses (Immunofluorescent stain- comprise the enteric nervous system, and along with the
ing with an antibody to the neuronal marker PGP9.5). glial cells, smooth muscle cells and interstitial cells of
Neuronal cells are grouped together in ganglia that inter- Cajal are the intrinsic components of the enteric
connect both within and between the myenteric and neuromusculature

ganglia that enmesh the GI tract. In the small and cells migrate into the oral and anal ends of the
large intestine, these plexuses are present in two embryo and enter the foregut and hindgut [7],
distinct layers, the outer myenteric plexus that colonizing the entire gastrointestinal tract. ENS
sits between the inner circular and outer longitu- maturity results from an adequate number of cor-
dinal muscle layers, and the inner submucosal rectly differentiated neurons with sufficient axon
plexus present between the mucosa and the inner outgrowth and branching. Several lines of evi-
circular muscle layer (Fig. 1.2). Recent data has dence show that enteric neuronal development is
suggested the existence of a third mucosal plexus not completed at birth. Indeed, in the murine gut,
[3, 4] but little conclusive evidence exists thus far changes in morphology of the plexuses [8] and in
in humans. The ENS comprises neurons and glia the total number of neurons have been reported
organized into aggregates of cell bodies or gan- between in the first 4 weeks of life [9]. Submucosal
glia. These are interconnected by bundles of plexuses appear later than myenteric plexuses,
nerve fibers that run along the individual plexuses and the number of submucosal neurons also
as well as those that run between them. The real increases during the same time period [10]. New
complexity of the ENS is revealed at the ultra- post-mitotic neurons continue to appear until
structural level where an intricate circuitry is 3 weeks of postnatal life in the rat gut [11].
evident. A variety of neuronal subtypes partakes Although the pan neuronal marker PGP9.5 is
in this and can be classed in terms of functional present very early in the embryonic gut (E10.5 in
and structural characteristics. Subclasses include the mouse) [12, 13], neurochemical phenotypic
sensory and motor, excitatory and inhibitory. differentiation occurs later during embryonic
There are other neuronal subtypes and neu- development and even in postnatal life for cholin-
rotransmitters present within the ENS (Fig. 1.3) ergic and peptidergic neurons [14, 15]. ENS neu-
akin to and aligned with those present in the CNS rochemical maturation reaches an adult pattern
befitting the title conferred upon the ENS as the only at 1 month of postnatal life. In infants, data
“second brain.” on functional maturation of the ENS are lacking
The development of the ENS is similarly com- but it has been reported that the number of cell
plex. The neurons and glia of the ENS all arise bodies present within ganglia appears to change
from precursor cells derived from the vagal, according to the age of the individual between
sacral, and rostral trunk neural crest [5, 6]. These 1 day of age and 15 years [16].
6 N. Thapar et al.

Fig. 1.3 Multiple transmitters of neurons that control Hepatol. 2012;9(5):286–94. Reprinted with permission
digestive function. From Furness JB. The enteric nervous from Nature Publishing Group
system and Neurogastroenterology. Nat Rev Gastroenterol

sequential segments along its length giving the

Enteric Muscle Coats appearance of concentric rings. In the large intes-
tine, bands of smooth muscle and connective tis-
The smooth muscle of the gastrointestinal tract, sue (taenia coli) run on its outside along its length.
although present within the mucosa and the blood Their functional role is not completely clear.
vessels of the submucosa, is primarily organized The enteric smooth muscle is organized in
into three discrete muscle layers. The innermost, syncytia of cells that are electrically coupled to
muscularis mucosa, sitting between the mucosa elicit upon activation contractile activity of the
and submucosa is the least developed of these lay- muscle layers. The circular and longitudinal mus-
ers, being only a few cells in thickness. The other cles work in concert by contracting to result in
two, grouped within the muscularis propria, are segmentation and shortening to execute peristal-
much thicker and comprise the inner circular mus- sis and aboral propulsion of gastrointestinal lumi-
cle layer, with its cells arranged concentrically, nal contents. Contraction of smooth muscle cells
placed between the submucosa and the myenteric derives from two basic patterns of electrical activ-
plexus of the ENS, and the outer longitudinal mus- ity across the membranes of smooth muscle cells:
cle layer, with its cells running along the long axis slow waves and spike potentials. The membrane
of the gut, placed between the myenteric plexus potential of smooth muscle cells fluctuates spon-
and the outermost serosal layer. In the small intes- taneously. These fluctuations spread to adjacent
tine, the circular muscle appears well developed in cells, resulting in “slow waves” which are waves
1 Introduction to Gut Motility and Sensitivity 7

of partial depolarization. The frequency of slow cells, a cell type with which they share the same
waves varies according to the localization in the mesenchymal progenitor. Regeneration of ICCs
GI tract: in the stomach, they occur at a frequency also appears possible [18]. Further studies are
of 3 per minute, in the duodenum/jejunum 12–15 required to understand the role of ICCs in
per minute and in the ileum 8 per minute. Slow disease.
wave activity is an intrinsic property of smooth
muscle cells independent of intrinsic innervation.
“Spike potentials” which result from exposition Autonomic Nervous System
to excitatory transmitters occur at the crest of the
slow waves and provoke muscle contractions at a The autonomic nervous system is also part of the
maximal rhythm dependent upon slow wave peripheral nervous system and traditionally fur-
frequency. ther subdivided into the parasympathetic and sym-
pathetic nervous systems with craniosacral and
thoracolumbar outflows respectively. As previ-
Interstitial Cells of Cajal ously stated, much of the parasympathetic inner-
vation to the GI tract travels via the vagus nerve
In 1893, a Spanish physician and professor of and sacral nerves and the sympathetic along mes-
pathology provided the first description of a dis- enteric blood vessels from the prevertebral gan-
tinct group of cells that appeared to reside in the glia. These tracts carry both sensory and motor
“interstitium” between enteric nerves and smooth innervation. Akin to their other functions these
muscles. These cells, now termed Interstitial cells two subdivisions schematically function in oppo-
of Cajal (ICC), are now established as critical sition to each other with the parasympathetic pri-
components of the enteric neuromusculature reg- marily excitatory to gut function by promoting
ulating gastrointestinal motility, playing roles as secretion and peristalsis and mainly mediating
pacemakers and as mediators of enteric motor physiological (nature and composition of the
neurotransmission. They are present in a number intestinal content and motility and contractile ten-
of subtypes and morphologies throughout the sion of the smooth muscle) rather than harmful
layers of the GI tract, each of which may relate to sensations, and the sympathetic inhibitory by
distinct physiological functions. One of the key decreasing peristalsis and reducing perfusion of
ICC subtypes, ICC-MY, are present in highly the GI tract and transmitting information on poten-
branching networks within the myenteric plexus tially noxious stimuli. As a consequence, disor-
of the small intestine and appear to initiate slow ders of the autonomic nervous system are related
waves that are spread passively to the adjacent to disturbances in GI motility and sensing.
electrically coupled smooth muscle cells.
Depolarization of neighboring smooth muscle
cells leads to activation of the contractile References
apparatus.
There has been considerable recent interest in 1. Gershon MD, Chalazonitis A, Rothman TP. From
neural crest to bowel: development of the enteric ner-
the potential role of ICC disorders in the patho-
vous system. J Neurobiol. 1993;24:199–214.
genesis of human gut motility disorders (reviewed 2. Furness JB. Types of neurons in the enteric nervous
by Burns [17]) and loss and reduced ICC num- system. J Auton Nerv Syst. 2000;81:87–96.
bers have been implicated in Hirschsprung’s dis- 3. Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar
N. Enteric nervous system stem cells derived from
ease, slow transit constipation, chronic intestinal
human gut mucosa for the treatment of aganglionic
pseudo-obstruction, and esophageal achalasia. gut disorders. Gastroenterology. 2009;136:2214–25.
Some debate exists over whether there is true loss e2211–13.
of ICCs, de-differentiation or loss of the cell sur- 4. Willot S, Gauthier C, Patey N, Faure C. Nerve growth
factor content is increased in the rectal mucosa of chil-
face receptor that defines ICCs c-kit. ICCs appear
dren with non-constipated irritable bowel syndrome.
capable of transdifferentiation to smooth muscle Neurogastroenterol Motil. 2012;24(8):734–9.
8 N. Thapar et al.

5. Le Douarin NM, Teillet MA. The migration of neural 12. Mori N, Morii H. SCG10-related neuronal growth-
crest cells to the wall of the digestive tract in avian associated proteins in neural development, plasticity,
embryo. J Embryol Exp Morphol. 1973;30:31–48. degeneration, and aging. J Neurosci Res. 2002;70:
6. Newgreen D, Young HM. Enteric nervous system: 264–73.
development and developmental disturbances–part 1. 13. Young HM, Bergner AJ, Muller T. Acquisition of
Pediatr Dev Pathol. 2002;5:224–47. neuronal and glial markers by neural crest-derived
7. Chalazonitis A, Rothman TP, Chen J, Vinson EN, cells in the mouse intestine. J Comp Neurol. 2003;
MacLennan AJ, Gershon MD. Promotion of the 456:1–11.
development of enteric neurons and glia by neuropoi- 14. Vannucchi MG, Faussone-Pellegrini MS. Differentiation
etic cytokines: interactions with neurotrophin-3. Dev of cholinergic cells in the rat gut during pre- and post-
Biol. 1998;198:343–65. natal life. Neurosci Lett. 1996;206:105–8.
8. Schafer KH, Hansgen A, Mestres P. Morphological 15. Matini P, Mayer B, Faussone-Pellegrini MS.
changes of the myenteric plexus during early postna- Neurochemical differentiation of rat enteric neurons
tal development of the rat. Anat Rec. 1999;256:20–8. during pre- and postnatal life. Cell Tissue Res. 1997;
9. Faussone-Pellegrini MS, Matini P, Stach W. 288:11–23.
Differentiation of enteric plexuses and interstitial cells 16. Wester T, O’Briain DS, Puri P. Notable postnatal
of Cajal in the rat gut during pre- and postnatal life. alterations in the myenteric plexus of normal human
Acta Anat. 1996;155:113–25. bowel. Gut. 1999;44:666–74.
10. McKeown SJ, Chow CW, Young HM. Development 17. Burns AJ. Disorders of interstitial cells of Cajal.
of the submucous plexus in the large intestine of the J Pediatr Gastroenterol Nutr. 2007;45 Suppl 2:
mouse. Cell Tissue Res. 2001;303:301–5. S103–6.
11. Pham TD, Gershon MD, Rothman TP. Time of origin 18. Faussone-Pellegrini MS, Vannucchi MG, Ledder O,
of neurons in the murine enteric nervous system: Huang TY, Hanani M. Plasticity of interstitial cells of
sequence in relation to phenotype. J Comp Neurol. Cajal: a study of mouse colon. Cell Tissue Res.
1991;314:789–98. 2006;352(2):211–17.
 Development of the Enteric
Neuromuscular System 2
Tiffany A. Heanue and Alan J. Burns

transverse colon. The hindgut develops into the

Gut Embryogenesis distal part of the transverse colon, the descending
colon, rectum, and proximal part of the anal
The gut begins to from around the fourteenth day canal. The blood supply to the foregut, midgut,
after fertilization in the human as an endoderm- and hindgut comes from the coeliac artery, the
derived primitive tube that subsequently becomes superior mesenteric artery, and the inferior mes-
surrounded by splanchnic mesoderm. Of the three enteric artery respectively.
germ layers, the endoderm gives rise to the epi-
thelial lining and glands, such as the liver and
pancreas, of most of the gut, the ectoderm gives Smooth Muscle Development
rise to the oral cavity (proximal stomatodaeum)
and the anus (distal proctodaeum), and the meso- Stages of Smooth Muscle Development
derm-derived splanchnic mesenchyme gives rise
to the smooth muscle and connective tissue. As The smooth muscle of the gut derives from the
development proceeds and the gut lengthens, it splanchic layer of the lateral plate mesoderm,
differentiates into three regions; foregut, midgut which is recruited to the primitive gut tube by
and hindgut. The foregut subsequently develops signals derived from the endoderm and is induced
into the pharynx, esophagus, stomach, and the to proliferate and undergo gut-specific mesoderm
proximal portion of the duodenum down to the differentiation (reviewed in [1]). Sonic hedgehog
opening of the bile duct, as well as the liver, bil- (Shh) is a key signaling molecule in early endo-
iary system, and pancreas. The midgut gives rise derm–mesoderm interactions. Shh is part of the
to the remainder of the duodenum, the small Hedgehog (Hh) family of cell signals known to
intestine and portions of the large intestine includ- be involved in crucial developmental processes in
ing the cecum, appendix, and colon to the distal both invertebrate and vertebrate species. Shh is
expressed in the endoderm of the gut and the
receptor for Hh, Patched-1 (Ptc-1), is highly
expressed in the adjacent mesoderm (reviewed in
T.A. Heanue, Ph.D. [2]). Shh−/− mice have significant gut defects that
Division of Molecular Neurobiology, National Institute
include a reduction in smooth muscle [3]. Gli
for Medical Research, Mill Hill, London, UK
family members (Gli1, Gli2, Gli3), which are all
A.J. Burns, Ph.D. (*)
transcription factors mediating the Hh pathway,
Neural Development Unit, UCL Institute of Child
Health, 30 Guilford Street, London, WC1N 1EH, UK have also been shown to be involved in gut devel-
e-mail: [email protected] opment. Thus, Hh signaling is essential for GI

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 9

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_2, © Springer Science+Business Media New York 2013
10 T.A. Heanue and A.J. Burns

tract organogenesis and considerable evidence aggregation and elongation of muscle precur-
suggests that defects in this pathway are involved sors, the first indications of the developing con-
in a number of human gut malformations includ- tractile apparatus are evident as thin bundles of
ing intestinal transformation of the stomach, duo- actin filaments, which are initially unattached to
denal stenosis, reduced smooth muscle, abnormal the cell membrane [5]. Several days later, thick
innervation of the gut, and imperforate anus [3]. myosin filaments form, which are also unat-
Within the embryonic gut, smooth muscle pre- tached to the cell membrane. Soon after birth,
cursors are initially small and round in shape, but however, extensive insertion of the contractile
as differentiation proceeds, cells become elon- apparatus to the cell membrane is evident, with
gated, circumferentially arranged and parallel to abundant microtubules oriented parallel to the
one another and will form the circular muscle cell length [5].
layer [4]. Cells from the outer portion of the cir- Although smooth muscle can undergo sponta-
cular layer stretch radially outward, towards the neous contractions, coordination of these contrac-
presumptive longitudinal layer, then form bun- tions is regulated through intrinsic innervation by
dles and bend perpendicularly to form an L-shape, nerves of the ENS (see below). Because smooth
thus acquiring the correct orientation of the lon- muscle cells of the gut are uninuclear, in contrast
gitudinal muscle layer [4]. The last layer of to multinuclear skeletal muscle cells, neighboring
smooth muscle to form at the base of the mucosal smooth muscle cells communicate via gap junc-
villi, the muscularis mucosa, also forms during tions to enable passage of electrical impulses
embryogenesis [4]. This radial patterning of the between cells and to allow generation of the coor-
gut muscle occurs similarly along the length of dinated progressive wave contractions character-
the gastrointestinal tract, though exhibiting a ros- istic of the gut wall. These gap junctions are
tral to caudal gradient of maturation, and takes observed perinatally in intestinal smooth muscle
place well before birth [5–7]. In the human gut, [5] consistent with the neuronally mediated orga-
the longitudinal, circular, and muscluaris muco- nized peristaltic activity that commences just
sae layers of smooth muscle are evident by week before feeding begins at birth [9]. However, ENS-
14 of development [7] (Fig. 2.1). The massive and ICC-independent organized spontaneous con-
(1,000 fold) increase in amount of the smooth tractions can also be observed in mouse intestine
muscle of the gut from embryogenesis to adult several days before birth [9]. Because gap junc-
stages is accomplished by a combination of a tions are not observed at these earlier time points,
three- to fivefold increase in cell size and a the mechanisms enabling such organized smooth
200–300-fold increase in cell number through muscle contractions are currently unknown.
mitotic division of existing muscle cells [5].
Peristaltic function of the gut requires the
development of the contractile apparatus of the Smooth Muscle Development Defects
smooth muscle cells, which enables the cell to in Motility Disorders
tense and relax, thus generating the contractile
motion. The contractile apparatus is composed Hirschsprung disease (HSCR) is a common
of bundles of actin and myosin filaments developmental disorder characterized by the
(myofilaments), attached to the cell membrane absence of enteric neurons and glial cells in a
via actin-rich dense bodies (the functional equiv- variable portion of the distal gut [10–12]. In the
alent of Z lines in skeletal muscle). Upon receipt aganglionic region of affected gut, the smooth
of contractile stimulus and signal activation, the muscle is tonically or spastically contracted,
myosin (thick) filaments slide over the actin which leads to bowel obstruction. Why an absence
(thin) filaments to produce cellular contractions of ENS neurons would lead to such muscle con-
[8]. Myofilaments are oriented in parallel arrays traction is currently unclear. One hypothesis is
along the long axis of the smooth muscle cells, that this results from the absence of innervation
and cause shortening along this axis. Studies of by fibers from relaxant neurons [13, 14], while an
chick embryonic intestine demonstrate that upon alternative model is that over-proliferation of
2 Development of the Enteric Neuromuscular System 11

Fig. 2.1 Development of enteric nervous system, smooth mucosae (mm), adjacent to the villi (v). The walls of blood
muscle, and interstitial cells of cajal within the developing vessels within the submucosa are also immunopositive for
human gut. (a) At week 11 of development, a(alpha)SMA- a(alpha)SMA (asterisks). p75NTR staining is present within
staining (green) is apparent in the circular (cm) and longitu- ganglia of the myenteric plexus (arrows) and in nerve fibers
dinal (Lm) muscle layers, located on either side of the within the submucosa (double arrowheads). (d) At week 11,
p75NTR-positive (red) cells (arrows) of the presumptive Kit immunostaining is widespread within the developing
myenteric plexus. Occasional areas of p75NTR immunoreac- smooth muscle layers, particularly surrounding (arrows) the
tivity are also apparent in the region internal to the circular presumptive myenteric ganglia (asterisks). At week 12 (e)
muscle layer, corresponding to the presumptive submucosal and week 14 (f), Kit-positive ICC (arrows) is restricted to the
plexus (double arrowheads). (b) At week 12, the circular areas surrounding ganglia (asterisks). Scale bar = 50 mm
(cm) and longitudinal (Lm) muscle layers are strongly immu- (a, b); 100 m(mu)m (c). Reproduced with kind permission
nopositive for a(alpha)SMA. Between the muscle layers, from Springer Science + Business Media B.V. from original
p75NTR labeling is present in groups of cells comprising article by Wallace AS, Burns AJ. Development of the enteric
myenteric ganglia (arrows). (c) At week 14, a(alpha)SMA nervous system, smooth muscle and interstitial cells of Cajal
labeling is strong in the circular (cm) and longitudinal in the human gastrointestinal tract. Cell Tissue Res.
(arrowhead, Lm) muscle layers, and weak in the muscularis 2009;319:367–82 (modified from Figs. 7 and 8)

extrinsic, stimulatory nerve fibers leads to distinguish between these and other models and
increased contractility of affected segments [15]. to shed light on why smooth muscle remains con-
Further experimentation will be necessary to tracted in affected segments in HSCR.
12 T.A. Heanue and A.J. Burns

Interestingly, in certain mouse models of function to make synaptic connections to appropriate

HSCR, aganglionic segments exhibit an increased target tissues, such as the muscle, the mucosa, and
thickness of the circular and longitudinal muscle the blood vessels of the gut, and to create intercon-
layers [16] and these thicker muscle regions dis- nections to other ENS neurons and ganglia as well
play an increased contractile force [17, 18]. as to extrinsic neurons. Such a wide spectrum of
However, defects in muscle layers are not functional requirements is satisfied by vast numbers
observed in all models of aganglionosis [19, 20]. (millions of neurons in the small intestine [26]) of
Thus, muscle hypertrophy may not provide a different neuronal types [27]. Overall the ENS is
generally applicable explanation for tonic con- estimated to contain more neurons than found in the
traction of affected segments in HSCR or other spinal cord [28]. ENS glial cells are even more
motility disorders, although it may provide expla- numerous (fourfold) than neurons and function as
nation for disease features in some cases. support cells for ENS neurons and may also play a
Defects in smooth muscle characterize some role in modulating neuronal activity or in interac-
rare cases of chronic intestinal pseudo-obstruc- tions with other gut cell types such as endothelial
tion (CIPO), and these are classified as myopathic cells and intestinal epithelial cells [29].
CIPO, and like most cases of CIPO, are largely
idiopathic [21]. Mouse mutations affecting devel-
opment of gut smooth muscle have been identified, Migration of ENS Precursors
and include defects in the proliferation of smooth
muscle progenitors and radial patterning of the The ENS derives from neural crest cells (NCC)
gut [22]. Further studies in mouse or other model that delaminate from the neural tube and migrate
organisms are helping to uncover the basic cel- towards the developing gut tube. The primary
lular processes required for normal development contribution to the ENS comes from vagal NCC,
of smooth muscle, and therefore shed light on the which begin migration at E9.0–9.5 in the mouse,
genesis of human gut diseases. and by 4 weeks gestation in human, and enter the
foregut and move in a rostral to caudal direction
to colonize the entire gut tube by E14 in mouse
The Enteric Nervous System and by 7 weeks gestation in human [7, 30, 31]
(see Fig. 2.1). In addition, trunk neural crest from
The smooth muscle of the gut is innervated by the posterior vagal region makes a small contribu-
intrinsic neurons of the enteric nervous system tion to the foregut ENS [31], whereas the hindgut
(ENS). In addition, extrinsic nerves, comprising receives contribution from the sacral neural crest,
vagal and spinal afferent neurons that have their which begin their migration at a later stage and
cell bodies outside the gut and communicate to enter and colonize exclusively the hindgut [32–34].
the CNS, make axonal connections to ENS neu- The myenteric ganglia emerges first during devel-
rons and modify their activity [23–25]. Here we opment, whereas the submucosal plexus origi-
focus on the gut intrinsic ENS, which can func- nates later when cells from the myenteric plexus
tion independently of the CNS to maintain local migrate through the circular muscle towards the
reflex activity to control muscular mixing and submucosa [35] and are clearly seen in the sub-
peristaltic movements, changes in blood flow, mucosal region of the human intestine at 11
and secretion of water and electrolytes [23]. weeks of gestation [7] (see Fig. 2.1).
The ENS consists of interconnected ganglia, A variety of studies have examined the behav-
containing neurons and glial cells. Ganglia are orga- ior and pattern of migratory enteric neural crest-
nized in two plexus layers which span the length the derived cells (ENCCs) as they move into and along
gut, an outer myenteric plexus, situated between the the developing gut. Time-lapse movies of
longitudinal and circular muscle layers, and an inner fluorescently labeled ENCCs, which are rendered
submucosal plexus lying between the circular mus- fluorescent through dye-labeling of cells or use of
cle and the muscularis mucosae [23]. ENS neurons transgenic mice possessing fluorescent ENCCs,
2 Development of the Enteric Neuromuscular System 13

have enabled their migratory behaviors to be mon- period the gut is growing considerably in length,
itored. ENCCs are found to advance through the and continues to grow during further embryonic
gut steadily as multicellular strands, with a few and postnatal stages. In order to continue expan-
isolated cells preceding the migratory wavefront sion into caudal gut regions as well as to keep pace
[36–38]. The pattern of advance changes as with the expanding length of the already colonized
ENCCs reach the cecum, when the advancing gut regions, the relatively small number of ENCCs
strand pauses and cells separate and adopt a soli- must therefore increase greatly in number through-
tary meandering behavior [37]. After several out the gut. For that reason, it is not surprising that
hours, the cells leave the cecum and continue proliferation of ENCCs is observed and is essen-
movement through the hindgut as a network of tially equivalent at all rostral–caudal positions
interconnected cells to complete gut colonization [47]. Nevertheless, the size of the starting pool of
[36]. Interestingly, immature neurons that are ENS progenitors has a significant impact on the
being generated even as ENCCs are migrating capacity of ENCCs to completely colonize the gut.
through the gut (see below) also exhibit rostral to In a number of experimental conditions in which
caudal migration, albeit more slowly than their the initial pool of ENCCs is reduced, there is a fail-
ENCC precursors [39]. Approximately half of the ure of ENCC to colonize the distal gut [19, 33, 48],
immature neurons migrate by caudal movement of or to appropriately populate the entire gut with
cell bodies along long leading processes [39]. ENS neurons [49]. Moreover, mathematical mod-
Among the signals involved in directing migra- els which suggest that ENCC proliferation is a key
tion of NCC along the gut, perhaps the best under- driver of colonization have been substantiated by
stood are the components of the RET pathway [40]. experimental data [50].
Loss of RET signaling results in gut aganglionosis Regarding molecular mechanisms influencing
in mice [41] and the RET gene is the main gene ENCC proliferation, the RET ligand, GDNF, has
implicated in HSCR in humans [10, 42, 43]. Within been shown to to increase the proliferation rate
the gut, the RET receptor and the glycosylphos- and numbers of enteric neural precursors in vitro
phatidylinositol (GPI)-linked GDNF family recep- and in vivo [49, 51, 52]. An additional level of
tor a(alpha)1 (GFRa(alpha)1) co-receptor are control of GDNF/RET signaling is mediated by
expressed on NCC, and the ligand, glial cell line- factors such as those within the endothelin recep-
derived neurotrophic factor (GDNF), is expressed tor-B (EDNRB) pathway. Activation of EDNRB
within the gut mesenchyme (Fig. 2.2), and has been specifically enhances the effect of RET signaling
shown, in vitro, to be a chemoattractant for NCC on the proliferation of uncommitted ENS progeni-
[44]. Consistent with this in vitro finding, GDNF is tors [53] and the EDNRB ligand, endothelin-3
expressed in the stomach when the ENCC wave- (ET-3) which directly regulates ENCC prolifera-
front is in the esophagus, and is elevated in the tion and differentiation [54], modulates the action
cecum as ENCC migrate towards this distal part of of GDNF by inhibiting neuronal differentiation
the gut. Thus, it appears that NCC move towards [52]. Another mediator of GDNF/RET signaling is
centers of GDNF expression that are upregulated Prokineticin-1 (Prok-1) which has been shown to
progressively further along the gut. More extensive maintain proliferation and differentiation of
information concerning the molecular mechanisms ENCCs [55]. Another factor shown to be involved
involved in ENS development can be found in the in ENCC proliferation is retinoic acid (RA), which
following reviews [11, 45, 46]. enhances proliferation of subsets of ENS precur-
sors and increases neuronal differentiation [56].

Proliferation in the ENS

Differentiation in the ENS
The colonization of the entire gut takes place over
many days (E9.0–E14 in the mouse), and from The mature ENS contains a large variety of neu-
week 4 to 7 in human gestation [7], and during this ronal cell types and glial cells, with neuronal
14 T.A. Heanue and A.J. Burns

Fig. 2.2 Sources, migratory routes and gene expression in (EDNRB). (c) Upon entering the foregut at E9–9.5, enteric
neural crest cells contributing to the ENS. (a) At approxi- neural crest-derived cells (ENCCs) begin to express RET.
mately embryonic day (E) 8.5–9 in the mouse, vagal neural Within the gut mesenchyme, the RET ligand glial cell-line-
crest cells (red arrow) invade the anterior foregut and derived neurotrophic factor (GDNF) is expressed at high
migrate in a rostral to caudal direction to colonize the levels in the stomach (green) and the EDNRB ligand
entire foregut (FG), midgut (MG), cecum, and hindgut endothelin 3 (EDN3) is expressed in the midgut and
(HG) and give rise to the majority of the enteric nervous hindgut (pink). (d) As ENCCs migrate caudally at approx-
system (ENS, red dots). Colonization is complete by imately E11, they encounter high levels of GDNF and
E15.5. The most caudal vagal neural crest cells, emanating EDN3 expression in the cecum (yellow). Cells behind the
from a region overlapping with the most anterior trunk wavefront begin progressive differentiation towards neural
neural crest cells (blue arrow), make a small contribution and glial cell fates. Beginning at E11.5, GDNF and EDN3
to the ENS of the esophagus and the anterior stomach (blue are expressed in the distal hindgut (not shown). Reproduced
dots). Finally, sacral neural crest cells (yellow arrow) also from Heanue and Pachnis (2007) Enteric nervous system
make a small contribution, beginning their migration at development and Hirschsprung’s disease: advances in
approximately E13.5 and migrating in a caudal to rostral genetic and stem cell studies. Nat Rev Neurosci 8(6): 466–
direction to colonize the colon (yellow dots). (b) As vagal 79. Panel (a) modified, with permission from The Company
neural crest cells (red) emigrate from the neural tube, they of Biologists Ltd, from Durbec et al. (1996) Development
express SRY-box 10 (SOX10) and endothelin receptor B 122(1): 349–58

types distinguishable on the basis of their mor- as ENCCs are migrating through rostral gut
phologies, immunohistochemical profiles, and regions, some of these ENCCs are undergoing
electrophysiological properties [27, 57–59]. Even neuronal differentiation [38, 60, 61], thus beginning
2 Development of the Enteric Neuromuscular System 15

the process of generating the wide range of neu- Ganglia Formation and Connectivity
ronal cell types present in the mature ENS. in the ENS
Nevertheless, ENS progenitor cells persist
amongst the pool of ENCCs and differentiation Ganglia are the functional units of the ENS. To
of distinct neuronal types continues throughout perform their tasks, they must contain the appro-
embryonic and postnatal development [59, 62]. priate number of neuronal subtypes and innervate
Differentiation of glial cells begins in the late appropriate targets that is, the muscle layers, the
embryonic period, around E15, and continues mucosa, and the blood vessels [23]. Unfortunately,
during the postnatal period [59, 63]. Interestingly, the mechanisms controlling the formation of gan-
cells expressing early neural differentiation mark- glia, the generation of neuronal diversity, and the
ers can continue to proliferate [47, 60], thus pro- processes of establishing appropriate axonal con-
viding an additional mechanism to expand ENS nections are not well understood. Nevertheless,
cell number to populate the continuously grow- some insights concerning ganglia formation can
ing gut. be obtained from various gut motility disorders. In
In order to generate the distinct classes of ENS contrast to HSCR patients that have hindgut agan-
neurons and glial cells, there is a progression dur- glionosis and megacolon, gut dysmotility has also
ing ENCC development from bipotential ENS been reported in patients where enteric ganglia are
progenitor cells, capable of giving rise to both abnormally large in size and/or number of neurons
neurons and glial cells, to separate neural and “hyperganglionosis,” or reduced in size “hypogan-
glial progenitor cells (see Fig. 2.2), and the fur- glionosis.” Hyperganglionosis occurs either as
ther subdivision of neural progenitors into pre- ganglioneuromas associated with multiple endo-
cursors of the distinct neuronal types. While the crine neoplasia type 2B (MEN2B), a heritable dis-
advancement of cells through the stages of this order due to M918T missense mutation in the RET
progressive lineage restriction can be identified gene [69], or as intestinal neuronal dysplasia
using molecular markers [59] (Fig. 2.2), the fac- (IND), a controversial, inconsistently described
tors influencing the changes in cell state are entity, characterized by features that include
largely unknown. Indeed, in only a few instances increased density of submucosal ganglia, increased
have transcription factors, such as Mash1, which numbers of ganglion cells per submucosal gan-
generates some serotonergic neurons [30], or glion, and/or ectopic placement of ganglia [70].
Hand2, which is involved in the development of Mice with mutations in the homeobox gene Enx
vasoactive intestinal polypeptide (VIP) neurons (Hox11L1) have been suggested as a model for
[64] and in terminal differentiation [65], been IND since these animals have megacolon and
identified. In most cases, genes affecting devel- increased numbers of large intestinal myenteric
opment of the ENS affect all lineages due to ganglion cells [71]. In contrast to hypergangliono-
defects in the survival or proliferation of early sis, hypoganglionosis, another condition that is
progenitor cells (reviewed in [45]). The capacity difficult to diagnose by suction biopsy, has been
for ENS progenitor cells to be propagated in cul- associated with intestinal pseudo-obstruction
ture has the potential in future to complement (reviewed in [72]). Although the molecular mech-
gene deletion studies in elucidation of the factors anisms causing hypoganglionosis are unclear, the
controlling progressive ENS lineage restriction. smaller ganglia may result from failure of devel-
It has been postulated that defects in the opment of neuronal subclasses [73], or from gene
development of specific subtypes of enteric neu- dosage effects since Gdnf+/− and Ret+/− mice have
rons may underline certain motility disorders hypoganglionosis [74, 75].
[27]. Although some ENS neurons of the human Regarding establishment of neuronal projec-
myenteric plexus have been characterized [66–68], tions within the ENS, limited data reveal that
the cataloging of ENS subtypes may still be too early-generated neurons that transiently exhibit
preliminary to enable motility disorders to be tyrosine hydroxylase (TH) immunoreactivity
analyzed on this basis. have long leading processes that project caudally,
16 T.A. Heanue and A.J. Burns

and will eventually give rise to caudally project- To investigate the physiological role(s) of
ing neurons that innervate the circular muscle or ICC, their development was disrupted using
other myenteric neurons [76]. This observation either injection of anti-Kit antibody into mice to
led to the suggestion that the same factors that block ICC formation, or genetically, using W
guide migration of ENCCs in a rostral to caudal mutant mice that have loss-of-function mutations
direction, or the migrating ENCCs themselves, in the c-kit gene, or steel mutant mice that are
are influencing the direction of axonal outgrowth deficient in the SCF ligand for Kit. Morphological
of this neuronal population. In the zebrafish, a analysis of anti-kit injected mice, or W or steel
correlation has been made between the orienta- mutants, revealed a lack of ICC within the myen-
tion of smooth muscle cells and the direction of teric plexus of the small intestine, and physiolog-
axonal projections; as circular muscle cells begin ical studies demonstrated a lack of intestinal
to differentiate and elongate around the circum- pacemaker activity in the same gut region
ferential axis, ENS neurons begin to extend axons [ 81, 85–87]. Thus, these studies demonstrated
circumferentially around the gut [77]. Whether that ICC associated with the myenteric plexus are
such a putative organizer role for smooth muscle necessary for pacing electrical slow wave activity
cell exists similarly in other vertebrate species is and contractions within GI muscles.
currently unknown. Finally, although neurons are In addition to the pacemaker role for ICC, a
known to make axonal connections to target tis- role for ICC in the mediation of neurotransmis-
sues and express synaptic proteins even at embry- sion, as originally proposed by Cajal, has seemed
onic stages [78–80], it is unknown at what time likely since long, thin intramuscular ICC are
point neurons are making functionally active syn- closely apposed to varicose nerve terminals, and
aptic connections, as the relevant electrophysio- electrically coupled via gap junctions to neigh-
logical analysis has yet to be performed. boring smooth muscle cells [88]. Analysis of
stomach tissues from W mutant mice that are
deficient in intramuscular ICC, but have normal
Development of Interstitial Cells patterns of enteric nerve fibers and smooth mus-
of Cajal cle cells, demonstrated a lack of nitric oxide-
mediated neuroregulation of smooth muscle [88].
ICC—Different Forms, Different These, and more recent findings for other neu-
Functions rotransmitters confirm that intramuscular ICC
play a fundamental role in the reception and
Interstitial cells of Cajal (ICC) are small network- transduction of both inhibitory and excitatory
forming cells located within the gut muscle lay- enteric motor neurotransmission [89].
ers that were first described by the Spanish
neuroanatomist Ramon Santiago y Cajal in the
late 1800s. However, it has only been in the last Embryological Origin of ICC
two decades that great progress has been made in
our understanding of the morphology and physi- ICC are derived from the mesoderm. Lecoin et al.
ological roles of ICC. These advances have been [20], using quail-chick interspecies grafting to
primarily due to the discovery that ICC express genetically label the vagal neural crest cell-
c-kit, the proto-oncogene that encodes the recep- derived precursors of the ENS, demonstrated that
tor tyrosine kinase Kit, the ligand for which is in chimeric embryos, the ENS cells were of quail
stem cell factor (SCF), and that anti-Kit antibody (donor) origin whereas ICC were of chick (host)
specifically labels ICC [81]. Consequently, stud- origin and therefore belonged to the gut mesen-
ies using anti-Kit antibody in gut from humans chyme lineage and were not neural crest-derived.
and laboratory animals have revealed a range of These authors also cultured aneural chick gut on
different ICC morphologies in different gut the chick chorioallantoic membrane and found
regions ([82]; for reviews see [83, 84]). that ICC developed in the absence of enteric
2 Development of the Enteric Neuromuscular System 17

neurons, thus concluding that ICC are of meso- in disease states, a lack of Kit-labeling could
dermal origin and develop independently from either indicate an actual loss of ICC from the gut
the enteric neurons with which they subsequently tissues, or a loss of Kit expression from ICC
form anatomical and functional relations. The which are still present within the gut but that may
same year, Young et al. [90], also using gut have a different phenotype. Experimental findings
explants, but in this case from the mouse, demon- support the idea that ICC can change phenotype
strated that when aganglionic segments of large (or loose Kit expression) under certain conditions
intestine were explanted under the renal capsule or insult. For example, in studies where Kit recep-
of adult mice, ICC but not neurons developed in tors were blocked during development, ICC
these explants, again indicating that ICC do not almost entirely disappeared from the small intes-
arise from the neural crest. tine. However, closer examination revealed that
In the human gut, Kit-positive ICC have been ICC had not undergone apoptosis, but had devel-
identified as early as week 9 of development, oped ultrastructural features similar to smooth
after the colonization of the gut by NCC and fol- muscle cells. These findings highlight plasticity
lowing the differentiation of the circular muscle between ICC and smooth muscle cells that is
layer. Unlike these other cell types, ICC do not regulated by Kit signaling [96, 97]. In addition to
appear to mature in a rostrocaudal wave, as Kit transdifferentiation, ICC appear to have some
immunoreactivity is more defined in the hindgut capacity for regeneration. In experiments where
than in the midgut at week 9. ICC rapidly mature the mouse intestine was exposed to a chemical
and, by week 11, Kit immunoreactivity is insult which induced loss of the myenteric plexus
restricted to cells surrounding the myenteric gan- associated ICC, a few weeks later, cells with
glia [7] (see Fig. 2.1), in a pattern that is more ICC-like features began to reappear [98, 99].
organized in the midgut than in the hindgut. A further example of the difficulty in interpreting
Similar reports of ICC surrounding myenteric potential loss/reduction of ICC is in human
ganglia have been described in the human fetal HSCR. Some studies of HSCR tissues have
small bowel [91, 92]. ICC development in the reported a reduction in the cellular density of ICC
human therefore appears to lag behind that of the or “disrupted” ICC networks within the agangli-
ENS by at least 3 weeks and slightly behind that onic region [100, 101], whereas others have
of smooth muscle differentiation, as evidenced observed normal ICC networks in aganglionic
by aSMA immunoreactivity. A similar develop- gut [102, 103]. The latter findings, together with
mental lag for ICC has also been reported in the the data outlined above from chick and mouse
mouse embryo [93], as ICC form after the gut has gut showing the ICC develop in gut deprived of
been colonized by neural precursors and after the neural crest-derived ENS precursors [20, 90, 104],
development of aSMA immunopositive muscle. suggest that ICC can develop in the absence of
enteric neurons.

ICC in Human Gastrointestinal

Motility Disorders ENS/Smooth Muscle/ICC Developmental
Interactions
Loss of ICC, or disruption of ICC networks, has
been reported in a wide range of GI diseases, Here we have outlined some key developmental
including achalasia, CIPO, HSCR, inflammatory aspects of gastrointestinal smooth muscle, the
bowel diseases, slow transit constipation, and enteric nervous system, and ICC, which together
others (for reviews see [83, 94, 95]). However, in comprise the gut neuromusculature. The neurons
many cases it is difficult to determine whether and glia of the ENS are derived from the neural
defects in ICC networks are the cause of motility crest, whereas the smooth muscle and ICC origi-
disorders, or whether disrupted ICC networks are nate from mesoderm-derived mesenchyme. In
a consequence of gut dysfunction. For example, order to colonize the entire length of the gut, and
18 T.A. Heanue and A.J. Burns

become orientated into myenteric and submu- 10. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al.
cosal ganglia, NCC receive essential signaling Hirschsprung disease, associated syndromes and
genetics: a review. J Med Genet. 2008;45:1–14.
cues expressed by the developing smooth muscle. 11. Young HM, Newgreen D, Burns AJ. The
ICC, which are closely related to smooth muscle Development of the enteric nervous system in rela-
cells but critically differ in their requirement for tion to Hirschsprung’s disease. In: Ferretti P, Copp
Kit signaling, appear to be able to develop in the AJ, Tickle C, Moore G, editors. Embryos, genes and
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cumstances is still open to debate. Smooth mus- Hirschsprung’s disease. Semin Pediatr Surg.
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 Development of Gut Motility
3
Heather M. Young, Elizabeth A. Beckett,
Joel C. Bornstein, and Sudarshan R. Jadcherla

developing laboratory animals and humans.

Introduction We also discuss the mechanisms that regulate
intestinal movements during development.
Coordinated movements of the gastrointestinal
tract are crucial for the primary functions of this
organ: digestion of food, absorption of nutrients Motility Patterns and Their Control
and removal of waste products. Several complex Mechanisms in the Mature Gut
motor patterns involving coordinated contrac-
tions and relaxations of the external muscle lay- Coordinated movements of the gastrointestinal
ers of the gut have distinct roles in gut motility tract include mixing, propagating motor activities
(see section below). These motility patterns have and receptive relaxation. These movements are
been intensively studied and characterized in regulated by multiple control systems including
adults, but there is far less known about gut motil- extrinsic neurons, intrinsic neurons (the enteric
ity during development. Here we review the types nervous system, ENS), interstitial cells of Cajal
of motor patterns that are present in the gut of (ICC) and myogenic mechanisms, which can all
operate simultaneously [1, 2]. The relative contri-
bution of each control system to a particular activ-
ity varies between different regions of the
gastrointestinal tract [3]. Furthermore, as discussed
H.M. Young, Ph.D. (*) later in this article, recent studies in animal models
Department of Anatomy & Neuroscience, University
also show that the relative contribution of different
of Melbourne, 3010, Parkville, VIC, Australia
e-mail: [email protected] control systems to contractile activity in the intes-
tine also varies with developmental age [4]. Thus,
E.A. Beckett, Ph.D.
Discipline of Physiology, School of Medical Sciences, the control of gut motility is very complex [2].
University of Adelaide, Adelaide, SA, Australia The primary function of the esophagus is to
J.C. Bornstein, Ph.D. act as a conduit between the pharynx and the
Department of Physiology, University of Melbourne, stomach, and the only motor pattern is peristalsis.
Melbourne, VIC, Australia During the pharyngeal phase of swallowing, the
S.R. Jadcherla, M.D., F.R.C.P.I., D.C.H., A.G.A.F. upper esophageal sphincter (UES) relaxes, and
Department of Pediatrics, Division of Neonatology, there is then a sequential contraction of esopha-
Pediatric Gastroenterology and Nutrition, The Ohio
geal muscle from the proximal to the distal end,
State University College of Medicine and Public Health;
Section of Neonatology, Nationwide Children’s followed by lower esophageal sphincter (LES)
Hospital, Columbus, OH, USA relaxation, so as to allow the bolus to enter the

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 23

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_3, © Springer Science+Business Media New York 2013
24 H.M. Young et al.

Fig. 3.1 An example of spontaneous primary esophageal esophageal clearance. Note the brief respiratory modification
peristalsis in a premature infant evoked upon pharyngeal and deglutition apnea during pharyngeal waveform suggest-
contraction. Such sequences facilitate swallowing and ing cross-communications between the pharynx and airway

stomach. This integrated sequence of reflexes exhibits different motor patterns in the fed and
induced by swallowing constitutes primary peri- fasted states. In the fed state, the distal stomach
stalsis (Fig. 3.1). Peristalsis is also induced by grinds and mixes. Extrinsic neurons are not
esophageal distension, which is termed second- essential for this contractile activity, but it can be
ary peristalsis. In humans, the upper third of the modulated by vagal pathways. Migrating motor
esophagus, which is striated muscle, is controlled complexes (MMCs) are waves of strong contrac-
entirely by neurons in the brainstem via the vagus tions that sweep slowly along the gastrointestinal
nerves. The lower, smooth muscle regions of the tract in the fasted state to clear indigestible food,
esophagus are controlled by the vagus nerve, mucous and epithelial debris. In humans, MMCs
intrinsic neurons and myogenic mechanisms [3]. occur around once every 2–4 h, and most origi-
Different motor patterns occur in the proximal nate in the distal stomach and propagate along
and distal stomach [3]. In the proximal stomach, the small intestine [3]. The initiation of MMCs is
receptive relaxation and accommodation occur, modulated by vagal input and motilin released
which are both mediated by neurons in the brain- from the duodenum, while the propagation of
stem via vago-vagal reflexes. The distal stomach MMCs is coordinated by enteric neurons.
3 Development of Gut Motility 25

Multiple motor patterns occur in the small and fetal or postnatal mouse intestine in vitro.
large intestines. Segmentation, alternating sta- However, because larval zebrafish are transpar-
tionary waves of contraction and relaxation, ent, propagating contractile activity and transit
mixes intestinal contents with digestive enzymes studies using fluorescent food have been per-
and exposes nutrients to the absorptive epithe- formed in zebrafish in vivo [8–13]. In this section
lium (small intestine) or facilitates water extrac- we focus by necessity on the small and large
tion (colon). Peristalsis, contraction waves that intestines as there are relatively few studies on
migrate in an anal direction, moves intestinal the development of motility patterns and their
contents to new gut regions and is essential for control mechanisms in the esophagus and stom-
elimination of undigested material. MMCs, ach of laboratory animals.
which are initiated in the stomach or proximal
duodenum, propagate along significant lengths of
the intestine. In humans, MMCs occur only in the Motility Patterns Present
fasted state and only in the small intestine [3]. In in the Developing Gut
other species, however, MMCs can occur in both
the fed and fasted states and also occur in the Although fetal mammals receive nutrition solely
colon. Haustration, the mixing of feces to absorb via the placenta, contractile activity in the gut
water, occurs in sac-like structures called haus- commences well before birth. The esophagus of
trations of the large intestine of some species preterm piglets (delivered by caesarean section at
including humans. 91% of full gestation) exhibits esophageal con-
Studies in animal models have shown that the tractions in response to oral feeding, but compared
ENS is essential for segmentation in the small to term piglets, the frequency of contractions is
intestine [5]. Peristalsis in the small and large lower and the contractions propagate at a lower
intestines is controlled by an interplay between velocity [14]. In fetal mice, shallow contractions
the ENS, ICC, and myogenic mechanisms [2]. that propagate both orally and anally are first
However, the ENS is essential for intestinal peri- observed in preparations of small intestine in vitro
stalsis as revealed by the bowel obstruction at embryonic day (E) 13.5 (the gestation period for
caused by the aganglionic region of infants with a mouse is around 19 days) [4]. Moreover, propa-
Hirschsprung’s disease. The ENS is also essential gating contractions are observed in zebrafish lar-
for the initiation and propagation of the MMC in vae before the yolk sac is fully absorbed [8–11].
the small intestine, although the CNS and hor- The physiological role of prenatal (or pre-yolk sac
mones can modulate MMCs [3]. Studies in the absorption) gastrointestinal contractile activity is
rabbit colon have shown that haustral formation unclear. Fetal mammals swallow amniotic fluid,
and propagation is neurally mediated [6]. which advances along the gut [15–17], and this
Furthermore, water and electrolyte secretion is meconium progresses towards the distal regions of
regulated by the ENS, as is the integration bowel during late fetal stages [18]. Although it is
between motility and secretion [7]. highly likely that the propagating contractile activ-
ity that occurs prior to birth contributes to the pro-
pulsion of meconium anally prior to birth, this has
Development of Motility Patterns yet to be conclusively demonstrated.
and Their Control Mechanisms—
Studies of Laboratory Animals
Development of Enteric Neurons
Unlike humans, the mechanisms controlling and Their Role in Motility During
motility patterns during development can be Development
examined in intact segments of gut of laboratory
animals in vitro or in vivo. Most studies of mam- The ENS arises from neural crest-derived cells
mals have been performed using segments of that emigrate primarily from the caudal hindbrain
26 H.M. Young et al.

[19, 20], although sacral level neural crest cells increases during postnatal development [33].
also give rise to some enteric neurons, mainly in Changes in the proportions of some subtypes of
the colon and rectum [21, 22]. Neuronal differen- enteric neurons have also been reported between
tiation commences early as pan-neuronal mark- weaning and adulthood in rats and guinea-pig,
ers are first expressed by a subpopulation of suggesting that the ENS is not fully mature at
neural crest-derived cells as they are migrating weaning [36–38].
along the gut in fetal mice and rats [23, 24]. The development of the innervation of the
In the mature ENS, there are many different muscle layers has been examined in a number of
subtypes of enteric neurons [25]. In the develop- species. In the dog, the plexuses of nerve fibers in
ing mouse gut, cells expressing markers for some the small intestine and colon are immature at
enteric neuron subtypes are present shortly after birth [39]. In the guinea-pig ileum, the density of
the first expression of pan-neuronal proteins [26], cholinergic nerve fibers in myenteric ganglia and
but different enteric neuron subtypes develop at in the tertiary plexus is higher at neonatal stages
different ages [27]. Expression of neuronal nitric than in adults [32], whereas in the mouse colon
oxide synthase (nNOS—the synthetic enzyme the density of cholinergic nerve fibers in the cir-
for nitric oxide), and choline acetyltransferase cular muscle layer increases during early postna-
(ChAT, the synthetic enzyme for acetylcholine) tal stages [40]. These differences might reflect
by developing enteric neurons have been the most the fact that mice are born at a developmentally
extensively studied. nNOS neurons in the mature earlier age than guinea-pigs.
ENS include interneurons and inhibitory motor Although enteric neuron differentiation com-
neurons to the external muscle layers [28]. ChAT mences prior to the presence of propagating con-
neurons include excitatory interneurons and tractile activity, studies in mice and zebrafish
excitatory motor neurons to the external muscle using pharmacological inhibitors of neural activ-
layers [29]. In both zebrafish and mice, nNOS ity or mutants lacking enteric neurons have
neurons are one of the first enteric neuron sub- shown that the first motility patterns are not neu-
types to appear during development [10, 26, 30, rally mediated [4, 11]. There is therefore a
31]. In guinea-pigs, although the total number of significant delay between when enteric neurons
myenteric neurons in the small intestine increases first develop and when neurally mediated motil-
between neonatal and adult stages, the total num- ity patterns are observed. This very likely reflects
ber of nNOS neurons in the neonatal guinea-pig the fact that the neural circuitry mediating motil-
is the same as in adults and so the percentage of ity patterns involves at least three different types
myenteric neurons expressing nNOS declines of neurons [41], which must develop and then
during postnatal development [32]. In zebrafish, form the appropriate synaptic connections with
the proportion of enteric neurons expressing each other and with target cells. In mice, neurally
nNOS does not change between 72 and 120 hpf mediated motility patterns are not observed until
(hours post-fertilization) [31]. In the rat, however, shortly before birth in the duodenum [4], and a
the proportion of myenteric neurons expressing week after birth in the colon [40]. In longitudinal
NOS increases postnatally [33]. ChAT immuno- muscle strips from postnatal rats, electrical field
reactivity is not detected until late in embryonic stimulation-induced contractions are reduced by
development in the mouse [34] although uptake a muscarinic acetylcholine receptor antagonist
of 3[H]-choline is detected considerably earlier starting at postnatal day (P) 14, whereas inhibi-
[35]. Similarly, although ChAT immunoreactiv- tion of nNOS caused a significant increase in the
ity is detectable in the zebrafish brain during contractile response only from P36 [33]. Thus,
embryonic development and in the ENS of adult cholinergic neuromuscular transmission to the
zebrafish, ChAT immunoreactivity is not detect- longitudinal muscle in the rat colon does not
able in the ENS during zebrafish embryonic develop until postnatal stages and precedes the
development [31]. In rats, the percentage of development of nitric oxide-mediated transmis-
ChAT-immunoreactive myenteric neurons sion. In the mouse small intestine, cholinergic
3 Development of Gut Motility 27

neuromuscular transmission commences at late that region [53, 54]. Furthermore, ICC are distrib-
fetal stages [42]. In contrast, cholinergic neuro- uted normally and slow wave activity is generated
muscular transmission in the guinea-pig taenia in the bowel of mutant mice lacking enteric neu-
and in the frog gut commences after inhibitory or rons [55, 56]. Hence ICC development and main-
nitric oxide-mediated transmission [43, 44]. In tenance is independent of crest-derived cells in
the longitudinal muscle of human and guinea-pig mice. In an infant with intestinal aganglionosis
intestine, nitric oxide-mediated transmission is extending into the jejunum, abundant ICC were
relatively more prominent at postnatal stages than present in the myenteric region, but degenerating
in adults [32, 45]. ICC were observed in the circular muscle of the
In summary, although enteric neurons develop aganglionic region [57]. Thus, in humans, ICC
early, the first gastrointestinal motility patterns are also arise independently of neurons, although
not neurally mediated. However, neurally medi- some subpopulations of ICC may directly or indi-
ated contractile activity is prominent by birth, and rectly require neurons for their long term survival.
is essential for propulsive activity as shown by the Developmental studies in mice suggest that
bowel obstruction that occurs proximal to the smooth muscle cells and ICC arise from a com-
aganglionic region in infants with Hirschsprung’s mon mesenchymal precursor [58, 59] and that dif-
disease. The first subtype of enteric neuron to ferentiation to the ICC phenotype during
develop is the nNOS neurons, and although there embryogenesis is dependent upon cellular signal-
are some exceptions, nitric oxide-mediated trans- ing via the tyrosine kinase receptor, Kit [42, 59–61].
mission develops earlier and/or is more prominent The natural ligand for the Kit receptor is stem cell
during pre- and postnatal development than in factor (SCF or steel), which is expressed in both
adults. As the relative importance of different neu- enteric neurons and smooth muscle cells [55, 56, 62].
rotransmitters to gastrointestinal contractile activ- Mutations leading to deficiency of Kit in W/Wv
ity changes significantly during development, mice or membrane bound SCF in Sl/Sld mice result
drugs that successfully treat motility disorders in in disruptions of particular ICC populations and
adults will not necessarily have similar effects in aberrant gastrointestinal motility [47–49]. Both
infants and children. migrating motor complexes and higher frequency
phasic contractions can be recorded from the small
intestine of W/Wv mice, which lack intestinal
Development of Interstitial Cells ICC-MY [63], but the phasic contractions are
of Cajal (ICC) and Their Role characteristically abrupt and uncoordinated [64].
in Motility During Development Treatment of embryonic jejunal explants with Kit-
neutralizing antibodies prior to the emergence of
In the adult gut, there are several different sub- cells with the ultrastructural characteristics of ICC
populations of ICC, most of which are in close prevents the development of ICC and slow wave
association with enteric neurons [46]. Different activity [42]. The postnatal maintenance of ICC
subpopulations of ICC play different roles. For also appears dependent upon Kit-signaling as
example, ICC at the level of the myenteric plexus injection of Kit neutralizing antibodies resulted in
(ICC-MY) mediate slow waves, the electrical loss of ICC and lethal paralytic ileus in neonatal
events that time the occurrence of phasic contrac- mice [61]. Loss of ICC due to Kit blockade is
tions [47–50], and ICC within the circular muscle accompanied by a loss of electrical slow wave
act as intermediaries in neuromuscular transmis- activity in the small intestine and reduced neural
sion [51, 52]. responses in the small bowel and colon [65]. In the
Unlike enteric neurons and glia, ICC do not absence of Kit-signaling, ICC appear to differenti-
arise from the neural crest during embryological ate to a smooth muscle phenotype, but appear to
development as ICC develop in explants of avian retain, at least in the short term, the ability to
and mammalian embryonic gut which have been regenerate the ICC phenotype if Kit signaling is
removed prior to the arrival of neural crest cells in restored [60].
28 H.M. Young et al.

During embryogenesis there is a rostral- in mutant (W/Wv) mice lacking ICC-MY, providing
to-caudal development of ICC along the gastro- further evidence that these contractile patterns
intestinal tract. In embryonic mice, the circular are myogenic1 rather than ICC-mediated. Closer
muscle layer differentiates prior to the longitudi- to the time of birth, after anastomosing networks
nal muscle layer. Nearly all of the mesenchymal of ICC-MY have established, slow waves and
cells between the serosa and the newly formed phasic contractions occur at a similar frequency
circular muscle layer, consisting of precursors of suggesting that myogenic contractions become
both longitudinal muscle and ICC, initially entrained by ICC-MY [4]. Around 5 days after
express Kit [42, 65]. As embryonic development birth, a second layer of Kit-positive cells, termed
progresses a subpopulation of these mesenchy- ICC-DMP, are evident in the region of the deep
mal precursors lose expression of Kit and differ- muscular plexus of the rodent small intestine [59,
entiate into longitudinal smooth muscle [59]. The 65, 69, 70]. Development of neuromuscular
Kit-positive cells on the circular muscle side of responses to stimulation is concomitant with the
this newly formed longitudinal muscle layer development of ICC-DMP and blockade of ICC-
develop into the anastomosing network termed DMP development with Kit neutralizing antibod-
ICC-MY. ies has been shown to lead to a severe attenuation
Motility patterns of the stomach during devel- of postjunctional responses to nerve stimulation
opment have not been extensively researched [71] suggesting their role as mediators of neu-
using laboratory animals. In mouse, 2 days prior rotransmission in the intestine.
to birth, ICC-MY and slow wave activity are
present in the gastric antrum whilst spindle
shaped intramuscular ICC (ICC-IM) are evident Role of Myogenic Mechanisms in
and neurally mediated responses can be recorded Intestinal Motility During Development
from the gastric fundus [66].
Intramuscular ICC (ICC-IM) are closely asso- Studies in embryonic mice and zebrafish have
ciated with the varicose terminals of both excit- shown that the first intestinal motility patterns to
atory and inhibitory motor nerves and without appear during development, spontaneous con-
ICC-IM neural transmission from enteric motor tractions that propagate anally and orally, are not
neurons is significantly compromised [51, 52]. mediated by neurons or ICC [4, 11]. Hence the
Despite this close anatomical arrangement contractions must be myogenic, that is, generated
between nerves and ICC-IM, the outgrowth of by the smooth muscle cells themselves. Motility
motor nerve processes does not appear to be patterns that are not mediated by either neurons
dependent upon the presence of ICC as the distri- or ICC are present in the intestine of mature ani-
bution of both excitatory and inhibitory nerve mals, but under normal conditions are not very
processes is normal in W/Wv fundus muscles prominent [72, 73]. However, propagating con-
devoid of ICC-IM. In contrast, the terminal pro- tractions in other organs of mature animals,
cesses of vagal intramuscular arrays do not ram- including the upper urinary tract, vas deferens
ify within the circular muscle layer of the stomach and uterus are entirely myogenic in origin [74].
in the absence of ICC-IM [67, 68]. In the duodenum and colon of fetal mice, the
Electrical rhythmicity can be recorded from myogenic contractions require the entry of extra-
segments of mouse small intestine 3 days prior to cellular calcium [4], but it is unknown how they
birth [42, 60]. However, the first propagating are initiated or propagated.
contractions in mouse intestine are evident in the
mid stages of embryonic development (embry-
1
onic day 13), prior to the emergence of a Kit In the field of gastrointestinal motility, the term “myo-
genic” has been used to describe contractile activity gen-
positive ICC network and slow wave activity at
erated by ICC as well as muscle cells, but here we use
embryonic day 18 [4]. The frequency of these ini- the term myogenic to refer to contractions specifically
tial contractions is similar in wildtype mice and originating from the muscle cells themselves.
3 Development of Gut Motility 29

Environmental Influences on Motility and myenteric and submucosal plexuses have a

Patterns During Development mature appearance by week 14 [78, 79]. As in
laboratory mammals, many subtypes of enteric
The composition of gut contents changes dra- neurons develop prior to birth [27]. Kit-
matically immediately after birth and then at expressing ICC-MY first appear around weeks
weaning. There is evidence from piglets that 7–9 [78, 79]. In the stomach, ICC-MY, ICC-IM
the introduction of solid food at weaning (intramuscular), and ICC-SEP (ICC located
induces changes in some of the properties of within connective tissue septa separating mus-
MMCs [75], but it is unknown whether changes cle bundles) are all present by the end of the
in luminal contents immediately following fourth month of development [80].
birth also induce changes in motility patterns. The simple physiological functions of the
Dietary components have recently been shown neonatal foregut, midgut, and hindgut, respec-
to affect motility and gene expression in the tively, are to facilitate (1) safe feeding by steering
ENS of mature rats; in particular, long term ingested material away from the airway, (2) gas-
exposure to resistant starch diet enhanced trointestinal transit and mixing of luminal con-
colonic propulsive motility and increased the tents to permit absorption and propulsion, and
number of ChAT immunoreactive myenteric (3) evacuation of excreta to modify the intestinal
neurons [76]. Furthermore, piglets treated with milieu. In this section on human neonates, we
a probiotic showed increases in the expression review the developmental aspects of (1) phar-
of some neurotransmitters in submucosal, but yngo-esophageal motility, (2) gastric motility, (3)
not myenteric, neurons [77]. Additional stud- small intestinal motility, and (4) colonic motility.
ies are required to determine whether the
changes in motility patterns that occur during
postnatal development are induced by, or coin-
cident with, dietary changes. Developmental Pharyngo-Esophageal
Motility is likely to be altered during fetal hypoxic Motility in Human Neonates
stress as the transit of fluoescein-labeled luminal
contents along the small intestine in fetal rabbits is Swallowing Prior to Birth
decreased after a 1-h hypoxic episode [17]. Numerous studies have shown that the human
fetus swallows amniotic fl uid [15, 81 ] . By 11
weeks gestation, the ability to swallow has
Motility in Human Neonates developed and by 18–20 weeks sucking move-
and Children ments appear. There is an increase in the vol-
ume swallowed with gestational age, and by
In human infants, gastrointestinal motility is very near term, the human fetus swallows around
complex, and as in laboratory animals, is almost 500 ml of amniotic fl uid per day [81 ] . Studies
certainly influenced by maturational changes in using a sheep model have shown that, as in
the CNS and ENS, gut muscle and ICC, as well adults, swallowing in near-term fetuses
as diet and changing anatomical postures during involves central cholinergic mechanisms [82] .
infancy. Furthermore, in the vulnerable high risk
infant in intensive care units, hypoxia, Upper and Lower Esophageal Sphincter
inflammation, sepsis and other comorbidity con- Functions and Esophageal Peristalsis
ditions can complicate the feeding process and in Human Neonates
gastrointestinal transit. Using micromanometry methods, upper esopha-
Immunohistochemical studies of human geal sphincter (UES), esophageal body and lower
fetuses have shown that neurons, muscle and esophageal sphincter (LES) functions have been
ICC differentiate from proximal-to-distal and characterized in neonates [83–85]. The resting
that the longitudinal and circular muscle layers UES tone increases with maturation from around
30 H.M. Young et al.

18 mmHg in 33 week preterm infants, to 26 that vago-vagal protective reflex mechanisms

mmHg in full term born neonates compared to 53 that facilitate esophageal clearance are present in
mmHg in adults. In contrast, the motor events healthy premature neonates, but these mecha-
associated with LES relaxation in healthy pre- nisms mature with age.
term infants 33 weeks and older have similar Esophageal provocation can also result in an
characteristics to adults [86]. increase in UES pressure [87, 88]. This reflex is
In 33 weeks preterm infants, primary esopha- the esophago-UES-contractile reflex, and is
geal peristalsis occurs, but considerable matura- mediated by the vagus. The UES contractile
tion occurs pre- and postnatally [83, 85]. For reflex has been studied in premature infants, and
example, evaluation of consecutive spontaneous like secondary peristalsis, the occurrence of UES
solitary swallows in preterm infants at 33 weeks, contractile reflex is volume dependent, and the
preterm infants at 36 weeks, full term infants and reflex matures during prenatal stages. This reflex
adults showed significant age-dependent changes may provide protection to the airways by limiting
in the amplitude and velocity of the peristaltic the proximal extent of the refluxate during spon-
contractions [84]. taneous gastroesophageal reflux events.
During anterograde movement of a bolus fol-
lowing swallowing or during retrograde move-
ment of a bolus during gastroesophageal reflux Gastric Motility in Human Neonates
events, the bolus comes in close proximity to the
airway. Peristalsis is the single most important Scant information is available about receptive
function that ensures clearance of luminal con- relaxation in the fundus in human neonates.
tents away from the airway. During primary Ultrasound studies of the fetal stomach detected
esophageal peristalsis, there is a respiratory gastric emptying as early as 13 weeks of gesta-
pause called deglutition apnea that occurs during tion [91], and the length of gastric emptying
the pharyngeal phase of swallow (see Fig. 3.1). cycles in fetuses increases just prior to birth [92].
This brief inhibition in respiration is due to a The rate of gastric emptying is not influenced by
break in respiratory cycle (inspiratory or expira- nonnutritive sucking, but is influenced by calorific
tory) and is a normal reflex. On the other hand, value and stress: Calorically denser formula
during esophageal provocation events (for exam- accelerates gastric emptying and extreme stress,
ple, infusion via a manometry catheter, or gas- such as the presence of systemic illness, delays
troesophageal reflux) proximal esophageal gastric emptying [93].
contraction and distal esophageal relaxation
result in secondary peristalsis, which occurs
independent of central swallowing mechanisms Small Intestinal Motility in Human
(Fig. 3.2) [87–89]. These reflexes prevent the Neonates
ascending spread of the bolus and promote
descending propulsion to ensure esophageal In 28–37 weeks of gestation preterm infants, the
clearance. majority of the contractile activity in the small
Secondary esophageal and UES contractile intestine consists of clusters of low amplitude
reflexes have been compared in 33 weeks and 36 contractions that propagate for a short distance or
weeks mean post menstrual age premature infants not at all [94]. Propagating, cyclical MMCs with
[90]. The occurrence of secondary peristalsis was clearly defined phases develop between 37 weeks
volume dependent, and the characteristics and term [95].
matured with age. Furthermore, as the premature In adults, motilin, which is released from
infant grew older, the occurrence of secondary mucosal cells in the duodenum, is an important
peristalsis increased significantly with increment regulator of MMCs, and initiation of phase III of
in dose volumes of air or liquids. Thus, it appears the MMC (intense rhythmic contractions) in the
3 Development of Gut Motility 31

Fig. 3.2 Swallow independent secondary esophageal esophageal provocations and contribute to esophageal and
peristalsis in a premature infant in response to a mid- airway protection by facilitating clearance
esophageal infusion. Such sequences are evoked during

antrum is correlated with an increase in plasma Developmental Colonic Motility

concentrations of motilin [3]. In human neonates, in Human Neonates
the fasting plasma concentrations of motilin are
similar to those in adults, but there are no detect- There is a marked lack of data on colonic motility
able increases in motilin levels coincident with in neonatal humans owing to technical limita-
the initiation of MMCs [96]. The antibiotic, tions and ethical concerns.
erythromycin, is also a motilin receptor agonist
and accelerates gastric emptying in adults [97].
Erythromycin triggers initiation of the MMC in Mechanisms Controlling Motility
preterm infants whose gestational ages exceed 32 in Human Infants and Children
weeks [98]. Administration of erythromycin fails
to trigger MMCs in infants younger than 32 As in laboratory animals, enteric neurons and
weeks, suggesting immaturity of the neuronal ICC appear to be essential for normal motility in
circuitry mediating MMCs or that the motilin human infants and children. An essential role for
receptor cannot be activated by erythromycin at enteric neurons in gut motility after birth is best
these ages. demonstrated by Hirschsprung’s disease, where
32 H.M. Young et al.

the segment lacking enteric neurons is unable to 9. Holmberg A, Schwerte T, Pelster B, Holmgren S.
propel gut contents. Genetic alterations of Kit, Ontogeny of the gut motility control system in
zebrafish Danio rerio embryos and larvae. J Exp
and reduced ICC density, have recently been Biol. 2004;207(Pt 23):4085–94.
directly linked to a severe case of idiopathic con- 10. Holmberg A, Olsson C, Holmgren S. The effects of
stipation and megacolon in a 14 year old child endogenous and exogenous nitric oxide on gut motil-
[99], demonstrating the critical relationship ity in zebra fi sh Danio rerio embryos and larvae.
J Exp Biol. 2006;209(Pt 13):2472–9.
between Kit function, ICC development and 11. Holmberg A, Olsson C, Hennig GW. TTX-sensitive
functional gastrointestinal motility patterns in the and TTX-insensitive control of spontaneous gut
human intestine. Other studies have reported motility in the developing zebrafish (Danio rerio)
alterations in ICC networks in Hirschsprung’s larvae. J Exp Biol. 2007;210(Pt 6):1084–91.
12. Kuhlman J, Eisen JS. Genetic screen for muta-
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but these defects may be an indirect consequence, 118–27.
rather than the cause, of the gut dysfunction. 13. Field HA, Kelley KA, Martell L, Goldstein AM,
Serluca FC. Analysis of gastrointestinal phys-iology
However, it is important to remember that motil- using a novel intestinal transit assayin zebrafish.
ity disorders in children are not necessarily due to Neurogastroenterol Motil. 2009;21(3):304–12.
defects in neurons or ICC. For example, studies 14. Rasch S, Sangild PT, Gregersen H, Schmidt M,
in mice have shown that defects in the gut muscle Omari T, Lau C. The preterm piglet—a model in the
study of oesophageal development in preterm neo-
can also result in motility defects [107]. nates. Acta Paediatr. 2010;99(2):201–8.
15. McLain Jr CR. Amniography studies of the gastroin-
testinal motility of the human fetus. Am J Obstet
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 Visceral Sensitivity
4
Christophe Faure

The central nervous system (CNS) continuously

receives information from the gastrointestinal Neuroanatomy and Processing of
(GI) tract related to the state of the organs and to Gastrointestinal Tract Sensitivity
the content of the gut. The CNS must integrate
this information with inputs from other organs or Visceral Innervation (Fig. 4.1)
from the environment in order to initiate suitable
responses. Most of the information originating Similar to somatic sensitivity, gut afferent sig-
from the GI tract does not reach the level of con- nals reach conscious perception through a three-
scious perception and is processed in the brainstem, neuron chain. Extrinsic innervation of the GI
below cortical level. Other sensations such as tract is composed of vagal afferents, spinal vis-
hunger, fullness, satiety, gas, focal gut distension, ceral afferents, and sacral afferents [2]. These
and need to defecate (as well as their physiological nerves contain efferent fibers that transmit infor-
correlates, i.e., gastric and rectal distension) that mation from the CNS to the gut and afferent (or
involve adapted behaviors reach the cortex. sensory) fibers that transmit information from
Abnormally heightened visceral sensitivity the viscera to the CNS. Visceral afferent fibers
may lead to abdominal pain and functional GI are composed of sensory neurons that, arising
disorders (FGID). Indeed, visceral hypersensitiv- from the cell body, project two neurites, one as
ity is considered a central pathophysiological peripheral fiber and one as central fiber. Visceral
mechanism of FGID [1]. Gastrointestinal pain is afferents participate to visceral sensation and in
reported as dull, vague, and diffusely localized. local reflexes controlling GI functions. Somatic
Cutting, crushing (e.g., mucosal biopsy sam- and spinal visceral afferents converging on dor-
pling) of the GI tract are not perceived when sal horn neurons result in viscerosomatic projec-
applied to conscious subjects. Stimuli for visceral tion or referred pain.
pain include distension or traction on the mesen-
tery as well as ischemia and inflammation, events
that stimulate afferent nerve terminals. Vagal Innervation
Vagal innervation is provided by the vagus
nerve which innervates esophagus, stomach,
C. Faure, M.D. (*) small intestine, caecum, and proximal colon.
Division of Pediatric Gastroenterology, Sensory afferent neurons predominate numeri-
Department of Pediatrics, Sainte-Justine
cally in the vagus nerve. Cell bodies are located
University Health Center, Université de Montréal, 3175
Côte Sainte-Catherine, Montréal, H3T1C5, QC, Canada in nodose ganglia and the central processes termi-
e-mail: [email protected] nate in the nucleus of the solitary tract (NTS).

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 37

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_4, © Springer Science+Business Media New York 2013
38 C. Faure

Muscle

Mucosa
CM MP LM

Nodose
1
Ganglion
Vagal
3

2 NTS

Prevertebral
Ganglion 6
7

5
Spinal 10 8

4
9

Dorsal Root
Ganglion

Fig. 4.1 Spinal and vagal innervation of the gastrointesti- either to the CNS (6) or via sympathetic nerves (7) to pre-
nal tract. Upper portion: sensory information from vagal vertebral ganglia, to the ENS, and to the gastrointestinal
receptors is carried by vagal afferent nerves (1) with nerve muscle (spinal reflex). Collaterals of spinal afferents also
cell bodies in the nodose ganglion to the sensory nucleus of form short reflex loops with postganglionic sympathetic
the solitary tract (NTS). Second order neurons transmit the nerves in the prevertebral ganglion (8). In addition to spinal
information either to higher centers in the CNS (3) or via afferents, sensory structures with nerve cell bodies are also
efferent vagal fibers (2) in the form of vagovagal reflexes located within the intestinal wall (9,10). CM circular mus-
back to the ENS. Lower portion: sensory information from cle layer, MP myenteric plexus, LM longitudinal muscle
spinal receptors located in the mucosa, muscle or serosa is layer. From: Mayer EA, Raybould HE. Role of visceral
carried by spinal afferent fibers (4) with nerve cell bodies in afferent mechanisms in functional bowel disorders.
the dorsal root ganglion to second-order neurons in the spi- Gastroenterology 1990;99:1688–704, copyright Elsevier.
nal cord. Second-order neurons transmit the information Adapted with kind permission of Elsevier

Vagal afferents are believed to be mainly medi- provided by the greater splanchnic nerve which
ating physiological rather than harmful sensa- forms three main ganglia from which they dis-
tions, transmitting information on nature and tribute to the viscera: the celiac ganglion distrib-
composition of the intestinal content and utes nerves to the esophagus, stomach, and
motility and contractile tension of the smooth duodenum; the superior mesenteric ganglion dis-
muscle. tributes nerves to the intestines down to the
ascending colon and the inferior mesenteric gan-
Spinal Innervation glion to the colon from the hepatic flexure to the
Visceral afferents running in the spinal cord are rectum. Sensory afferent neurons account for
referred as “spinal afferents” when the term 10–20% of fibers in spinal afferents and cell bod-
“sympathetic innervation” is restricted to spinal ies are located in dorsal root ganglia (DRG) at the
efferent innervation [2]. Spinal innervation is cervical, thoracic, and upper lumbar spine [2].
4 Visceral Sensitivity 39

Their central processes terminate in the dorsal Spinal Terminals

horn of the spinal cord. Spinal afferents transmit Spinal terminals are less well characterized and
information on potentially noxious mechanical or are anatomically not clearly identifiable. Studies
chemical stimuli and are involved in sensation of have shown that mechanonociceptors mediating
visceral pain. However, it should be kept in mind transduction of pain evoked after high amplitude
that, in the CNS, vagal inputs likely integrate distension are spinal afferents [4]. Fine “varicose
with the inputs from the spinal pathways and branching axons” that appear as specialized end-
therefore perception of pain is the result of modu- ings can be demonstrated in the serosa and mes-
lation of vagal and spinal afferences [3]. Vagal enteries around blood vessels [6]. The mechanisms
and spinal afferents are predominantly unmyeli- of mechanotransduction are currently unknown.
nated C-fibers or thinly myelinated A-delta fibers
with low conduction velocity. Enteroendocrine Cells
Enteroendocrine cells are contained within the
Sacral Innervation intestinal mucosa throughout the GI tract distal to
The distal third of the colon is innervated by the the esophagogastric junction and provide an
pelvic nerve and the pudendal nerve. This part of interface between external milieu and terminal
the GI tract receives dual spinal innervation from endings of afferents. They resemble the sensory
splanchnic and pelvic afferents [3]. Pelvic spinal cells in the lingual epithelium taste buds. They
afferents innervate the pelvic organs through have an apical tuft of microvilli exposed to the
parasympathetic nerves. Cell bodies are located luminal content and release bioactive molecules
in the DRG. (serotonin—synthetized by enterochromaffin
(EC) cells—and hormones such as CCK, leptin,
orexin, ghrelin) that stimulate afferent terminal in
Sensory Terminals the lamina propria in response to appropriate
stimuli. Enteroendocrine cells are involved in
At the level of the gastrointestinal tract, sen- chemosensitivity and respond to nutrients play-
sory neurons and enteroendocrine cells serve ing a key role in the glucose homeostasis [7]. It
as transducers. Vagal mechanoreceptors are has also been recently shown that gut is able to
located in the mucosa or muscle layer and spi- “taste” odorants, spices and bitter taste via
nal receptors are located in the mucosa, mus- enteroendocrine cells [8]. EC cells contain sero-
cle, or serosa [4]. Gut sensory terminals and tonin which is known to be released in response
receptors include mechanoreceptors, chemore- to chemical stimuli [9] and plays a key role in the
ceptors, thermoreceptors, and nociceptors [5]. gut mechanosensitivity in response to mucosal
Recently, most evidence points toward poly- deformation. When acting on 5-HT3 receptors,
modality of the visceral receptors. serotonin release is involved in the peristaltic
reflex by activating intrinsic neurons (IPAN) and
Vagal Terminals in visceral sensations by activating mucosal end-
Vagal sensory endings terminate in the intestinal ings of sensory afferents.
wall in three different ways [4]. “Intramuscular
arrays” are located within the circular or longitu- Receptors on Visceral Afferents Involved
dinal muscle layers and appear to be stretch in Visceral Pain
receptors. “Intraganglionic endings” (IGLE) are A large number of bioactive substances and
situated at the surface of myenteric ganglia and chemical mediators have been implicated in the
are activated by tension of the gut wall. They are sensory signal transduction of visceral pain [10].
supposed to transmit signals that are perceived as These substances produce their effects by three
nonpainful sensation of fullness. Mucosal projec- distinct processes: (1) direct activation of a
tions extend into the lamina propria and corre- receptor, which generally involves the opening
spond to mucosal receptors [6]. of ion channels; (2) sensitization which results
40 C. Faure

Fig. 4.2 Some of the potential receptor mechanisms underly- tein-coupled receptors (PAR2 [19] and PAR4 [20]) leading to
ing activation (depolarization) and sensitization at the termi- a calcium-dependent modulation of ion channel activity.
nal of a gastrointestinal sensory afferent [11, 12]. Separate Sensitization, however, may be mediated by increased intrac-
mechanisms underlie activation and sensitization. Some ellular cAMP. Adenosine and PGE2 can generate cAMP
mediators such as serotonin (5-HT) cause activation via directly through G protein-coupled stimulation of adenylate
5-HT3 receptors, whereas others like PGE2 acting at EP2 cyclase (AC). In contrast, histamine (Hist) may act indirectly
receptors sensitize visceral afferent responses to other stimuli. through the generation of prostaglandins. The actions of
Still others, for example, adenosine (Adeno), cause both stim- cAMP downstream are currently unknown but may involve
ulation and sensitization, possibly through distinct receptor modulation of ion channels, interaction with other second
mechanisms. Bradykinin (BK) has a self-sensitizing action, messengers (e.g., calcium), or even changes in receptor
stimulating discharge through activation of phospholipase C expression. AA, arachidonic acid; ASIC, Acid-sensing ion
(PLC) and enhancing excitability via prostaglandins (PGs) channels; COX-1, COX-2, cyclooxygenase-1 and −2; DAG,
after activation of phospholipase A2 (PLA2). Inflammatory diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PARs, pro-
mediators can be released from different cell types (e.g., sym- tease activated receptors; TRPA1, Transient receptor potential
pathetic varicosities, mast cells, lymphocytes, and blood ves- cation channel A1; TRPV1 and TRPV4, transient receptor
sels) present in or around the afferent nerve terminal. 5-HT, potential cation channel subfamily V member 1 and 4. From
ATP, H + and capsaicin (Cap) can directly activate cation Kirkup AJ, Brunsden AM, Grundy D. Receptors and trans-
channels (NSCCs) such as TRPA1 [13], TRPV1 [13–15], mission in the brain-gut axis: potential for novel therapies.
P2X [16], TRPV4 [17, 18], and ASIC [14, 15]. Adenosine, I. Receptors on visceral afferents. Am J Physiol Gastrointest
histamine, prostaglandins (not PGE2), and proteases such as Liver Physiol 2001;280:G787-94. Modified with permission
mast cell tryptase (Tryp) and thrombin (Thro) act on G pro- from The American Physiological Society

in afferent hyperexcitability; and (3) through Central Pathways of Visceral Sensitivity

genetic change that alters the phenotype of the
afferent nerve (alterations in the expression or Vagal Central Pathway
activity of channels and receptors). Figure 4.2 Vagal afferents project in the brainstem to the NTS
depicts the complexity of receptors and bioac- which displays a viscerotopic organization [21].
tive substances involved in visceral sensitivity The NTS acts as a relay for the enormous amount of
in terminal afferents. data originating from the abdominal viscera and,
4 Visceral Sensitivity 41

in turn, it sends out a network to the motor nucleus and encodes sensory and emotional information
(nucleus ambiguus [NA] and dorsal motor nucleus related to pain. The prefrontal cortex is believed to
[DMN]) providing the circuits for basic reflex of the play a key role in the integration of sensory infor-
GI tract. The NTS also projects fibers to higher cen- mation and in the affective aspect of the sensation.
ters: (1) information is relayed to parabrachial nuclei Furthermore, this region is also involved in the
(PBN), which in turn are connected to higher brain generation of and the choice between autonomic
centers (amygdala system) and (2) long projections and behavioral response patterns, and has been
terminate in the thalamus, hypothalamus, and ante- shown to be a putative biological substrate of cog-
rior cingulate cortex (ACC) and insular cortical nitive influences (including placebo effect) on
regions regulating arousal, emotional, autonomic, emotions and the affective dimension of pain.
and behavioral responses [2, 3]. Quantitative meta-analysis techniques have
recently permitted to pool the results of 18 studies
Spinal Central Pathway conducted between 2000 and 2010 using PET or
After entering the spinal cord, first-order neurons fMRI in controls and IBS subjects undergoing
make synapse in the dorsal horn and second-order supraliminal rectal distension (painful or not). Data
neurones project to the brain through a number of from the healthy control subjects confirm that
different tracts: spinoreticular, spinomesenceph- regions activated in response to supraliminal rectal
alic, spinohypothalamic, and spinothalamic [22]. distension include zones associated with visceral
The spinothalamic tract is classically subdivided sensation (bilateral anterior insula, bilateral midcin-
into lateral spinothalamic tract that mediates the gulate cortex, and right thalamus), emotional
sensory-discriminative aspects of pain (localiza- arousal (right perigenual ACC), and regions associ-
tion, intensity), and medial spinothalamic tract ated with attention and modulation of arousal (left
mediating the motivational-affective aspects of inferior parietal, left lateral, and right medial pre-
pain (suffering, unpleasantness). The lateral spi- frontal cortex) [23].
nothalamic tract projects to the ventral posterior
lateral nucleus of the sensory thalamus, from which Descending Modulatory Pathways
information is relayed to the somatosensory cortex Pain afferent stimuli reaching brain structures
(S1 and S2), and the insula cortex. The medial spi- induce projections able to modulate ongoing
nothalamic tract projects to medial dorsal and ven- transmission of those inputs at the level of the
tral medial posterior nuclei of the thalamus and dorsal horn thus achieving a descending modula-
mainly projects, with spinoreticular, spinomesen- tory control. Descending modulation can be
cephalic, and spinohypothalamic tracts, onto brain- inhibitory, facilitatory, or both [2, 22].
stem and midbrain structures such as reticular At the cortical level, the ACC is the key region
formation, NTS, periaqueductal gray (PAG) and involved in this control through projections
PBN. From these structures, third-order neurons toward the amygdala and the PAG. Thus, cogni-
project to areas involved in emotional functioning, tive and affective factors may exert influence on
like the anterior cingulated cortex ACC and the pain transmission through the ACC. The
orbitomedial prefrontal cortex (PFC). amygdala and the PAG project in turn to the locus
coeruleus, the raphe nuclei, and the rostrolateral
Central Processing of Visceral Sensitivity ventral medulla, which then send projections to
The main function of somatosensory cortex (S1 the dorsal horn and modulate the synaptic trans-
and S2) is to provide information about intensity mission of sensory information at this level.
and localization of the stimulus (sensory-discrimi-
native). The ACC mainly processes pain affects
(unpleasantness, pain-related anxiety) and cogni- Visceral Hypersensitivity
tive aspects of the pain experience (attention,
anticipation). However, important interactions Definitions applied in visceral sensitivity have
between these two systems are certainly present. been borrowed from the somatic pain field.
The insula integrates internal state of the organism Hypersensitivity is defined as an increased sensation
42 C. Faure

of stimuli (appraised by measurement of threshold pathway anomalies…) in IBS patients. Functional

volumes or pressure for first sensation or pain). brain imaging techniques have permitted to dem-
Hyperalgesia is an increased pain sensation to a cer- onstrate, in adults, the importance of a role for
tain painful stimulus and allodynia a stimulus previ- CNS dysregulation of pain processing in IBS.
ously not perceived as being painful that becomes Recently, preliminary data on visceral afferents
painful. Visceral hypersensitivity is defined as an have been obtained in humans predicting
exaggerated perceptual response (hyperalgesia, allo- significant progress in this field [45, 46].
dynia, abnormal somatic referral) in response to
peripheral events. Theoretically, visceral hypersensi-
tivity could be the result of changes in visceral affer- Peripheral Mechanisms
ent signal processing (reflecting increased visceral
afferent input to the brain from the gut such as Inflammation
peripheral sensitization at the level of the gastroin- It is accepted that IBS onset may be triggered by
testinal tract) or a consequence of alterations in pain enteric bacterial infection that may have conse-
modulation mechanisms (i.e., central sensitization quences on local inflammation, EC cell and mast
or pain inhibition process at the level of the central cell counts [47, 48]. Low-grade inflammation has
nervous system), or due to a variable combinations been reported in the enteric ganglia [49] and the
of these pathways. mucosa [49, 50] of patients with IBS. The
In pediatrics, several independent groups have mucosal inflammation has been reported to cor-
reported that 75–100% of children affected by relate with fatigue and depression in adults with
IBS have a low rectal sensory threshold for pain IBS [51]. Proinflammatory cytokine (IL-1, IL-6,
(i.e., visceral hypersensitivity) as compared to and TNF-a(alpha)) production by peripheral
control children [24–28]. In adults, the preva- blood mononuclear cells is upregulated in patients
lence of visceral hypersensitivity varies from with IBS [52]. The major role of inflammation in
20% [29] to 94% [30] across studies suggesting IBS has been confirmed by microarray studies on
that visceral hypersensitivity is a more reliable colonic specimens that have emphasized the key
diagnostic marker in children than in adults. role of inflammatory cells in FGID [53].
Aberrant viscerosomatic projections have also
been reported in children with IBS and FAP who, Mast Cell Hyperplasia and Mucosal
in response to rectal distension, refer their sensa- Innervation
tion to aberrant sites compared to the controls, Abnormal mast cell numbers (increase [54–56] or
i.e., with abdominal projections on dermatomes decrease [57]) and close proximity to mucosal
T8 to L1 wherein controls referred their sensa- enteric neurites has been reported in stressed rats
tion to the S3 dermatome. In adults and in chil- [54, 55] and noted in the descending colon of
dren, visceral hypersensitivity has been shown to adult patients with IBS [56, 57]. Mast cell activa-
be “organ-specific” with a low rectal sensitivity tion might be a means whereby psychological
threshold in IBS patients [30–37], a low gastric factors perpetuate mucosal inflammation; in ani-
sensitivity threshold in FD [38–41] and “diffuse” mal studies, stress increases mast cell numbers
hypersensitivity in mixed IBS + FD patients [42]. and activation [54, 55]. In humans, cold stress
Data from studies on visceral hypersensitivity induces mast cell degranulation in the gut [58],
in FGID and specifically in IBS favor the pres- and in IBS, both fatigue and depression scores
ence of heterogeneous causes and mechanisms in correlate significantly with the mast cell counts
a population of patients. Animal models have of the lamina propria [51]. It has been shown that
permitted investigations to uncover cellular and the mucosa releases mediators that activate affer-
molecular abnormalities in the gastrointestinal ent nerves and might therefore mediate visceral
tract as well as in the CNS (spinal cord and brain) hypersensitivity [59]. Tryptase [19, 59] and nerve
[43, 44]. In humans, studies have similarly found growth factor (NGF) [60, 61], secreted by acti-
several changes in the rectal and colonic mucosa vated mast cells, have been reported as involved
(inflammation, mast cell infiltration, serotonin in visceral hypersensitivity.
4 Visceral Sensitivity 43

Serotonin (5HT) Pathway TRPV1 and TRPV4

Serotonin is secreted by enterochromaffin (EC) A role of TRPV1 in visceral hypersensitivity is
cells and plays a critical role in the regulation of supported by several studies in rodents showing
GI motility, secretion, and sensation through that TRPV1 mediates visceral nociception behav-
specific receptors [62–66]. The 5HT transporter ior [14, 15, 75]. In adult humans, a potential role
(SERT) terminates the actions of 5HT by remov- of TRPV1 is supported by a higher density of
ing it from the interstitial space [67–69]. Changes TRPV1 fibers in the colonic mucosa of patients
in EC cell numbers and 5HT content, release, and with IBS as compared to controls [76].
uptake have been demonstrated in an animal Interestingly, Sugiuar et al. [77] have shown that
model of post-infectious visceral hypersensitivity TRPV1 function is enhanced by 5HT in colonic
[70]. Coates et al. [71] reported also that mucosal sensory neurons and Gatti et al. [78] have reported
5HT, tryptophan hydroxylase-1 messenger RNA that PAR-2 activation exaggerates TRPV1-
(TpH1, the rate-limiting enzyme in the biosyn- induced cough. TRPV4 mediates somatic mecha-
thesis of 5HT) and SERT mRNA were all nosensation. Recent studies have also emphasized
significantly reduced in colonic mucosa of adult the role of TRPV4 expression and function in vis-
patients with IBS. Camilleri et al. [72] did not ceral nociception [17, 18, 79]. TRPV4 is expressed
confirm results on SERT mRNA. In children 5HT in visceral afferent neurons [18] and epithelial
content was found significantly higher in the rec- colonic cells [17]. Interestingly, TRPV4 is thought
tal mucosa of pediatric subjects with IBS as com- to be the mediator of PAR-2 induced colonic sen-
pared to controls and SERT mRNA was sitization [17, 79]. Whether TRPV4 expression at
significantly lower in patients than in controls the colonic level participates in the transmission
[73]. Park et al. [74] have shown a correlation of the nociceptive message is unknown. No human
between EC cells and rectal hypersensitivity in studies on TRPV4 are currently available.
adults suggesting that these cells play a role in
visceral sensitivity. Other Potential Mechanisms
Voltage gated sodium channels and cannabinoid
PAR2 and PAR4 receptors have been reported as involved in vis-
Protease-activated receptors (PAR) are G-protein- ceral sensitivity in animal studies but data in
coupled receptors that are activated after cleav- humans are lacking [86].
age by proteases of their N-terminal domain,
which releases a tethered ligand that binds and
activates the receptor. In the GI tract, PARs can Central Mechanisms
be activated by mast cell tryptase, pancreatic
trypsin, and exogenous proteinases [80]. PAR-1, When measured by using rectal distensions in
PAR-2, and PAR-4 are distributed throughout the humans, the perceptual response expressed by
GI tract. PAR-1 and PAR-2 are involved in modu- the subject and measured as the rectal sensory
lation of intestinal inflammation [81, 82] and threshold can be separated into two components
PAR-2 [83] and PAR-4 are key players in visceral according to the signal detection theory [87–89]:
pain and hypersensitivity. Activation of PAR-2 is the perceptual sensitivity (the physiological
pronociceptive [19, 84] and PAR-4 is conversely capacity of the neurosensory apparatus of the
an inhibitor of visceral hypersensitivity [20, 85]. rectum to detect intraluminal distension, i.e., the
It is conceivable that visceral hypersensitivity ability to detect intraluminal distension) and the
may result from disequilibrium between the pro- response bias (how the sensation is reported).
nociceptive effect of PAR-2 activation (or over- The perceptual sensitivity reflects the ability of
expression) incorrectly counterbalanced by the the organ to detect and transduce the stimulus to
antinociceptive effect of PAR-4 activation (or low the central nervous system. The response bias is
expression). the reporting behavior (intensity, painfulness)
44 C. Faure

which is a cognitive process influenced by past The association of visceral hypersensitivity

experience and psychological state. Though with somatic thermal hyperalgesia has been
perceptual sensitivity can be related to periph- reported by some authors at least in a subset of
eral mechanisms, response bias results from IBS adult patients [35, 94, 95] suggesting that
central modulation of the stimuli and processing abnormal pain processing may be present in these
of the sensation. patients. One pediatric study did not found such
somatic thermal or mechanical hyperalgesia but
Central Sensitization showed a decreased sensitivity at the thenar
Central sensitization is a phenomenon that has [96].
been described in chronic somatic pain [90, 91]: Increased response bias (i.e., a tendency to
that is a peripheral injury triggers a long-lasting report as painful visceral sensations) with a simi-
increase in the excitability of spinal cord neurons lar perceptual sensitivity than controls (i.e., same
inducing an increase in the afferent activity sec- ability as controls to discriminate rectal disten-
ondary to profound changes in the gain of the sions) which favors the hypothesis of a central
somatosensory system. This central facilitation abnormal processing of visceral sensations has
results in allodynia, hyperalgesia, and a receptive been reported by one group [97] but was not
field expansion that enables input from non- confirmed by others [98].
injured tissue to produce pain (secondary hyper-
algesia). In an animal model of stress-induced
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 Inflammation, Microflora, Motility,
and Visceral Sensitivity 5
Sonia Michail and Mun-Wah Ng

microbiota. For example, impaired intestinal tran-

Introduction sit caused by disarray of the migrating motor
complexes (MMC) can result in the development
This chapter addresses the relationship between of small bowel bacterial overgrowth [1]. Disordered
the gut microflora and the neurogastrointestinal MMC contractions are common in IBS where
system. It is divided into several sections that fur- decreased MMC contractions in the small bowel
ther dissect the contribution of the bacterial con- are seen in constipation-predominant IBS, and
tent of the gut towards the development of accelerated intestinal transit in diarrhea-predominant
motility disorders, with a main focus on the most IBS [2]. In addition, the autonomic nervous sys-
common functional and visceral hypersensitivity tem modulates gastrointestinal mucus secretion
disorder—irritable bowel syndrome (IBS). which forms the biofilm, home to the many of the
enteric microbiota [3]. It also influences immune
activation of the gut, directly, through modulation
The Effect of the Brain on Gut of the response of the gut immune cells to luminal
Environment bacteria, or indirectly, through modification of the
ability of luminal bacteria to reach the gut immu-
Communication between the brain and the gut (see nocytes. Interestingly, stress and stressful stimuli
Fig. 5.1) is modulated by the autonomic nervous can enhance the permeability of the intestinal
system, both sympathetic and parasympathetic. epithelium, which allows bacterial antigens to
This gut–brain axis controls gut functions ranging cross the intestinal epithelium triggering an
from gastrointestinal secretions to motility and immune response in the intestinal mucosa [4–9]
immune response. In turn, the vitality of the gut and causing a significant reduction in the tight
microbiome, at least in part, is determined by the junction proteins which leads to a compromise in
gastrointestinal transit and motility which, when the epithelial barrier function and the development
impaired, can affect the delivery of nutrients to the of leaky gut [10]. Therefore, the brain and its axis
can greatly influence the gut milieu.
S. Michail, M.D. (*)
The Children’s Medical Center, Gastroenterology,
One Children’s Plaza, Dayton, OH 45404, USA
e-mail: [email protected]
Mucosal-Gut Microbial Interaction
M.-W, Ng, M.D.
Stress can also play an important role in
Pediatrics Department, Gastroenterology & Nutrition
Division, Children’s Hospital Los Angeles, mucosal-microbiome interaction and host pro-
Los Angeles, CA, USA tection. For example, secretion of mucosal

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 49

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_5, © Springer Science+Business Media New York 2013
50 S. Michail and M.-W. Ng

defensins, which are antimicrobial peptides, can inhibit or slow down the intestinal transit [19].
play an important role in host defense mecha- Gut bacteria can also modulate gut transit
nisms against inflammatory and infectious dis- indirectly through the production of microbial
eases of the gastrointestinal tract [11]. The metabolites such as short-chain fatty acids or
secretion of such defensins by Paneth cells is peptides such as N-formylmethionyl–leucine–
enhanced by stress [12]. Stress can also impact phenylalanine [20–22]. Disturbance in the intri-
the secretion of neuroendocrine signaling mol- cate balance between different enteric microbial
ecules such as catecholamines, serotonin, and populations might, therefore, predispose the host
cytokines, which are secreted by neurons, to altered gut motility and secretion, which results
immune cells, and enterochromaffin cells, into in diarrhea or constipation. These changes are, in
the gut lumen in response to different stress turn, likely to influence the balance of enteric
stimuli [13–15]. Furthermore, norepinephrine microbiota. Therefore, the gut microbiome can
release in the intestine during stress and trauma directly influence gut homeostasis by the regula-
induces expression of virulence factors in tion of bowel motility and modulation of visceral
Pseudomonas aeruginosa which contributes to pain and immune responses [23–26] (Fig. 5.1).
gut-derived sepsis [16], stimulates the growth of
several other strains of enteric pathogens, and
intensify the virulence of Campylobacter jejuni Irritable Bowel Syndrome
[17]. These reports can help us appreciate the
association of stressful events with the develop- IBS is a common disorder afflicting millions of
ment of gastrointestinal disease such gastroen- adults and children around the world. From the
teritis and subsequent development of post pediatric perspective, it is estimated that IBS
infectious IBS [18]. affects up to 25% of school-age children and ado-
lescents, accounts for a significant number
(2–4%) of office visits to primary care doctors,
Bidirectional Signaling and represents about 25–50% of all patients who
visit a gastroenterologist’s clinic [27]. The past
The gut microbiome, much like the enteric several years have witnessed an emergence of
nervous system, can affect the intestinal motility. new concepts related to the pathophysiology of
For example, Lactobacillus acidophilus and IBS, which include alterations in gut motility,
Bifidobacterium bifidum are capable of promot- small-bowel bacterial overgrowth, microscopic
ing motility, while other members of the gut inflammation, visceral hypersensitivity, and
microbiome such as Escherichia species can changes related to the brain–gut microbial axis.

Brain
Autonomic nervous system
Hypothalamic-Pituitary-Adrenal Axis
Stress

Gl motility
Secretions
Gut permeability GUT
Mucosal immune system MICROBIOME
Fig. 5.1 Bidirectional
Neuroendocrine molecules
relationship of the brain–gut–
enteric microbiota axis
5 Inflammation, Microflora, Motility, and Visceral Sensitivity 51

Altered Gut Motility with IBS had abnormal breath testing. These
patients were then randomized to receive neo-
In IBS, disordered gut motility has been observed mycin or placebo for 1 week. A follow-up ques-
along the length of the gastrointestinal tract tionnaire revealed that patients in the neomycin
[28–31]. The major migrating complex (MMC), group reported a 35% reduction in symptomatol-
which consists of periodic, contractions that ogy as compared to 11.4% in the placebo group
sweep the luminal contents from the stomach to [38]. More recently, Peralta and colleagues
the colon, becomes disorganized. Several studies assessed 97 patients who met Rome II criteria
have shown that patients with IBS tend to have and found that 56% of these patients had positive
abnormalities in these contractions. For example, lactulose breath tests [39].
Vassallo et al. measured colonic electronic Although the exact mechanisms by which
barostat and perfusion manometry in 16 subjects altered fecal flora induce disease are poorly
and demonstrated a greater frequency of pro- understood, it has been shown that fecal short
longed, high amplitude and greater preprandial chain fatty acids produced by microbiota, which
colonic motility, which may explain the increased are critical for maintenance of the colonic epithe-
perception of pain in these patients. Other studies lium, are significantly reduced in children with
assessing colonic transit times in IBS, showed a diarrhea-predominant IBS [40]. Symptoms espe-
shorter colonic transit in patients with diarrhea- cially related to gas production are reduced by an
predominant IBS [32, 33] consistent with the pre- exclusion diet, suggesting an alteration in the
senting symptomatololgy. More importantly, the activity of hydrogen-consuming bacteria and fur-
dysmotility seen in these patients can predispose ther emphasizing the importance of fermentation
them to develop small-bowel bacterial over- in the pathogenesis of IBS [41]. Lactulose breath
growth, which is another proposed etiology for testing in IBS subjects does not seem to reflect
the development of IBS symptoms. malabsorption but the pattern of hydrogen excre-
tion is suggestive of bacterial overgrowth [42]
and suggests that IBS might be associated with
The Contribution of the Gut Microbiome rapid excretion of gaseous products of fermenta-
Towards IBS tion [43]. On the other hand, increased bacterial
methane production was seen with constipation-
Small-Bowel Bacterial Overgrowth predominant IBS [44]. Postprandial serotonin
Small-bowel bacterial overgrowth has emerged release was also blunted [45], suggesting a pos-
as a possible cause of IBS since Vantrappen and sible neurochemical basis for impaired motor
colleagues’ work which suggested that it may function. The discovery that specific changes in
occur in specific motility disorder such as a gut microbiota contribute to IBS pathophysiol-
reduction in the major migrating complex [1]. ogy could aid in the development of new thera-
Further studies have confirmed this finding in peutic strategies [46, 47].
this patient population [34–36]. A large study of
202 patients with IBS found that 78% of these The Gut Microbiome in IBS
patients had evidence of bacterial overgrowth The gut microbiome is the array of microorgan-
demonstrated by abnormal lactulose-methane- isms that dwell along the human gastrointestinal
hydrogen breath testing. In the study, 25 of 47 tract. The human microbiota is estimated to con-
patients experienced eradication of bacterial tain as many as 1014 bacterial cells-a number that
overgrowth on follow-up after treatment with is 10 times greater than the number of human
antibiotics. Analysis of this subset of patients cells present in our bodies [48–50]. The micro-
revealed that those who had successful eradica- biota colonizes every surface in contact with the
tion of bacterial overgrowth reported improve- external environment but the colon is the most
ment in their IBS symptoms [37]. Another study heavily colonized and is estimated to contain
by Pimentel showed that 84% of 111 patients over 70% of all the organisms in the human body.
52 S. Michail and M.-W. Ng

The human gut has a large surface area [51] and onstrate that the concentration of Streptomycetes,
is rich in nutrients, making it a preferred site for Rhodococci, and other members of the
bacterial colonization. The architecture of this Actinomycetales order become dozen folds higher
population is dynamic and evolves from birth to in quantity [55]. In another study by Malinen, a
adulthood. It is influenced by the diet, state of reduction of Lactobacilli, Clostridium coccoides,
health, external environment and other similar and Bifidobacterium catenulatem counts were
factors. The microbiome is closely associated seen in diarrhea-predominant IBS compared with
with many aspects of human health, from nutri- healthy individuals [56]. Si and colleagues noted a
tional status to immune and stress response. The reduction of fecal Bifidobacteria and an increase
intricate balance in the make-up of the gut micro- in Enterobacteriaceae, as well as lowered resis-
bial population, as well as the presence or absence tance to microbial colonization of the bowel in
of key microbial elements is crucial in ensuring patients with IBS [57]. Taken together, these stud-
health of the host. Although it is embraced as ies show encouraging associations between the gut
largely beneficial, it has been postulated that microbiome and IBS.
altered bacterial populations or products of bac-
terial metabolism may contribute to the develop-
ment of disease in the gastrointestinal tract as Intestinal Inflammation
well as remote areas of the body. The mecha-
nisms through which microbiota exerts its Considerable attention has been recently
beneficial or negative influences on the host directed towards the possibility of microscopic
include the production of signaling pathways and inflammation as a contributor to the develop-
recognition of bacterial proteins by intestinal epi- ment of IBS [58, 59]. Low-grade inflammation
thelial and mucosal host immune cells. found in biopsies of different parts of the intes-
Recent data propose a role for the gut micro- tine in subjects with IBS has fueled this con-
biota in the development of both central and cept [47, 58, 60, 61]. The release of certain
peripheral neural processes. These interactions, inflammatory mediators such as cytokines,
termed the “brain–gut–enteric microbiota axis” interleukins, and histamine, may affect nearby
[52], as discussed, can be bidirectional, with enteric nerves, causing alteration in gut func-
potential ramifications for disruption of this axis tion and sensory perception leading to IBS
leading to abnormal neurogenic stimulation of symptomatology [60, 62]. The study by
the enteric system and the development of disor- Chadwick et al. led the way to the new concept
ders such as IBS. The activation of any of the of IBS as an inflammatory condition. In their
central nervous system and the gut–brain axis has study of 77 IBS subjects, 55% were diarrhea
potential in influencing enteric microbiota both predominant; and none had a confirmed infec-
directly through interaction between the gut tious origin for IBS [58]. While 38 subjects
microbiome and the host, and indirectly via had normal histology, 31 demonstrated micro-
changes in their environment [3]. scopic inflammation and 8 fulfilled histologic
In animal studies, the impact of stress on the criteria for lymphocytic colitis. Interestingly,
composition of the enteric microbiota has become even in the group with normal histology, immu-
evident [53, 54]. Stress was characterized by nohistology demonstrated inflammation with
transient reductions in the levels of the enteric increased intraepithelial lymphocytes as well
microbiota in rhesus monkeys. In postnatal, as an increase in CD3+ and CD25+ cells in the
maternal separation-induced stress, reduction in lamina propria. Therefore, all subjects had
Lactobacilli was associated with the appearance mucosal immune activation.
of stress-indicative behaviors. Additional studies further support the role of
So is there a quantitative difference in the gut inflammation in IBS. Gonsalkorale and col-
bacteria in IBS? Several studies are beginning to leagues demonstrated that subjects with IBS have
address this question. Osipov and colleagues dem- a reduction in interleukin-10 (IL-10), which has
5 Inflammation, Microflora, Motility, and Visceral Sensitivity 53

an anti-inflammatory effect [63]. Barbara and A study by Verdu showed that administration of
colleagues’ work demonstrate an increase in Lactobacillus paracasei attenuates the antibiotic
colonic mast cell degranulation with direct cor- induced visceral hypersensitivity in mice [68].
relation between the proximity of mast cells in Perhaps the most interesting link between gut
the mucosa and clinical pain severity [62]. bacteria and visceral sensitivity is highlighted by
Furthermore, Tornblom and colleagues examined Rousseaux et al. [69] establishing that oral admin-
full-thickness jejunal biopsies in 10 subjects istration of L. acidophilus induced the expression
obtained during laparoscopy [64] and noted low- of mu-opioid and cannabinoid receptors in epi-
grade infiltration of lymphocytes in the myenteric thelial cells, and mediated analgesic functions in
plexus in all patients and many had evidence of the intestine in a manner similar to that induced
neuronal degeneration, longitudinal muscle by morphine.
hypertrophy and abnormalities in the number and
size of interstitial cells of Cajal. There is also evi-
dence to support an alteration in the ratio between Potential Therapeutic Applications
the cytokines IL-10 and IL-12 favoring a Th1
response similar to what is seen in peripheral The modification of the enteric microbiota to
blood mononuclear cells [65]. Spiller further pro- treat subjects with IBS and visceral hypersen-
posed that the inflammatory changes could repre- sitivity is attractive due to its ease, relative
sent an immune response to an initial enteric safety, and current lack of other effective thera-
infection in individuals who become susceptible peutic alternatives. Such modifications can be
by a relative deficiency of anti-inflammatory achieved by the administration of antibiotics,
cytokines [66]. probiotics, or prebiotics. Clinical studies have
Although embracing this theory broadens produced variable responses to such treatments
therapeutic options, yet efforts to treat the and vary depending on age, predominant symp-
inflammation in an attempt to improve symptoms toms, and bowel habits. Our current under-
have been largely unsuccessful. Subjects with standing of IBS pathophysiology remains
post-infectious IBS randomized to either predni- incomplete, and although the complexity of the
solone 30 mg daily versus placebo showed no network of interactions within the enteric
improvement in their symptoms even though T microbiota and visceral hypersensitivity is
lymphocytes decreased by 22% as compared to emerging, some studies have provided evidence
11.5% in the placebo group [67]. Therefore, the for a beneficiary role for enhancement or
clinical significance and application of this manipulation of the gut bacteria. The use of
important concept of IBS being an inflammatory nonabsorbable antimicrobial therapies such as
condition are yet to be defined. Rifaximin has shown some promise and probi-
otics and prebiotics are also emerging as poten-
tial therapies. A recent study by Pimentel [70]
Modulation of Visceral Hypersensitivity validated that rifaximin therapy for 2 weeks
provided significant relief of IBS symptoms,
Visceral hypersensitivity is becoming more rec- bloating, abdominal pain, and diarrhea. In
ognized as a potential contributor to the develop- another study, 54 patients with positive lactu-
ment of pain in IBS. Studies are now beginning lose breath tests were treated with a 7-day
to utilize the concept of the gut microbiome and course of rifaximin. Follow-up after 3 weeks
probiotics to modulate this visceral hypersensi- revealed that half of their subjects had a subse-
tivity. Animal studies using the probiotic quent negative lactulose breath test and a sta-
Lactobacillus farciminis demonstrate significant tistically significant improvement in symptoms.
attenuation of stress-induced proteins during col- These results were similar to those found in
orectal distension in rats and suggest a link to the another recent study by Majewski and associ-
epithelial cell cytoskeletal contraction [25, 26]. ates, in which a 4-week course of rifaximin led
54 S. Michail and M.-W. Ng

to improvement in IBS-related symptoms and a effective in reducing symptoms and decreasing

negative breath test in patients who previously hydrogen and methane production in IBS [38, 79],
had positive tests [71]. Although these results suggesting major role for intestinal bacteria as a
are encouraging, other researchers have failed contributor to symptoms of IBS.
to confirm these findings and further research
is needed in this area [72].
An important study by O’Mahony et al. [65] Conclusions
showed that Bifidobacterium infantis not only
resulted in symptom reduction in IBS, but also Strong evidence suggests that the gut micro-
correlated with normalization of proinflammatory biome plays an important role in functional gas-
cytokines, suggesting an immune modulating trointestinal disorders and interactions between
effect of probiotics. The study by Bazzocchi the gut and the nervous system influence intesti-
et al. [73] is the first observation showing a clin- nal motility and inflammation. Although several
ical improvement related to changes in the com- reports suggest a disruption in the balance of the
position of the fecal bacterial flora, fecal enteric microbiota in patients with IBS, consid-
biochemistry and colonic motility pattern, all of erably more data are needed to establish whether
which was induced by administration of probi- these changes are merely seen due to the dysmo-
otics, in patients with functional diarrhea. In tility or indeed there is a causative role for these
constipation-predominant IBS, Agrawal and findings. While most of the studies addressing
colleagues [74] show improvements in abdomi- the role of the enteric bacteria rely on traditional
nal girth and gastrointestinal transit, as well as culture techniques to identify the microbiome,
reduced symptomatology after 4 weeks of studies utilizing molecular technology in identi-
Bifidobacerterium lactis consumption. fying the microbiota would prove useful in fur-
Pediatric studies addressing the role of probi- ther investigating the role of these bacteria in
otics in IBS have recently emerged (Table 5.1). gastrointestinal symptomatology and disease.
A study published by Bausserman and Michail Results from a small number of well-designed,
[75] designed to determine whether oral admin- randomized, controlled, clinical trials suggest
istration of the probiotic Lactobacillus GG that, not only does regular intake of certain pro-
under randomized, placebo-controlled, double- biotic bacteria help to treat the symptoms of
blinded conditions would improve symptoms of IBS, but their effects go beyond symptoms and
IBS in children, showed a lower incidence of are associated with modulation of biological
perceived abdominal distension but did not alter parameters, such as intestinal transit, abdominal
any of the other parameters. Another double- girth and inflammatory markers that in turn
blinded, randomized controlled trial by influence the gut–brain axis.
Gawronska et al. [76] designed to determine the Further understanding of the gut microbiota
efficacy of a 4-week therapy with Lactobacillus will improve our knowledge of their role in
rhamnosus GG (LGG) in treating functional health and disease, and allow for improved
abdominal pain disorders (FAPD) in children future therapeutic and prophylactic modalities.
showed a higher incidence of treatment success Although significant strides have been made in
(i.e., no pain) in children with IBS receiving the our journey of deciphering the codes of the gut
probiotic. A more recent study by Guandalini microbiome, our ability to delve deep into this
and colleagues [77] suggests a beneficial role fascinating organ has been hampered by the
for VSL#3 (Sigma-Tau Pharmaceuticals, Inc.) complexities of its inhabitants. The introduc-
in children with IBS. Finally, reports of amelio- tion of non-culture-based molecular techniques
ration of symptoms of bloating and flatulence in that enable quantitative assessment of the entire
patients with IBS when treated with a poorly enteric microbiota coupled with encouraging
absorbed antibiotic, Rifaximin [77, 78], and the results from probiotic research continue to
poorly absorbed antibiotic Neomycin has been improve our understanding in this area.
 5

Table 5.1 Summary of published pediatric reports of probiotic role in irritable bowel syndrome
Author Year Type of probiotic Duration in weeks Population Type of trial Outcome of study
Bausserman and 2005 LGG (1010 CFU given 6 Age: 6–20 (n = 50) R, DB, PC Lower incidence of
Michail [75] BID) perceived abdominal
distention in LGG group,
but no difference in other
parameters
Gawronska [76] 2007 LGG (3 × 109 CFU given 4 Age : 6–16 (n = 104) R, DB, PC LGG group more likely to
BID) have no pain, reduced
frequency of pain, but not
Inflammation, Microflora, Motility, and Visceral Sensitivity

pain severity than controls

Guandalini [77] 2010 VSL#3 (4–11 y/o: 1 sachet 6 Age : 4–18 (n = 59) R, DB, PC Relief of symptoms,
daily; 12–18 y/o: 1 sachet lowered abdominal pain/
BID) discomfort, bloating/
gassiness, and life
disruption in VSL#3 group
R randomized, PC placebo controlled, DB double-blinded, LGG Lactobacillus GG, VSL#3 proprietary mixture of Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium
infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, and Streptococcus thermophilus (Sigma-Tau Pharmaceuticals,
Inc.)
55
56 S. Michail and M.-W. Ng

17. Cogan TA, et al. Norepinephrine increases the patho-

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 Integration of Biomedical
and Psychosocial Issues in Pediatric 6
Functional Gastrointestinal
and Motility Disorders

Miranda A.L. van Tilburg

seems anxious and Johnny is out of school regu-

Introduction larly around fear of symptoms.
This scenario is recognizable for many clini-
Treating gastrointestinal symptoms in children is cians working with children who suffer from func-
often more difficult than it may seem. Consider tional gastrointestinal and motility disorders.
the following case. Johnny is a 6 year old child Psychosocial factors often play a role in these dis-
who presents with nausea and abdominal pain. orders and no clinician working with this group of
Upon history taking the child appears to experi- patients will deny its influence. But the interpreta-
ence early satiety and some minor weight loss. tion of how psychological symptoms affect the
You notice pallor and irritability. After thorough etiology and maintenance of these disorders varies
diagnostic work-up John is diagnosed with considerably among clinicians. Are psychological
delayed gastric emptying. The family is sent home issues primary causes of some disorders? Can psy-
with a prescription for Metoclopramide and chological disturbances affect digestive processes?
referral to a dietician. Several months later In the case of Johnny: Were the continuation of his
Johnny returns to you and appears to be doing symptoms after successful treatment of the gastric
well. Pallor has disappeared and weight loss has emptying, primarily due to: (1) anxiety of his fam-
been stopped. Nevertheless problems continue at ily, who may too easily over-interpret normal
home around feeding. Johnny still refuses food symptoms as signaling disease; or (2) was there a
and continues to complain of nausea and abdom- behavioral component to his symptoms in the first
inal pain. You suspect psychological factors may place, that was not addressed with medication
be playing a role. The symptoms started around therapy thereby leading to ineffective treatment?
the time Johnny’s parents got a divorce. Mother Answers to some of these questions can affect the
course of suggested treatment for Johnny and other
children like him. In this chapter, first the theoreti-
M.A.L. van Tilburg, Ph.D. (*) cal models explaining the role of psychosocial
UNC Center for Functional GI and Motility Disorders, issues in health and disease will be discussed.
130 Mason Farm Rd. #4105. CB 7080, Chapel Hill,
NC 27599-7080, USA
These are implicit working models guiding clini-
cal care and scientific research and are important
Department of Medicine, Division of Gastroenterology
and Hepatology, University of North Carolina at Chapel
to explore. Then, the current scientific evidence
Hill, Chapel Hill, NC, USA for the role of psychosocial factors on physiologi-
e-mail: [email protected] cal functioning will be presented.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 59

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_6, © Springer Science+Business Media New York 2013
60 M.A.L. van Tilburg

between biomedical processes and symptoms. For

Psychological Issues in Health example, under the biomedical model the frequency
and Disease and amount of gastric acid refluxing into the esoph-
agus should explain the intensity of heartburn com-
Biomedical Model: A Symptom plaints. However, there are patients with very severe
Has Either a Physiological acid reflux for years, who are not symptomatic
or Psychological Origin until developing Barrett’s esophagus. On the other
hand, there are others with minimal acid reflux
Under guidance of the biomedical model, medi- whose life is severely affected by their symptoms.
cine has seen one of the greatest advances in its The only way to explain these findings with the
existence over the past centuries. It has been biomedical model is to see the first person as a
responsible for some of the most impressive dis- “tough” or stoic child, silently suffering while con-
coveries of modern Medicine such as the develop- tinuing with his/her life, while the second is a
ment of penicillin, vaccines, etc. It is still widely “wimp” complaining at the tiniest bit of discom-
popular today among many clinicians and patients. fort. The first elicits admiration and the second
The biomedical model envisions a direct relation contempt. However, imperfect associations between
between disease and symptom: Cause A will lead biomedical processes and symptoms are so ubiqui-
to symptoms B. The more disease causing A is tous that they seem to be the rule rather than the
present the more symptoms will be observed. If A exemption. The biopsychosocial model, first pro-
is eradicated the symptoms will disappear. This posed by Dr. Engel [1], posits that biochemical
straightforward model of health and disease alterations do not directly translate into illness.
focuses primarily on biological origins; but argues The appearance of symptoms is an interplay
that in lieu of a disease or structural abnormality, between many factors including biomedical,
psychological factors can cause symptoms. For psychological, and social factors, e.g., bacteria
example, if no biomedical reason can be found for A leads to more symptoms under stressful
stomachaches (such as lactose intolerance) then circumstances.
these symptoms can be attributed to psychosocial The biopsychosocial model has been widely
distress, i.e., anxiety or school avoidance. The bio- adopted by researchers and clinicians to explain
medical model is simple and elegant but com- health and disease and is particularly useful for
pletely ignores contextual influences on health and understanding and studying functional gastroin-
disease: Symptoms are either caused by biological testinal disorders. There is a robust literature
or psychological causes. This straight-forward and describing the influence of both physiological
appealing approach has led to the notion that if and psychological factors on the illness presenta-
symptoms are not in “the body” it must be “all in tion of functional gastrointestinal disorders in
the head.” It also explains our fascination with particular irritable bowel syndrome (IBS). These
drugs as a “quick fix” for real symptoms worthy of studies will be discussed later in this chapter.
a clinician’s time while behavioral or supportive
therapy have become synonym to treating symp-
toms that are either feigned or a result from being System Theory: Physiological and
“crazy” and not belonging in a physician’s office. Psychological Processes Are Constantly
Interacting to Cause Symptoms

Biopsychosocial Model: Symptoms Can Although the biopsychosocial model was presented
Be Altered by Psychosocial Processes by Dr. Engel as a system theory it is nowadays often
presented in a reductionist way. Some authors
By the mid 70s of the last century the powerful bio- reduce mental and social phenomena to basic bio-
medical model started to show little cracks. It logical phenomena such as activation of the autono-
became clear that there was no perfect association mous or central nervous system (CNS) and
6 Integration of Biomedical and Psychosocial Issues 61

Hypothalamic-Pituitary-Adrenal (HPA) axis [2]. The Brain–Gut Axis

Johnny from our case at the beginning of the chap-
ter may be anxious which leads to CNS and HPA Nowadays the role of psychosocial variables in
axis activation, interacting through the brain–gut functional gastrointestinal and motility disorders
axis with the enteric nervous system culminating in is widely recognized and the biopsychosocial
gastrointestinal symptoms. Systems theory approach is commonly endorsed in explaining
acknowledges that psychosocial processes undoubt- these disorders. The biopsychosocial model pos-
edly have biological correlates. However, it argues tulates that psychosocial factors can interact with
that the different systems—biological, psychologi- the gut through the brain–gut axis: the bidirec-
cal, and social—interact with each other but cannot tional communication between enteric nervous
be reduced to the lowest—molecular—level. The system in the gut and the brain. This means that
reasoning behind this is simple: we cannot under- emotions and thoughts have the capability to
stand the meaning of psychosocial processes by affect gastrointestinal sensation, motility, and
purely studying its biological correlates; subjective inflammation. Reciprocally, gastrointestinal pro-
phenomena are equally important. cesses are able to affect perception, mood, and
The biopsychosocial model is also sometimes behavior. Dysregulation of the brain–gut axis is
reduced to a hierarchy of unidirectional cause thought to be at the core of many functional gas-
and effects relationships which includes causes, trointestinal disorders.
precipitants, modulators, or sustaining forces [3]. With regularity the question is asked whether
In Johnny’s case anxiety and delayed gastric psychological issues are a cause or consequence
emptying can be thought to independently cause of the brain–gut axis dysregulation. Some authors
or sustain his symptoms and it is up to the physi- have found increased anxiety before a diagnosis
cian to decide which one is most important and of functional gastrointestinal and motility disor-
thus should be treated first. Viewing psychosocial ders [4] while others have argued that increased
and biomedical factors as somewhat independent psychosocial distress may be a consequence of
processes largely denies the reality of the situa- having to deal with a chronic, unpredictable con-
tion in which there are feedback loops between dition [5]. A large community based study found
all parts of the system. Johnny’s delayed gastric that both positions may be right: Psychosocial
emptying caused pain and fullness, which made comorbidity was as likely to be present before as
him anxious around food. His fears of having after seeking care for abdominal pain [6]. The
pain after a meal in turn may have led to hyper- question is if it really helps to know which one
vigilance and increased the sensitivity of his came first. If we conceive of our body as a system
nerves to normal digestive processes thereby in which psychosocial and biomedical factors
worsening his symptoms. Thus, anxiety is both interact continually, then the question of what
cause and effect in this circular loop. came first is not relevant. Both factors will inter-
Systems theory is an attempt to understand act to cause symptoms and understanding the dis-
these complex feedback loops over time and order is exploring this interaction. For example,
discovering the interrelated causes that sustain in the case of fecal incontinence we do not ask if
specific symptom over time. Unfortunately such the child was constipated first and then became
nice integrated models of proximal causes and anxious about evacuation of large bowel move-
effects over time are difficult to study. The need ments; or anxious about potty training and then
for complex study designs and statistical meth- experienced large stools due to withholding. Both
ods has seriously hampered the testing of sys- may be true and will lead to the same symptom:
tems theory in functional gastrointestinal and fecal incontinence. Both factors need to be
motility disorders. Recent developments of sys- addressed to ensure successful resolution of
tem theory methodology in other fields show symptoms. Thus, rather than trying to solve the
promise for application in functional gastroin- “Chicken-and-egg” dilemma we should focus on
testinal and motility disorders. understanding how the different components of
62 M.A.L. van Tilburg

the system interact to create these symptoms. In sles; (2) the subjective experience of stress which
the following section we summarize the literature is usually measured by self-reports of perceived
on psychosocial influences on functional gastro- stress; and (3) stress reactions which includes
intestinal and motility disorders. behavioral (e.g., withdrawal or confrontation),
emotional (e.g., anger, fear, anxiety, depression),
and physiological reactions (e.g., skin conduc-
Psychosocial Influences on Functional tivity, blood pressure, cortisol, and cate-
Gastrointestinal and Motility cholamines). Thus, stress in addition to being
Disorders itself, is also causing itself and resulting in itself.
It is important to realize which aspect of stress is
There are many psychosocial aspects relevant to being referred to when reading and interpreting
functional gastrointestinal and motility disorders the scientific literature on stress.
such as personality [7], self-esteem [8, 9], early Stress can be felt in the gut. We are all familiar
childhood experiences [10, 11], to name only a with the typical butterflies associated with young
few. Out of all the possibly relevant psychosocial love, feeling squeamish when being forced to
factors the most often studied is the concept of deliver bad news and the run to the bathroom before
stress. We all know what stress is and what it the start of an important race or game. Stress has
feels like. However, defining stress is more elu- been found to alter gut functioning. It has effects on
sive than it seems. First there are the events that GI sensory, motor, and immune functioning; which
may be stressful: being stopped by a policeman are also etiological pathways for many functional
for speeding, giving a speech in front of several gastrointestinal and motility disorders.
colleagues, taking your child to the Emergency
Room. These are called stressors. Second, there
are individual reactions to stress: feelings of Stress and Gastrointestinal
anger/fear, trouble concentrating, and physical Motor Functioning
reactions such as accelerated heartbeat, tensed
muscles and increased perspiration. It is impor- Motility disturbances are a hallmark symptom of
tant to realize that not all potential stressors lead many functional gastrointestinal and motility dis-
to stress reactions and that stress can be both pos- orders which may result in symptoms such as
itive and negative. What is stressful for one per- altered stool consistency, nausea, or bloating.
son may be pleasurable to another or have little There is evidence to suggest that stress induces
impact whatsoever to a third person. A parachute changes in motility. For example, under stressful
jump or deep sea dive may elicit enormous fear conditions gastric emptying decreases and colonic
and anxiety in some while others find it highly transit accelerates [13, 14]. These stress-induced
pleasurable and for very experienced profession- motility changes are caused by increases in corti-
als it may just a simple routine. Therefore, stress cotrophin-releasing factor (CRF). CRF is best
is a subjective experience created by the appraisal known as the principal instigator of the physio-
of an environmental demand as harmful, threat- logical response to stress through the
ening or challenging and appraisal of our ability Hypothalamic-Pituitary-Adrenal (HPA) axis and
to meet this demand [12]. If a person has ade- CRF 1 receptors have been found to regulate
quate resources to deal with a difficult situation behavioral reactions to stress [15–18]. But the
he or she may not experience stress; but if the effects of stress on motility seem to operate out-
demand (almost) exceeds one’s resources a per- side of this system. It has been reported that acti-
son will be under a great deal of stress. When the vation of CRF receptors in the brain induces
term “stress” is used it may refer to the following: propulsive motor function and diarrhea without
(1) the stressors, which are usually major life involving the HPA axis, but rather through stimu-
events such as trauma, abuse or divorce but can lation of autonomic nervous system [19, 20].
also be the cumulative effect of small daily has- Central CRF stimulates the vagal nerves
6 Integration of Biomedical and Psychosocial Issues 63

innervating to the proximal colon which results The role of stress on visceral sensitivity has
in release of colonic serotonin [19, 21]. Serotonin only been examined in abdominal pain related
is involved in various gastrointestinal motility functional gastrointestinal disorders. Many studies
processes such as the gastric accommodation have found reduced pain thresholds in reaction to
reflex, small bowel transit, and the colonic stress—which is equivalent to more easily report-
response to feeding [22]. Therefore serotonin ing pain under stress. Studies in rats have shown
abnormalities in the gut can lead to motility dis- that early-life stress is associated with colonic
turbances in functional gastrointestinal and motil- hypersensitivity in adulthood [30–34]. In humans,
ity disorders [22]. This is supported by the fact acute stress, induced by cold water hand immer-
that medications aimed at altering gut serotonin sion (physical stressor) or dichotomous listening
have been found to be effective in treating several (mental stressor), seems to reduce pain thresholds
functional gastrointestinal and motility disorders as well [35, 36]. But other types of stressor have
including IBS, constipation, functional dyspep- yielded mixed effects. Past stressful experiences
sia, and gastroparesis [22]. (e.g., abuse history) and psychological distress
In addition to motility, CRF receptors have (e.g., anxiety or depression) have been associated
also been implicated in visceral hypersensitivity with decreased pain thresholds in some studies
and immune functioning (for an over view see [26, 37–40] while others have reported no effects
Tache et al. [23]), the two topics which are dis- of stress at all [26, 39, 41–43]. Thus, most studies
cussed next. report increased sensitivity with stress but some
did not find any effects and one study actually
found decreased sensitivity [44]. The reason for
Stress and Gastrointestinal Sensory the inconclusive evidence may be related to the
Functioning way visceral sensitivity is measured.
In most barostat protocols increasing levels of
One of the most consistent findings in painful pressure are presented to the patient who is asked
functional gastrointestinal and motility disor- to indicate first perception of discomfort. This
ders is visceral hypersensitivity. Hypersensitivity experimental design is believed to be vulnerable
to gut distension—the reporting of first sensa- to psychological response biases in particular
tion of pain at lower levels of pressure than fear of pain [45]. Naliboff and colleagues found
normal—has been found in more than half of that when offering unpredictable changes in vol-
adult patients who suffer from IBS and func- ume, differences in pain thresholds between IBS
tional dyspepsia [24]. Visceral sensitivity is patients and controls disappeared [46]. Dorn and
usually measured by using the barostat tech- colleagues added to these findings by showing
nique. The barostat inflates a balloon to differ- that rather than increased neurosensory sensitiv-
ent pressure levels in the stomach, colon, or ity (the ability to discriminate between pressure
rectum while the patient is asked to report level levels), lower pain thresholds in IBS are explained
of discomfort and pain (for guidelines on using primarily by an increased psychological tendency
the barostat in children see van den Berg et al. to report pain [47]. One of the non-sensory cues
[25]). As the barostat technique is invasive there that influence pain threshold ratings is hypervigi-
are few studies in children. The results of these lance to symptoms. IBS patients have a higher
studies show that visceral hypersensitivity is a tendency to label visceral sensations as unpleas-
common phenomenon in children with painful ant during barostat testing [46]. Thus, visceral
gastrointestinal disorders [25–27]. In addition, hypersensitivity can either be caused by hyper-
visceral hyposensitivity in the rectum has been vigilance or perceptual sensitivity and both may
reported in children with constipation [28, 29]. have associations with stress. Dorn found some
Reduced sensation in the rectum corroborates indication that increased psychological distress is
the fact that these children do not easily feel an associated with hypervigilance but others have
urge to defecate. not been able to replicate this [46–48].
64 M.A.L. van Tilburg

If we assume that under certain circumstances 6/44, and the somatosensory cortex, areas associ-
stress can affect visceral sensitivity, an important ated with pain intensity encoding [53]. Thus, there
question becomes at what level in the neural sys- is evidence that psychological factors can influence
tem these effects are most dominant. Sensations brain reactions to visceral pain, specifically areas
from the gastrointestinal tract are relayed to spi- related to emotion modulation, but the exact mech-
nal dorsal horn. Visceral sensory information is anism still needs to be determined.
then conveyed to supraspinal sites and finally to
cortical areas where they are perceived [49].
Descending emotional pathways via the periaq- Stress and Gastrointestinal Immune
ueductal gray to the dorsal horn can amplify or Functioning
suppress new afferent signals from the gut.
Amplification of these signals can occur at any The role of the immune system in functional gas-
level in this neural pathway. Evidence is building trointestinal and motility disorders, specifically
that the Central Nervous System is an important IBS, has received a lot of attention in the past
site of modulating the pain response. Brain decade. This line of research initially focused on
responses to visceral stimuli are increased in IBS patients who developed IBS following an infec-
patients compared to controls in areas related to tious gastroenteritis. Later, low grade inflammation
conscious experience of visceral sensations within the gut wall as well as altered immunologi-
(specifically the Insular Cortex) as well as areas cal function and alterations in gut flora were found
related to emotion modulation and emotional in functional gastrointestinal disorders of nonin-
response to threat including the Anterior Cingulate fectious origin including IBS, functional dyspep-
Cortex, hypothalamus, and the amygdala. Thus, sia, and noncardiac chest pain [54–56]. Many
IBS patients tend to responds with more affective innate and adaptive immune parameters have been
and attentional responses to visceral stimuli. In studied but among the most robust findings are
addition, decreased activation in the periaque- increased levels of mast cells, monocytes, and
ductal gray shows decreased efferent inhibition T-cells as well as increased intestinal permeability
of pain signals [49]. (for a review see Ohman and Simren [57]).
Though the brain is the most likely level for Although most studies have been done in adults,
psychological input to interface with visceral increased gut inflammation has also been shown in
input, very few studies have investigated the role children who suffer from functional abdominal
of psychological factors in modulating the Central pain [58–61]. Outside the field of gastroenterology,
Nervous System response to visceral sensations there are many studies which suggest that psycho-
Berman and colleagues studied anticipation of vis- logical distress affects the immune system in
ceral pain [50]. They found that negative affect healthy adults (for a meta-analysis see Denson
reduces anticipatory brain stem inhibition. et al. [62]). For example stress reduces antigens
Reduced anticipatory brain stem inhibition in turn production following vaccinations [63, 64],
was associated with increased brain responsive- increases susceptibility to colds [65] and medita-
ness to actual distention [50]. Ringel and col- tion decreases IL-6 responses to a laboratory psy-
leagues observed that during rectal distension, chosocial stressor [66]. The role of stress on the
patients with IBS and abuse history show greater immune system in functional gastrointestinal and
posterior/middle dorsal and anterior cingulate cor- motility disorders has received little attention. In
tex activation, as well as reduced activity of the rats and rodents stress increased low-grade
supragenual anterior cingulate (a region implicated inflammation in the gut postinfection [67] as well
in pain inhibition and arousal) [51, 52]. In a case as esophageal and intestinal permeability [68].
report of a patient with of severe IBS and post- Studies in humans also suggest that stress is associ-
traumatic stress disorder, resolution of emotional ated with low grade inflammation in functional
distress was associated with reduction in activa- gastrointestinal disorders. Piche et al. [69] and
tion of the midcingulate cortex, prefrontal area Schurman et al. [61] observed that depression and
6 Integration of Biomedical and Psychosocial Issues 65

anxiety scores in IBS patients are correlated with ioral changes in mice; symptoms changes that are
increased mast cell counts. Dinan and colleagues also characteristic of many functional gastroin-
[70] found that increased stress response in IBS testinal disorders [86–88]. Dysbiosis may stimu-
patients (measured by plasma adrenocorticotropic late the vagal nerve. The vagal nerve has been
hormone levels after CRF administration) is asso- implicated both in neurological control of the
ciated with increased IL-6 levels. Anxiety has been immune system particularly cytokine control [89]
reported to be associated with increases in cytokine as well as in dysregulation of the brain–gut inter-
levels in IBS but only after exposure to Escherichia actions in functional gastrointestinal disorders
coli lipopolysaccharides [71]. These are early indi- [90]. Vagal sensory neurons react to potentially
cators that stress and the immune system interact in dangerous bacteria in the GI tract independently
functional gastrointestinal and motility disorders. of an immunological reaction to their presence: It
Psychological distress may affect immunologi- has been reported that the vagal nerve is stimu-
cal response and reducing stress could be helpful. lated hours before bacteria are able to colonize
But there is also data to suggest that immune acti- [91, 92]. In fact mice with dysbiosis show anxi-
vation may drive psychological distress and brain ety-like behavior in the absence of circulating
related changes. Activation of the immune system pro-inflammatory cytokines and classic sickness
either by viral infection or by administration of behaviors [93]. In addition, administration of a
cytokines or lypopolysaccharide (found on the probiotic reduced anxiety-like behavior in mice
outer membrane of gram-negative bacteria) induces with colitis, but only if they had an intact vagus
cytokine secretion and trigger depression and anx- nerve [94]. Thus, the vagal nerve can provide sig-
iety in healthy volunteers [72, 73]. In addition, nal to the brain on dysbiosis before inflammatory
immune-targeted therapies such as interferon-alpha responses reach the brain through the systemic
treatment for Hepatitis C or cancer have been circulation. Goehler argues that the adaptive
known to induce anxiety and depression in a value of enhanced anxiety during gut infection
significant percentage of patients [74–76]. Those may lay in threat avoidance [78]. Behavioral
who develop major depression during treatment responses to an infection such as psychomotor
have increased pretreatment IL6 and IL-10 concen- retardation may leave an animal vulnerable to
trations [77]. These findings suggest that that predators. Avoidance of dangerous situations
increased immune activation is a causal risk for the such as open spaces is essential and accomplished
development of major depression. Based on these by early inducement of anxiety to stimulate threat
observations Goehler et al. [78] have suggested that avoidance. This will put the animal in less danger
“Some of the negative affective experiences associ- once sickness behaviors are full-blown. Given
ated with gastrointestinal disorders may not be that even low grade inflammation can induce
under the voluntary control of the patient.” alterations in mood, this may be partially respon-
Although it yet has to be determined how sible for increased anxiety and depression in
infections in the gut influence the brain and mood, functional gastrointestinal disorders.
it has been suggested that the brain may react
directly to the bacterial composition of the GI
tract [78, 79]. The gut contains different species Conclusion
of microbiota, many of which still need to be
characterized by culture. Imbalances in gastroin- There is clear evidence that psychosocial factors
testinal microbiota, or “dysbiosis,” have been can alter gut physiology. Stress-induced changes in
found in many chronic gastrointestinal disorders CRF leads to motility disturbances such as decreased
such as IBD [80], antibiotic-induced diarrhea gastric emptying and increased colonic transit. In
[81, 82] and IBS [83–85]. Inducing dysbiosis, addition, patients who are distressed usually dis-
either with the use of oral antibiotics or by replac- play increased visceral hypersensitivity which is
ing the microbiota, leads to low grade under the control of emotion-regulation areas of
inflammation, visceral hyperalgesia, and behav- the central nervous system. Although not studied
66 M.A.L. van Tilburg

extensively in functional gastrointestinal and treating the biological factors that were driving
motility disorders there is a large body of litera- his symptoms. He needed an integrated treatment
ture suggesting that stress alters immune func- approach that consisted of improving delayed
tioning. The reverse—that alterations in gastric emptying (physiological factor) as well as
physiology can affect stress levels—has not been helping him overcome his fear of eating (personal
studied widely. There is some evidence that factor) and his mother’s anxiety (social factor).
immune activation may induce psychological Symptoms in children with functional gastroin-
distress. This process may be driven by changes testinal disorders result from an interplay among
in gut microbiota which are relayed to the brain biomedical causes and many possible psychoso-
through the vagus nerve. cial factors such as anxiety, depression, hyper-
One caveat to the above line of research is the vigilance to symptoms, inadequate coping, the
almost exclusive focus on a single disease entity: way parents respond to their pain, bullying,
IBS. More research is needed in other functional unsanitary toilets at school and many more.
gastrointestinal disorders to determine if the
effects of stress on gut physiology are general to
a larger group of patients. In addition, pediatric References
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 Functional Gastrointestinal
Disorders: An Anthropological 7
Perspective

Sylvie Fortin, Liliana Gomez,

and Annie Gauthier

Introduction Epidemiology

In the biomedical and social sciences, the strong Functional gastrointestinal disorders (FGIDs)
tendency towards specialization of knowledge and may be defined as gastrointestinal dysfunction in
practices often leads to a separation of the biopsy- the absence of apparent physiological lesions.
chosocial and cultural aspects of the experience of The prevalence rates of FGIDs are 13–20% in the
illness. In this chapter, our objective is to highlight general Canadian population, 10–15% in the
the main contributions of anthropology to the field global population [1], and approximately 10% in
of medicine, and especially the specialty of func- the pediatric population [2].
tional gastrointestinal disorders (FGIDs). First, we In some of the first prevalence studies of
present the most recent epidemiological data, FGIDs, it was suggested that non-Western coun-
along with an overview of the current state of tries were less affected than Western countries [3,
research into these disorders. Second, we briefly 4]. Yet in South Africa, an increase in consulta-
explain the anthropological approach and method, tions for this type of disorder was observed with
underscoring its main contributions to the under- recent industrialization and the advent of exten-
standing of FGIDs. Then we look at the contribu- sive lifestyle changes. Also, studies in Nigeria [5,
tions of anthropology to studies on patient–clinician 6], Kenya [7], and Ivory Coast [8] found preva-
relations with respect to FGIDs. We wind up with lence rates similar to those in North America.
some concluding remarks and proposals for ave- Last, some studies report a tendency towards an
nues of research and thought. evening out of prevalence rates of these disorders
in various countries: United States 10–15%,
Sweden 13.5%, China 15.9%, Singapore 8.6%,
S. Fortin, Ph.D. (*) Pakistan 14%, Taiwan 22.1%, and Nigeria 26.1%
Anthropology Department, Université de Montréal, [9]. Although different instruments used to mea-
C.P. 6128, Succ. Centre-ville, Montréal, Québec, sure prevalence make international data compari-
Canada, H3C3J7
sons difficult, variations in rates have been
e-mail: [email protected]
attributed to food, hygiene, and psychosocial fac-
L. Gomez, M.Sc.
tors [10, 11].
Research Center, Sainte-Justine University Hospital,
Montreal, Quebec, Canada Also, population studies in a number of coun-
tries suggest significant similarities in the percep-
A. Gauthier, Ph.D.
Research Center, Sainte-Justine University Health tion of symptoms and decisions to seek medical
Center, Montreal, Quebec, Canada help for FGIDs [7, 12–16]. Sex differences have

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 71

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_7, © Springer Science+Business Media New York 2013
72 S. Fortin et al.

been pointed out, however: in cases of FGIDs,

women, regardless of national origin, are more Contributions of Anthropological
likely than men to express their pain and seek Approach and Method
medical help [7, 17–19]. While knowledge in the to Understanding of FGIDs
field is constantly advancing, much is still
unknown about the factors involved in the onset Medical anthropology is keenly interested in the
and evolution of FGIDs [20, 21]. Nevertheless interaction between the body and its social and
there seems to be consensus that FGIDs are cultural setting that is so fundamental to FGIDs.
caused and maintained by a combination of bio- Classically, it distinguishes between three related
logical, psychological, and social factors.1 concepts:
In the three-pronged bio–psycho–social 1. Disease—Medically identified pathology
model, genetic factors, along with environmental (organic dysfunction, psychological deficit,
factors in the early years of life, family upbring- etc.).
ing with respect to food and digestion, specific 2. Illness—Patient’s subjective experience (dis-
family dynamics, exposure to infections, types of ease as experienced).
somatization, and various ways of expressing and 3. Sickness—Disease as a social phenomenon:
developing narratives of suffering [22, 23], are representations of the disease and the patient,
considered to form the basis of physiological pro- but also health problems such as maltreatment
cesses (abnormal motility or visceral hypersen- and substance abuse. From this standpoint,
sitivity) and psychosociological processes anthropology approaches the body as both a
(susceptibility to stresses of everyday life, psycho- physical and symbolic entity, a cultural and
logical condition, coping skills, development of organic construct, rooted in a specific time and
social support). In each person with an FGID, place [24].
these interactive processes lead to an individual The question of FGIDs therefore cannot be
constellation of symptoms and behaviors that confined to merely the abdominal region; it must
influence the person’s reactions to the disorder. be broadened and deepened to include personal
Given this complexity, multidisciplinary research experience, life trajectory, and relationships with
would seem to be essential and of great benefit in others and the social setting. To anthropologists,
supporting clinicians who work with children, the body is also a mediator that lets a person give
adults, and families affected by FGIDs. Pooling form to a discomfort or distress that cannot other-
biomedical and social science expertise makes it wise be expressed. FGIDs are seen as indicative
possible to build on acquired epidemiological of restrictive social, political, and economic liv-
and clinical knowledge to better grasp the protec- ing conditions, or painful events or situations that
tive and vulnerability factors associated with the leave their marks on the body.
onset and evolution of FGIDs, and gain a better Together, these different levels of understand-
understanding of the intricate relationship ing of the body constitute “the personal experi-
between the biological, social, and cultural ence of disease,” which involves the social world,
dimensions of the human body. subjectivity, and psychophysiological processes
[25]: a reciprocal relationship between the
patient’s social world and body/self or, in other
1
The generally accepted hypothesis to explain the pain is words, between the patient’s outer and inner
that there is a combination of sensory and motor activity
environments [23].
along the brain–gut axis. It appears that the information
we receive from the outside through our senses and per- Anthropological methods (whether taking a
ceptions (emotions, thoughts, smells, sights), by the nature phenomenological, ethnographic, or grounded-
of the neural connections in the higher centers, can affect theory approach) can lead to a better understand-
gastrointestinal sensations, motility, hormone secretion,
ing of the experiences of children with FGIDs, in
and inflammation [8]. This physiological action seems to
have a variable influence on the endocrine system, immune a number of ways. Observing family situations
function, and human behavior. and conducting in-depth interviews with families
7 Functional Gastrointestinal Disorders: An Anthropological Perspective 73

and children, often at home, can reveal dimen- tients, provided answers to our initial research
sions missed in clinical encounters or by stan- questions related to the underrepresentation of
dardized instruments, which often use closed migrant children in the overall pediatric FGID
questions, or that provide further illumination of patient population. While this kind of method is
existing data. For example, children and their particularly well suited to qualitative data analy-
mothers sometimes have trouble stating exactly sis, it does not ensure statistical accuracy. The
how often abdominal pain has occurred within a interest of this approach lies in its capacity to
given time frame, so their answers do not always bring out the quality of the sample and the depth
correspond to the options offered by the Rome III of the information gathered. The ultimate goal is
criteria. The same is true of the location of the to better understand the phenomenon at hand,
pain and other accompanying symptoms [26]. focusing on its internal logic, rather than its gen-
Through the use of anthropological methods, the eralization [30, 31].
intensity and description of the pain are better
understood in a context that makes sense to the
children and their families, in keeping with the The Patient–Physician Relationship
concept of illness [23, 27] described above.
The anthropological approach to FGIDs thus One of anthropology’s contributions to medicine
follows interview guidelines that focus on the is the fact that it situates each patient and his or
narratives of children and their parents, requiring her family in their own specific life situation.
careful listening to what they have to say and This approach is even more appropriate for a
close attention to the practices in their living pediatric population, since children seek support
environments that shape their experiences. From and help from their parents when they are in pain,
this perspective, verbal and nonverbal communi- of course, but also because it is the parents who,
cation, as well as the dynamics and practices on the child’s behalf, seek a cure, turning to medical
observed intertwine, thus enriching the data to and health institutions to varying degrees.
be analyzed. The accounts recorded in the clini- In-depth knowledge of the family’s life and inter-
cal setting can then be compared with the narra- nal dynamics helps us better define the roles each
tives and observations collected through family member may play in mobilizing various
anthropological study and placed in perspective formal and informal resources, both individual
so that they shed light on each other, with a view and community, to relieve FGIDs. In addition to
to gaining a deeper understanding of the various a better grasp of the wealth, variability and limi-
processes involved. tations of the resources used, in-depth knowledge
Analytical models vary according to the of the family’s life fosters a better appreciation of
specific research questions being examined. For the interaction between family climate and the
example, in a recent multidisciplinary (anthro- search for solutions, or even the origin of the
pological and pediatric gastroenterological) problem. All this information is invaluable to cli-
exploratory study of children with FGIDs and nicians and in designing treatment plans that are
their families (users and nonusers of health-care sensitive to the patient’s life situation.
services) [28], we used the “signs, meanings, Beyond the family’s curative strategies and
actions” model [29]. This model made it possible practices, the anthropological approach explores
to articulate the children’s and parents’ point of and delves more deeply into the children’s and
view as it pertained to (1) signs, that is, the per- families’ explanations and interpretations of gas-
ception of symptoms related to FGIDs; (2) mean- trointestinal symptoms. These explanatory models
ings and explanations attributed to them; and are a way of addressing the etiology of problems
(3) actions undertaken to ease the pain and cho- based on the experiences and words of the people
sen therapeutic paths. Thematic analyses by concerned. They offer explanations of episodes of
migrant versus nonmigrant respondents, as well illness and influence how patients and clinicians
as gastroenterological clinic patients versus nonpa- alike behave with regard to health problems.
74 S. Fortin et al.

Similarly, these explanations are one of the most A number of studies have documented prob-
important dimensions in establishing good com- lems in clinical encounters concerning FGIDs.
munications and developing a solid therapeutic Researchers talk about unsatisfactory therapeutic
alliance between children, their parents, and the relationships, repeated consultations, and often
gastroenterologist [32]. Yet the different parties superfluous and sometimes even harmful inter-
concerned do not always agree on the same explan- ventions [36–39]. To a certain extent, these prob-
atory model. In fact, a series of studies on profes- lems reflect the limitations of our conception of
sional and lay etiological models of diseases have FGIDs. In this context, an anthropological
highlighted the potential differences between the approach makes it possible to nurture the care-
frameworks that determine the actions and giver–patient–family relationship and explore its
approaches of experts and those of the people con- many issues, such as how the gastroenterologist,
sulting the experts [33, 34]. It is important to the child, and the family members negotiate mean-
examine these differences for several reasons: ings and roles; areas of agreement and disagree-
1. In clinical practice, doctors often have trouble ment among these different parties; or even the
sharing their knowledge of FGIDs, due to the impact of the diagnosis and medical recommen-
patient’s or family’s reluctance or refusal to dations on the child’s life. An anthropological
accept an outside expert’s explanation of the approach can document what it is that patients
symptoms. and their families take away from the clinical
2. Divergent perceptions and practices associ- encounter, advice offered, and practices sug-
ated with strongly contrasting sociocultural gested; their impressions of how well they have
points of reference in a pluralistic setting can been heard and of whether the child is on the road
lead to communication problems. to better health. As in other research settings [26,
3. The perceptions and conceptions of FGID 40–42], it is very much a matter of enriching the
symptoms are often not associated with plain encounter with different types of expert and lay
or objective facts, but much more with per- knowledge and negotiating about them, in a spirit
sonal interpretations. of disciplinary complementarity (anthropology,
Furthermore, for children and their parents, medicine) and possible contribution to new ana-
categories of explanations may be approached lytical paradigms and new clinical approaches.
from different angles and take on a variety of con- Finally, given that many children and adults
notations. Here, once again, the study mentioned who suffer from FGIDs do not seek medical help
earlier involving 43 Montreal families of diverse [43–46], anthropological research on families
origins [28, 35] found that food, stress, and hered- who did not consult a doctor (or were not recruited
ity were the main lay explanations of abdominal through a health-care institution) may reveal
pain. However, these explanations are invested invaluable information about FGIDs. We are
with different meanings from one cultural group thinking here more particularly of sociocultural
to another and from one family to another, or even protective and vulnerability factors related to the
within the same household. For example, respon- onset and evolution of FGIDs, the updating of
dents express different relationships to the cate- which requires methods that can continually be
gory “food,” depending on whether they are adjusted to suit people’s specific life situations.
talking about its instrumental, nutritional, social, Family relationships, for example, and more
or emotional dimensions. These different conno- specifically those between parents and children,
tations affect the way families respond to abdomi- may channel and soothe stomach pains, just as
nal pain. As Cook [32] points out, better knowledge they may, in another context, exacerbate tensions
of the different meanings attributed to food, as that may trigger them. Depending on the context,
well as of the eating habits of children and their these relationships may support or hinder the
families, is essential to a successful partnership mobilization of care resources both within the
between health professionals and the children, family and in the broader sphere of health-care
adults, and families who consult them. services. This means that the same factors may
7 Functional Gastrointestinal Disorders: An Anthropological Perspective 75

both protect children’s health in some cases and 6. Olubuyide IO, Olawuyi F, Fasanmade AA. A study of
increase their vulnerability in others. By putting irritable bowel syndrome diagnosed by Manning criteria
in an African population. Dig Dis Sci. 1995;40:983–5.
the different factors into context, anthropology 7. Lule GN, Amayo E. Irritable bowel syndrome in
provides a framework for thinking about FGIDs Kenyans. East Afr Med J. 2002;79:360–3.
from a pluralistic perspective, as they are experi- 8. Soubeyrand J, Condat JM, Leleu JP, Ticolat R,
enced by different groups of human beings, in Niamkey E, Beda BY. Functional colonic pathology
in the Ivory Coast. Sem Hop. 1983;59:247–51.
settings that can be unique or quite similar. 9. Quigley E, Gwee KA, Olano C, et al. Irritable bowel
syndrome: a global perspective. Global guideline.
Munich: World Gastroenterology Organisation; 2009,
Conclusion p. 20
10. Heizer WD, McGovern S. The role of diet in symp-
toms of irritable bowel syndrome in adults: a narrative
Anthropology has made many valuable contribu- review. J Am Diet Assoc. 2009;109:1204–14.
tions to the gastroenterology of FGIDs. Qualitative 11. Zuckerman MJ, Drossman DA, Foland JA, et al.
data supplement epidemiological statistics by pro- Comparison of bowel patterns in Hispanics and non-
Hispanic whites. Dig Dis Sci. 1995;40:1763–9.
viding depth and informative details on the social 12. Barakzai MD, Fraser D. The effect of culture on
and symbolic world of children and their families. symptom reporting: Hispanics and irritable bowel
This information helps identify the protective and syndrome. J Am Acad Nurse Pract. 2007;19:261–7.
vulnerability factors associated with these disor- 13. Gwee KA, Ghoshal UC. Epidemiology of irritable
bowel syndrome in Asia: something old, something
ders, provides clues about the necessary conditions new, something borrowed. J Gastroenterol Hepatol.
of a better therapeutic alliance, and aids in under- 2009;24:1601–7.
standing the dynamics at work when people seek 14. Landau DA, Levy Y, Bar-Dayan Y. The prevalence of
health services. Last, by combining the social and gastrointestinal diseases in Israeli adolescents and its
association with body mass index, gender and Jewish
biological dimensions, anthropology reminds us ethnicity. J Clin Gastroenterol. 2008;42:903–9.
that we need to consider culture differently, taking 15. Lu CL, Chen CY, Luo JC, et al. Significance of Rome
as a starting point the people who embody it; to be II-defined functional constipation in Taiwan and com-
open to potential medical pluralism; and to work parison with constipation-predominant irritable bowel
syndrome. Aliment Pharmacol Ther.
with a view to developing fruitful interdisciplinary 2006;24:429–38.
partnerships that will advance science and help 16. Wigington WC, Johnson WD, Minocha A.
children and their families. Epidemiology of irritable bowel syndrome among
African Americans as compared with whites: a popu-
lation-based study. Clin Gastroenterol Hepatol.
2005;3:647–53.
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 Part II
Motility and Sensory Testing
 Esophageal Manometry
8
Roberta Buonavolontà, Marina Russo,
Rossella Turco, and Annamaria Staiano

vomiting, in order to allow the egress of gastric

Introduction contents from the esophageal lumen. The UES is
present by at least 32 weeks gestation and is func-
The esophagus acts as a conduit for the aboral tional at birth [2]. However, swallowing coordina-
transport of food from the mouth to the stomach. tion may be poor in the first week of life and in
The three structural components of the esophagus premature infants <1,500 g [3, 4]. Structurally, the
are the upper esophageal sphincter (UES), the UES is ~0.5–1 cm long at birth and increases in
esophageal body, and the lower esophageal sphinc- length to ~3 cm in the adult [1].
ter (LES) [1]. The UES is a physiologically defined The LES is the high pressure zone localized at
as a zone of high intraluminal pressure between the esophago-gastric junction, which regulates
the pharynx and the cervical esophagus which the flow of contents between the esophagus and
comprises the functional activity of three adjacent the stomach. The main function of the LES is to
muscles together with cartilage and connective tis- create a high-pressure zone to prevent retrograde
sue. The main functions of the UES are to provide movement of gastric content into the esophagus.
the most proximal physical barrier of the gastroin- During swallowing and belching, the LES
testinal (GI) tract against pharyngeal and laryngeal promptly relaxes in order to allow the passage of
reflux during esophageal peristalsis, and to avoid ingested food or air in appropriate directions. At
the entry of air into the digestive tract during nega- the time of swallowing, the LES relaxes promptly
tive intrathoracic pressure events, such as inspira- in response to the initial neural discharge from
tion. The UES relaxes both transiently during the swallowing center in order to minimize resis-
swallowing, in order to allow the entry of a bolus tance to flow across the esophago-gastric junc-
into the esophagus, and during belching and tion. This relaxation starts within 2 seconds after
the peristaltic contraction has begun in the proxi-
R. Buonavolontà, M.D. mal esophagus and lasts 5–10 s until the peristal-
Department of Pediatrics, University of Naples, tic wave reaches the distal esophagus. During
Naples, Italy relaxation, LES pressure falls to the level of gas-
M. Russo, M.D. • R. Turco, M.D. tric pressure. As the LES relaxes (an active pro-
Department of Pediatrics, University of Naples Federico cess), it is passively opened by the bolus propelled
II, Naples, Italy by the peristaltic wave. The LES relaxation is fol-
A. Staiano, M.D. (*) lowed by an after-contraction of the upper part of
Pediatric Gastoenterology Division, Pediatrics sphincter, which likely represents the end of con-
Department, University of Naples “Federico II”,
via Pansini 5, Naples 80131, Italy traction wave as it reaches the distal esophagus.
e-mail: [email protected] Swallow-induced LES relaxation is part of

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 79

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_8, © Springer Science+Business Media New York 2013
80 R. Buonavolontà et al.

primary peristalsis [5]. Like the UES, LES length perfused catheters with volume displacement
increases with age, from 1 cm in the newborn to transducers or strain gauge transducers with
2–4 cm in the adult [6, 7]. LES pressure also var- solid-state circuitry. Each design has distinct
ies with age, going from 7 mmHg in a premature advantages and disadvantages. With water-perfused
infant of 27 weeks gestation to 18 mmHg at term systems, a pneumohydraulic pump perfuses
and from 10 to 45 mmHg in adults [8, 9]. distilled water through the lumens of the multilu-
Esophageal manometry has been considered men manometric catheter. Each lumen is con-
the “gold standard” test for the evaluation of nected to an external volume displacement
esophageal motor function. Esophageal manom- pressure transducer and terminates at a side-hole
etry allows the physician to assess peristalsis by or sleeve channel within the esophagus, sensing
measuring the shape, amplitude and duration of the intraluminal pressure at that position by the
the esophageal contractions [10]. The clinical use relative obstruction to the flow of the perfusate.
of esophageal manometry is in defining the con- In addition to having well defined, time-tested
tractile characteristics of the esophagus in an response characteristics, other advantages of the
attempt to identify pathological conditions. perfused manometric system are (1) relatively
Esophageal manometry is performed differently inexpensive, (2) easy availability of 8-lumen
in children than in adults because of the differ- extruded polyvinyl tubes that can be made into
ences in size of the esophagus, cooperation by manometric assemblies of varied sensor
the patient, and neurologic and developmental configuration, (3) compatibility with sleeve
maturation. These differences require special devices for assessing sphincter function, and
equipment as well as technical expertise to per- (4) temperature stability. Disadvantages of per-
form the study, handle the patient, and properly fused manometric systems are as follows: (1)
interpret the findings [11]. proper equipment maintenance, which is essen-
tial for the system to achieve published response
characteristics, requires relatively skilled person-
Equipment nel; and (2) recording characteristics are unsuit-
able for accurate pharyngeal studies [8].
A manometric apparatus consists of a pressure The main alternative to the water-perfused
sensors and transducers combination, which manometric system is a manometric assembly
detects the intraluminal pressure and changes it incorporating strain gauge sensors and solid-state
into an electrical signal, and a recording device to electronic elements. In these manometric sys-
amplify, record, and store that electrical signal. tems, the manometric probe contains the trans-
Although each component can potentially affect ducers at fixed locations along its length. The
recording fidelity, most attention is rightfully probe plugs into a small box containing the elec-
focused on the pressure sensor and transducer tronic elements, connected to the recorder. The
combination. Recorders (whether they are ink advantages of intraluminal strain gauge systems
writing polygraphs, thermal writing polygraphs, are (1) their vastly expanded frequency response,
or computers with analogue to digital converters) making them suitable for recording any intralumi-
all possess response characteristics far in excess nal pressure activity and (2) their less cumbersome
of that required for recording esophageal pres- nature compared with perfusion pumps, requir-
sure complexes. Specific recorders are most eas- ing less skilled personnel to perform clinical
ily distinguished by the number of pressure studies and less equipment maintenance. The
signals (channels) that can be recorded simulta- main disadvantages are as follows: (1) the mano-
neously, ease of use, convenience of data storage, metric probes are expensive, sometimes fragile,
accessibility of stored data, and price. The pres- and unmodifiable; (2) manometric probes are
sure sensor and transducer components of a subject to several physical constraints with
manometric assembly function as a matched pair respect to the number of sensing elements and
and are available in two general designs: water- the proximity of the elements to each other; and
8 Esophageal Manometry 81

(3) there is no equivalent of a sleeve device com- ent, abnormal motor activity as measured by
patible with this system [8]. “conventional manometry” is defined in terms of
With either system, the spacing of the sensing a few basic patterns: incomplete sphincter relax-
ports depends on the size of the patient. The ation, esophageal spasm, hypertensive contrac-
interval between perfusion ports or transducers tions, and loss of tone and motility [15–17]. This
may need to be as close as 1–3 cm apart to accom- classification is simple; however, even for experi-
modate the shorter esophagus in infants. During enced physiologists in specialist centers, interob-
perfusion in infants and small children, the perfu- server agreement in the interpretation of
sion rate may need to be lower because of the size manometric measurements is poor [18]. Only
of the esophagus, the fluid tolerance of infants, achalasia and severe diffuse esophageal spasm
and the potential for aspiration. Care must be are specific disorders with manometric abnor-
exercised to compensate for the slower flow rate malities that are absent in healthy subjects. Other
by decreasing the system compliance [11]. esophageal motility disorders are poorly defined,
often include “abnormalities” that can be found
in symptom-free individuals as well [19, 20] and
Performing the Test are inconsistent over time [21].

Esophageal manometry is best performed with-

out sedation. In many children, however, sedation High Resolution Manometry
is necessary. Midazolam and chloral hydrate have
been shown to be effective with minimal or no High-resolution manometry (HRM) was devel-
influence on pressure measurements [12, 13]. oped to increase interpretative consistency and
A natural reflex swallow may be induced in diagnostic accuracy of esophageal manometry
young infants and neurologically abnormal chil- [22, 23]. Addition of the dimension of spatial
dren by gently blowing in the child’s face relationship to conventional recording methods
(Santmyer swallow) [14]. has two minimum requirements: recording sites
The single most difficult technical aspect of that are positioned closely enough (usually at
esophageal manometry in children is coopera- 1-cm intervals) to allow accurate interpolation of
tion. Physicians performing manometry in chil- data between sites and an appropriate computer
dren must have great patience. The patient’s system for acquisition of the data and creation
cooperation can, however, be improved by the and display of the desired three-dimensional plots
use of age-appropriate relaxation techniques. For [22]. Axial interpolation has already proved use-
example, infants relax with swaddling and use of ful in understanding the correct relationship of
a pacifier. Toddlers are comforted by having a pressure data when unusual wave forms occur,
favorite blanket or toy. School-age children for example, multi-peaked waves [23]. Three-
benefit from being allowed to handle and exam- dimensional topographical plots are convenient
ine equipment before the procedure. Adolescents methods of visually representing the large amount
benefit from a thorough review of what to expect of data provided by the increased number of
before the procedure. Recording artifacts are recording sites.
common in the pediatric patient and occur more Both perfused (Medical Measurement
commonly than in adults. Specific behaviors Systems, Enschede, The Netherlands) and solid-
(e.g., crying or squirming) should be noted on the state systems (Manoscan and Manoview, Sierra
tracing itself to allow proper interpretation upon Scientific, Los Angeles, USA) to perform HRM
completion of the study [11]. are now available. The water-perfused catheters
Despite the technical advances, considerable for HRM with 21–32 channels and, more recently,
time and expertise are required to obtain a techni- up to 36 pressure sensors, contain smaller lumina,
cally adequate and maximally informative study which are perfused at very low rates. In children,
of esophageal function by this technique. At pres- at least 80% of the esophageal body and one
82 R. Buonavolontà et al.

sphincter could be sampled with the catheter with required for zero adjustment (e.g., to match intra-
21 lumens in either a proximal or distal recording gastric pressure). Likewise, the first contour level
position. With this design, a 20 cm segment is as well as the pressure interval for subsequent
sampled simultaneously. Data acquired by HRM rings can be modified as required. The axial trans-
can be analyzed and presented either as multiple formations of manometric data are available only
line plots or as a spatiotemporal plot. on the developed system. Individual frames are
Three types of data display can be generated created by splining data across all recording sites
and are available for review immediately after at a specified time following an inserted or adjusted
completion of the recording sessions, each taking event marker. All frames are then viewed as an
into consideration both time and space relation- animated movie, the animation speed adjusted by
ships of manometric data. Surface plots are three- the investigator (Figs. 8.1 and 8.2) [22].
dimensional representations examined from On a theoretical level, HRM provides advan-
different elevations or perspectives; contour plots tages over conventional techniques for the assess-
represent three-dimensional data in a single ment of esophageal function. One of the most
“overhead” perspective as is commonly used to important advantages of HRM is that it makes
display geographic or weather data; and axial diagnostic esophageal manometry easier and
transformations represent data at a single time quicker to perform. It takes away the need for a
across all of the recording channels, the dimen- pull-through and precise positioning of the mano-
sion of time being represented by an animation of metric catheter with respect to the LES.
the data frames. In all cases, the initial step Manometry can thus simply be performed by a
involves alignment of the manometric data on a lab technician or nurse, and only limited experi-
planar surface [22]. ence in esophageal manometry is required. The
The surface plots are created by exporting three pattern of esophageal peristalsis and sphincter
dimensional data sets to a program specifically activity defines whether esophageal motor activ-
designed for geographic mapping. The developed ity is normal or abnormal. The intra-bolus pres-
system creates x, y, z data sets for specified time sure and esophago-gastric pressure gradient
intervals following designated event markers define whether or not this activity is consistent
inserted during analysis. For these data sets, x rep- with effective function. On a practical level,
resents the recording site position on the catheter HRM makes it easy to acquire good quality pres-
in cm, y the time after the event marker in seconds, sure measurements from the esophagus, facili-
and z the pressure amplitude at that time and loca- tates positioning of the catheter and removes the
tion in mmHg. In creating surface plots, a grid of need for a pull-through procedure. Moreover spa-
data is first established, the gridline interval being tiotemporal plots of pressure information make it
determined by the investigator for both the x and y easy to identify normal and abnormal patterns of
directions. For the purposes of esophageal plot- esophageal motility [15].
ting, gridlines are usually positioned at 0.2 cm and
0.2-s intervals. The z value (pressure amplitude) is
interpolated at each grid intersection using avail- Clinical Use of High Resolution
able neighboring data for establishing the most Manometry
appropriate value. Resultant plots can be tilted for-
ward or rotated as required to best visualize the The advantages of HRM have been described in
three-dimensional data [22]. Contour plots repre- a series of recent publications [24]. Closely
sent an overhead perspective of surface plots, each spaced pressure channels provide detailed pres-
contour ring encircling amplitudes of equal or sure information that reveals the segmental
greater value than that specified on the color leg- nature of esophageal peristalsis. This is impor-
end. A series of concentric rings indicates a tant because motor abnormalities can be limited
regional pressure peak on the plot. In the devel- to a short segment of the esophagus and will be
oped system the plot baseline can be shifted as missed by pressure sensors spaced too far apart
8 Esophageal Manometry 83

Fig. 8.1 High resolution manometry. (a) Tracings are is performed, and colors are applied to pressure levels
aligned on a planar surface so that spatial relationships of according to a scale. (c) Overhead “contour maps” reveal
pressure data between recording sensors can be estab- the segmental nature of esophageal peristalsis
lished. (b) Interpolation of pressure data between sensors

[25, 26]. HRM increases the accuracy by which malities per se [27]. HRM identifies patients
bolus transport can be predicted from manom- with poor coordination between the proximal
etry [25]. This is significant because abnormal and mid-esophagus (wide “transition zone”),
bolus transport is a more important cause of focal hypotensive contractions or focal spasm
esophageal symptoms than manometric abnor- that would be missed by conventional manometry.
84 R. Buonavolontà et al.

Fig. 8.2 A complete peristaltic chain is seen in this amplitudes represented by the isobaric contour regions are
image. The segmental pressure architecture resembles shown in the color legend (in mmHg above gastric base-
what is seen in the healthy adult. The three intersegmental line pressure; pressures below the first isobaric contour
troughs are indicated on the figure, and the pressure are shown in dark blue)

Crucially, HRM can distinguish between abnor- motility disorders, while the topographical
malities that disturb bolus transport from abnor- method correctly identified all patients with
malities that have no effect on function (i.e., achalasia within the group with aperistalsis.
improves sensitivity and specificity of mano- They concluded that the topographical methods
metric investigation) [25]. The measurement of are more accurate than traditional techniques in
pressure gradients within the esophageal body diagnosing the type of severe motor dysfunc-
and across the gastro-esophageal junction (GEJ) tion and provide additional information impor-
provides an objective assessment of the forces tant in the clinical practice of esophageal
that direct bolus transport [28]. The clinical manometry [30].
importance of this is illustrated by the finding Published case series supply vivid examples
that the pressure gradient across the GEJ has of clinically important pathology detected by
higher accuracy for the diagnosis of achalasia HRM that was not provided (or not properly
than conventional measurements of sphincter appreciated) by conventional investigation:
relaxation (Figure 8.3) [29]. HRM has been 1. The loss of coordination (wide “transition
shown to increase diagnostic accuracy. In a zone”) between the proximal (striated) and
group of 212 unselected adult patients, Clouse mid-distal (smooth muscle) esophagus.
et al. reported manometric disagreement in 12% 2. Focal esophageal spasm limited to the mid-
between HRM and conventional manometry. esophagus.
Compared against “final diagnosis” six months 3. Detection of an abnormal pressure gradient
after the investigation, conventional manometry (i.e., resistance to flow) localizes pathology
failed to identify several patients with achalasia within the pharynx and UES (e.g., cricopha-
and other causes of hypotensive and aperistaltic ryngeal bar) [31].
8 Esophageal Manometry 85

Fig. 8.3 Peristaltic segments are absent in this child with achalasia. The peristaltic chain is replaced by isobaric con-
tour stripes spanning the esophageal body

4. Functional (e.g., achalasia) resistance to bolus mately diagnosed as having achalasia [32]. The
transport across the GEJ can be measured and first and second pressure troughs were similarly
pseudo-relaxation of the LES in vigorous distributed across esophageal length in each age
achalasia is clearly seen. group, but the third trough was located propor-
5. Structural resistance to bolus transport caused tionately less closely to the upper margin of the
by peptic stricture, extrinsic compression can resting LES in the neonates compared with
be identified on HRM. This ability to differen- infants/toddlers or children [32]. The first pres-
tiate the functional and structural anatomy of sure segment was more consistently present in
the GEJ greatly improves the ability to iden- children than in the other two age groups, and the
tify problems post-fundoplication [25]. percentage of swallows with the third pressure
One important observation made in adults that trough was decreased in neonates compared with
accentuates the value of HRM is that esophageal children. Consequently, completely formed peri-
peristalsis is comprised a specific chain of staltic chains were less commonly observed in
sequential pressure segments. These segments, the neonates, but the number of subjects was too
one in the striated-muscle region and two in the small to confirm that this was a clinically mean-
smooth-muscle region, appear as concentrated ingful finding [32]. No differences were found in
pressure loci separated from each other by lower the presence or distribution of the pressure seg-
amplitude pressure troughs on the three-dimen- ments within the esophageal body in subjects
sional maps [26, 32–35]. who had symptoms ultimately attributed to
Staiano et al. reported that the same chain of esophageal disease or who had other explana-
pressure segments identified previously in adults tions for the presenting complaints.
was recognized in every child with the exception Staiano et al. have recently demonstrated in an
of seven with aperistalsis, six of whom were ulti- HRM study of healthy preterm and term neonates
86 R. Buonavolontà et al.

that maturation of the peristaltic chain continues the presentation or manifestations of GERD in
to occur through late gestation and beyond term infants [36].
birth. The same segmental architecture of peri- Recently, Goldani et al. have illustrated the
stalsis was observed in term and preterm neonates use of HRM in a pediatric age group while using
as reported previously in children and adults, and a standardized protocol and analytical method.
no additional pressure segments or troughs were Despite the inherent limitations of the pediatric
identified by subjective review of the maps. It population, the authors introduced a new proto-
was suggested that maturation may continue col in unsedated children in the context of a clini-
through the infant/toddler period such that pres- cal setting, moving from research into clinical
ence of the complete peristaltic chain at rates application. The ability to analyze data using spa-
matching the adult pattern only becomes most tiotemporal plots normalized to gastric baseline
evident during childhood years [36]. pressure eliminates a great deal of motion arti-
Although the three contraction segments could facts, which previously required many children
be identified in each age subgroup (neonates, to be sedated for the procedure [38]. The addi-
infants/toddlers, children), the percentage of tional use of solid swallow has been described in
complete peristaltic chains appeared reduced in adults to diagnose esophageal spasm in patients
the very small number of neonates studied. The with dysphagia who underwent normal conven-
segmental architecture was distinctive for each tional manometry [39]. Goldani et al. were the
infant such that identifying peristaltic sequences first to describe the usefulness of solid swallows
was simple using high-resolution manometric in pediatric patients. Further studies are needed
techniques. The second and third segments over- to determine normal patterns of esophageal solid
lapped in the distal esophagus as they do in adults bolus transit in children, given the finding that
[23] such that part of the segment would extend healthy adults may need more than one swallow
into the neighboring region, yet a set of concen- to clear solid boluses from the esophagus, and
tric isobaric contour lines focused on the region that subjects have poor perception of whether
(the defining characteristics of a segment) was such boluses cleared the esophagus on any given
absent. The first and third segments were present swallow [40].
in ³50% of swallows in very few of the preterm Goldani et al. introduced the new parameter
neonates and in a significantly larger proportion DCIa, which may be useful for the assessment of
of full-term neonates. In contrast, the second seg- hypotensive peristalsis in patients with peristaltic
ment was well developed in ³50% of swallows in dysfunction. On the basis of all the evidence pre-
all preterm and full-term neonates, even in the sented above, we advocate that children should
youngest of studied subjects [36]. These findings ideally not be sedated for HRM and should adhere
indicate that the second segment develops early to the following protocol: (1) identify LES using
and is most consistently present, even in preterm standard manometry tracing if necessary; (2) run
neonates. This segment may have particular value a baseline recording of LES pressure, allowing
in esophageal clearance [37], its early develop- for an initial 3 min “ settling down ” period. Once
ment, thus, being of teleologic importance [36]. all relevant structures are identified; (3) adminis-
In addition, the authors demonstrated that ter (a) wet swallows—ten swallows at a minimum
although all the segments can be identified in of 20 s intervals of 0.5–5.0 ml, aiming for the
infants as young as 27 weeks of gestational age at maximal tolerated volume, 5 ml for those older
the time of examination, the consistency of their than 5 years of age, 2 ml for those under 5 years,
presence continues to increase through the nor- 0.5–1 ml for infants, and consider wet swallows
mal gestational period. At full term, only 55% of unsafe in patients with oropharyngeal dysphagia,
swallows have a complete segmental chain, indi- (b) check MRS offering about 100 ml of liquid by
cating that further development occurs in early means of a straw or a bottle (increases sensitivity
infancy. These results support a potential role of to LES dysfunction, e.g., intrabolus pressure is
inadequate esophageal body motor function in high in achalasia), (c) consider solid swallows if
8 Esophageal Manometry 87

the patient has symptoms triggered by the con- adults, seems to be an uncommon mechanism in
sumption of solid food (increases diagnostic sen- NIC with undetectable LES [51], but no data exist
sitivity and clinical significance of manometric regarding the use of HRM in NIC.
findings), preferably test the triggering solid food Finally, HRM has facilitated in children the
or at least one slice of toast in subsequent amounts routine measurement and analysis of physiologi-
of 2 × 3 cm in size. This protocol is adapted from cal parameters not normally appreciated during a
what is recommended in adults [15] and is conventional manometric evaluation. Although
expected to fit into the pediatric age. Conventional HRM study protocols and normative data are
analytical methods and the new DCIa variable well established in adults [15, 38, 52], pediatric
may be useful to further clarify paradigms regard- data are sparse. HRM is simple to use and easy to
ing the pathophysiology of motility abnormali- learn for those with a basic knowledge of conven-
ties and consequently improve the diagnosis of tional manometry. No sleeve sensor is required
pediatric esophageal motility disorders [40]. (an electronic “virtual-sleeve” provides an identi-
Esophageal dysmotility is frequent in children cal recording if required) and it has several advan-
suffering from esophageal atresia (EA) and tra- tages over conventional esophageal manometry
cheo-esophageal fistula and frequently is associ- [25]. HRM may prove to have clinical advantages
ated with gastroesophageal reflux (GER). The in pediatric patients as it has in adults, but further
incidence of GER varies from 41% based on proof of its usefulness in these subjects will be
symptoms only [17] to 68% measured by pH mon- required. Current limitations of HRM in pediat-
itor, 72% by barium swallow, and 65% by scin- rics relate largely to the pneumohydraulic perfu-
tiscan [41]. The dysmotility may be congenital. sion of a catheter having multiple microlumina
Cheng et al. reported a Chinese boy with achala- and the need for fastidious maintenance of this
sia, identified by the esophageal conventional system to ensure accurate recordings. Recent
manometry, associated with EA [42]. In adults, development of a 36-sensor solid state catheter
Dutta et al. reported that the pressure and contrac- having circumferential pressure transducers
tility profile of the esophagus was abnormal in the embedded along its length has eliminated water
majority of patients, even in the absence of symp- perfusion, allows sampling of the entire esopha-
toms [43]. In children, no data exist yet regarding gus without catheter repositioning, and has
the use of HRM in children treated for EA. simplified HRM in adults [32].
Gastroesophageal reflux, often severe and with
respiratory complications, occurs with increased
frequency among children with psychomotor retar-
dation. It has been reported that GER occurs in up to
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 Antroduodenal Manometry
9
Osvaldo Borrelli, Valentina Giorgio,
and Nikhil Thapar

gation commonly performed in adults and

Introduction children for definitive clinical purposes. A sub-
stantial development has been the ability of the
Antroduodenal manometry (ADM) is a diagnostic recording equipment to digitize on line mano-
tool that provides both qualitative and quantita- metric recordings so that the latter can be easily
tive assessment of foregut motor function by analyzed by computer programs. Although the
recording intraluminal pressure changes within test is still performed in highly specialized
the gastric antrum and proximal small intestine. motility centers, ADM has provided an improved
Specifically, such pressure readings provide a understanding of the pathophysiology of neuro-
measure of coordination and contractile acti- muscular disorder of the stomach and small
vity of the foregut. Since first manometric intestine.
recordings, methodological improvements have
steadily occurred, progressing ADM manometry
from a purely research technique to an investi- Normal Motility

In healthy individuals the primary function of the

O. Borrelli, M.D., Ph.D. (*)
small intestine is the absorption of nutrients, and
Division of Neurogastroenterology & Motility,
Department of Paediatric Gastroenterology, ICH the motor pattern is programmed to promote this
University College of London, Great Ormond Street function by assuring a timely propulsion of lumi-
Hospital for Children, London, UK nal contents and avoiding stasis or excessively
e-mail: [email protected]
rapid transit of luminal contents. Under physio-
V. Giorgio logic conditions, the motor activity of the antrum
Division of Neurogastroenterology & Motility,
and the small intestine is characterized by pat-
Department of Paediatric Gastroenterology,
Great Ormond Street Hospital for Children, terns of organized motor activity in the fasting
London, UK and postprandial periods [1].
N. Thapar, B.Sc.(hon), B.M.(hon), M.R.C.P., Fasting or interdigestive gastrointestinal motil-
M.R.C.P.C.H., Ph.D. ity comprises a sequence of three main compo-
Gastroenterology Unit, University College London, nents or phases with a combined total average
Institute of Child Health, Division of
duration of about 100 min (50–180 min), which
Neurogastroenterology and Motility,
London, UK together constitute the so-called migrating motor
complex (MMC) (Fig. 9.1) [2, 3]. Phase III of the
Department of Paediatric Gastroenterology,
Great Ormond Street Hospital for Children, MMC, the most distinctive and well-studied
London, UK pattern of gastrointestinal motor activity, is a

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 91

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_9, © Springer Science+Business Media New York 2013
92 O. Borrelli et al.

Fig. 9.1 Normal Migrating Motor Complex recorded in a the duodenum. A period of quiescence (phase I) follows
child with recurrent vomiting. All three phases (Phase I, phase III; the latter is preceded by intermittent phasic
Phase II and Phase III) are well represented. The phase III activity (phase II)
is seen starting in the antrum and migrating aborally along

characteristic burst of high amplitude rhythmic tal ileum [5]. The duration of phase III progres-
contractions of at least 2 min duration occurring sively increases in the aboral direction ranging
at the maximum frequency allowed by the under- between 2 and 5 min in the duodenum and
lying myoelectrical rhythm for a given segment 10–20 min the distal ileum [2, 6–8]. Conversely,
of the gastrointestinal tract [4]. For instance in the propagation velocity of phase III decreases
the antrum the contractions occur at a rate of 2–3 from 5 to 10 cm/min in the proximal small bowel
per minute, whereas in the proximal small bowel to about 0.5–1 cm/min in the distal ileum [1, 2,
this increases to 10–14 per minute. In children, 7]. The average amplitude of single contractions
phase III, may begin anywhere from the stomach is at least 40 mmHg in the antrum and 20 mmHg
to the ileum, but in about 70% it starts in the gas- in the small intestine. Finally, the mean interval
tric antrum, 18% in the proximal duodenum, 10% between episodes of phase III varies with age. It
in the distal duodenum, and 1% in the proximal ranges between 25 and 45 min in newborn,
jejunum [2, 3]. Migration is a basic requisite of approximately 60 min in children less than
phase III activity, which usually propagates abo- 2 years, and 85–110 min in adolescent and adults
rally over various lengths of the small intestine; [3, 8–12]. Significant variation occurs between
however, only 50% of these propagate beyond subjects and within the same individuals [2, 13, 14].
the middle jejunum, and only 10% reach the dis- Phase III activity is usually succeeded by
9 Antroduodenal Manometry 93

quiescence or phase I, which is defined as less prandial contractions usually propagate over a
than three pressure waves every 10 min [15]. shorter distance than those of phase III, and
Phase I is followed by a period (Phase II) of almost 80% of them propagate less than 2 cm
irregular contractions (more than three pressure [24]. These minute movement of postprandial
waves every 10 min), which represent in the small contractions are devoted to mixing and grinding
intestine about 70–80% of the whole cycle. of the nutrient chyme, stirring, spreading, and
Phases I and III of the MMC require an intact exposing the intestinal contents to a larger sur-
enteric nervous system (ENS) with modulation face, and thus promoting its optimal absorption.
by the central nervous system and gastrointesti- Moreover, minute aboral transport is also
nal regulatory peptides [5, 16, 17]. For instance, sufficient in preventing bacterial colonization.
endogenous motilin blood concentration peaks Thus, normal postprandial motor activity is a
during late phase II and phase III of the MMC compromise between optimal absorption and
cycle [18, 19]. However, motilin is not required adequate clearance. The postprandial period
for initiation or aboral migration of Phase III in lasts from the time of the evident increase in fre-
the small bowel, but seems to be involved in the quency and/or amplitude of contractions occur-
antral participation of phase III [20, 21]. ring after the introduction of a meal to the onset
Conversely, Phase II activity seems to rely more of the following phase III, and is affected by the
on extrinsic modulation of CNS, given it is sup- amount of calories as well as by the composi-
pressed during sleep and abolished after vago- tion of the meal [25]. For instance, fats induce a
tomy [5, 16]. The importance of MMC is more prolonged fed pattern than protein and
highlighted by the fact that its absence is associ- carbohydrates. Extrinsic neural control is a pre-
ated with bacterial overgrowth [1]. Indeed, the requisite for a normal postprandial pattern, since
pulsatile flow ahead of phase III is of clinical persisting MMC activity after meal intake has
importance for clearing secretion, debris and been reported after vagal cooling [26, 27].
microbes during the interdigestive period, and Neural reflexes, endocrine and paracrine mecha-
colonization of the foregut with gram-negative nisms also play also a key role [17]. In small
bacteria is observed when phase III is impaired or infants less 32 week’s post-conceptional age,
absent [22]. For this reason phase III has been who usually receive only small volumes of
termed the “gastrointestinal housekeeper.” MMC enteral feeding, the fasting pattern is not dis-
cycles do not occur in the intestine of premature rupted by either the bolus or continuous feed-
infants age less than 34 weeks, which instead ing. Between 31 and 35 week’s post-conceptional
show a pattern of clustered phasic contractions age, the larger volumes of enteral feeding induce
lasting between 1 and 20 min and occurring every a degree of postprandial activity, but it is only
4–35 min. As post-conceptional age increases, over 35 week’s post-conceptional age that a dis-
this activity becomes longer and the frequency of ruption of cyclical activity can be seen with
occurrences decreases. By term, well-defined feeds [10].
cyclical fasting motor activity is present with dis- The presence of other distinct motility pat-
tinct phase I, II and III activity, with the latter terns has been identified in both healthy individ-
showing less variability in term of length and ual and patients. Discrete clustered contractions
intervals [11, 23]. (DCCs) or cluster of contractions (CCs) are
Following the ingestion of food, the MMC defined as the presence of 3–10 pressure waves
cycle is interrupted and replaced by a pattern of of slow frequency, each having a significantly
regular antral contractions associated with higher amplitude and duration compared to iso-
apparently uncoordinated contractions of vari- lated individual contractions [15, 28]. They
able amplitude in the small intestine, termed propagate aborally for less than 30 cm at rate of
“postprandial” or “fed” pattern (Fig. 9.2) [5, 16, 1–2 cm/s and usually show a rhythmic pattern
24]. These phasic contractions also show vari- with regular intervals of quiescence lasting at
able frequency and propagation. Typical post- least 30 s (Fig. 9.3) [3]. DCC are usually recorded
94 O. Borrelli et al.

Fig. 9.2 Normal postprandial activity characterized by irregular but persistent phasic activity. Note the normal antral
activity during the fed state

during phase II, although are occasionally also ing contractions or prolonged intestinal contrac-
seen during the postprandial period (phase III- tions are pressure waves of prolonged duration
like activity) [3, 14, 28, 29]. Postprandially, clus- (>20 s) and large amplitude more than 30 mmHg.
ters of contractions seem to occur in association In healthy individuals they occur primarily in the
with mechanical obstruction or intestinal pseudo- distal ileum and propagate uninterruptedly and
obstruction, and they are characteristically non- rapidly with highly propulsive force over long
propagated [30]. Bursts of contractions are distance in aboral direction in the small intestine
defined as sequences of intense irregular pres- and colon [33, 34]. “r” waves are simultaneous
sure waves, which do not correspond to the increases in pressure throughout all the record-
definition for phase III or for DCC (Fig. 9.4). ing sensors, usually associated with regurgita-
They can be clearly distinguished from back- tion or frank emesis, and represent the manometry
ground pressure wave activity during both phase correlate of the abdominal wall contraction in
II and the postprandial period. Short bursts of patients with rumination syndrome.
propagating contractions have been described in
healthy individuals, whereas sustained bursts of
contractions confined to one limited segment Technical Aspects
(non-propagated) lasting for a period of >30 min
and associated with tonic intermittent baseline Manometry is by nature a highly technical evalu-
pressure elevation are considered an abnormal ation. When knowledgeably used, manometric
neuropathic pattern [21, 31, 32]. Giant migrat- examination provides an accurate description of
9 Antroduodenal Manometry 95

Fig. 9.3 Discrete cluster of contractions (DCCs) (arrows) presence of 3–10 pressure waves of slow frequency, which
recorded in the duodenum and jejunum during the post- can propagate aborally for less than 30 cm
prandial period in a normal child. DCCs are defined as the

intestinal neuromuscular function but only if Low Compliance Perfused

physical principles and equipment characteristics Manometric System
are respected. In general, manometric data are
reliable only if the methodology used to acquire The water infusion system includes a catheter
them is accurate. composed of small capillary tubes, a low compli-
A manometric apparatus set-up consists of a ance hydraulic capillary infusion pump and exter-
pressure sensor and transducer combination that nal transducers. In adults, the small capillary tubes
detects the gastric and small intestine pressure usually have an internal diameter of approximately
complex and transduces it into an electrical sig- 0.4–0.8 mm and an opening or port at a known
nal, and a recording device to amplify, record point along the length of the catheter. In adults, the
and store that electrical signal. The pressure most commonly used catheters have an overall
sensor/transducer components of a manometric diameter of 4.5 mm [35]. In children in order to
assembly function as a matched pair and are reduce the diameter of the catheter smaller capil-
available in two general designs: either water lary tubes (with internal diameters of 0.35 mm) are
perfused catheters connected to a pneumohy- utilized; moreover the study is performed at lower
draulic perfusion pump and to volume displace- infusion rates [36]. The manometric probes are
ment transducers, or strain gauge transducers usually tailored to the child’s size, and the distance
with solid state circuitry [35]. between the recording ports should be decided
96 O. Borrelli et al.

Fig. 9.4 Short burst of contractions (arrow) recorded in ground pressure wave activity during phase II. The record-
the proximal jejunum during phase II lasting more than ing was performed with a 20-channel manometric catheter
2 min. These can be clearly distinguished from back- (side holes 2.5 cm apart)

based on the purpose of the investigation [35]. the water filled tubes that is transmitted to the
Since one antral recording site is insufficient to external transducers. High-fidelity recordings of
provide an accurate recording of antral motor intraluminal pressure are achieved by infusion
activity due to its continuous forward and back- rates from 0.1 to 0.4 mL/min, even if they may
ward movement, the manometric catheter should provide an unacceptable amount of water to small
have at least five recording ports with the two most babies or premature infants. In order to overcome
proximal side holes spaced 0.5–1.5 cm apart posi- this problem perfusion rates as low as 0.02 mL/
tioned 1 cm proximal to the pylorus to provide min have been successfully used [37]. Furthermore,
measurements of antral activity, while the remain- for prolonged studies the use of a balanced saline
ing side holes positioned in the small intestine and solution should be considered.
spaced 2.5–5 cm apart in infants and toddlers and A device activating the pressure transducers,
5–10 cm apart in children and adolescents [35, storing their signals, and displaying the latter in
36]. Each capillary tube is connected to an external such a way to allow immediate interpretation and
transducer. The infusion pump, a simple and essen- analysis is needed. The personal computer has
tial device for stationary manometry, perfuses the become the heart of any manometry system. It
capillary tubes providing a constant flow rate with- interfaces with purposed-designed electronic mod-
out increasing the compliance of the manometric ules that activate and receive signals from pressure
system. When a catheter port is occluded (e.g., by transducers, whereas commercially available soft-
a muscular contraction), there is a pressure rise in ware programs are essential for acquiring,
9 Antroduodenal Manometry 97

displaying and storing pressure recording data. [39]. It has been calculated that for a given num-
Actually, the technical adequacy of different com- ber of pressure recording points on a recording
mercially available device recording systems is assembly, solid-state catheters are 20 times more
quite comparable. Probably the dominant consid- expensive than a perfused manometric assembly.
eration that should determine the choice of a sys- In the last years the improvement in miniaturiz-
tem is the level of technical assistance and the ing transducers has allowed the production of
training available locally to support the user. solid-state catheter with up to 36 recording chan-
The required characteristics of the manomet- nels with an external diameter comparable to that
ric recording apparatus are defined by the magni- of the water perfused manometric catheter used
tude of the pressure to be recorded and the in small infants and children. However, there is
frequency content and waveform of foregut con- still a very little experience in pediatric patients.
tractile waves. It has been shown that the fre-
quency response of manometric systems required
to reproduce foregut pressure waves with 98% High Resolution Manometry
accuracy is of 0–4 Hz (maximal recordable dP/
dt: 300 mmHg/s). Most of commercially avail- Manometric techniques have improved in a step-
able manometric systems can provide a pressure wise fashion from few pressure recording chan-
rise rate of 300–400 mmHg/s, which is adequate nels to the development of high-resolution
for faithful recordings in the gastric antrum and manometry (HRM), which is a relatively recent
small intestine. technique that enables more detailed definition,
both in term of space and time, of pressure
profiles along segments of the gut [40]. This has
Solid-State Manometric System been achieved by a combination of new mano-
metric assemblies allowing intraluminal pressure
The main alternative to the water-perfused mano- to be recorded from up to 72 pressure sensors
metric system is a manometric assembly incorpo- spaced less than 2 cm. At the same time, advances
rating strain gauge sensors and solid state in computer processing allow pressure data to be
electronic elements [38]. In this system, the presented in real time as a compact, visually intu-
manometric probe contains miniature strain itive “spatiotemporal plot” of gastric and small
gauge pressure transducers built into the catheter intestine pressure activity. HRM recordings may
at a fixed location along its length, so that pres- reveal the complex functional anatomy of the
sure changes directly influence the transducers to foregut, and recent studies suggest that spatiotem-
generate electrical output signals. The probe can poral plots may provide objective measurements
be plugged into a small box containing the elec- of the intraluminal pressure profile in the small
tronics, which is then connected to the recording intestine, and improve the sensitivity and
device and to a personal computer. In the ambula- specificity of manometric recording by removing
tory system the recording devices are blind and much of the ambiguity usually encountered using
need to be connected to a personal computer with line plot analysis [41]. However, further efforts to
the appropriate software to display and analyze define the role of HRM in the diagnosis and man-
the recording. The main advantage of using solid- agement of neuromuscular disorders are needed.
state catheters is that the pressures are recorded
directly from the area and are unrelated to the
relative position of the subject; therefore mano- Methodological Aspects
metric studies may also be performed with the
subjects in the upright position. This, and the fact Preparation of the Patient
that it does not require water perfusion, makes
solid-state catheters suitable for long-term ambu- Before starting the ADM manometric recording
latory monitoring of the intraluminal pressure it is important to assess patient information with
98 O. Borrelli et al.

regard to medical history, symptoms, medication, also be placed through an existing gastrostomy,
and allergies. Any drug with a known effect on or jejunostomy. The manometric probe should be
gastrointestinal motility should be discontinued positioned deep enough in the small intestine in
at least 72 h before the study. order to avoid its falling back into the stomach as
It is important to emphasize that ADM a consequence of postprandial gastric distension
manometry in children is performed in a different or duodenal contraction. The tube placement can
fashion to that in adults due to differences in size, be performed either fluoroscopically or endo-
cooperation, and neurological and developmental scopically [45]. Under fluoroscopy the probe
maturation. Performing manometric studies in placement usually requires high skill to pass the
children require great patience from the operator. pyloric region, which may be easier with a firm
The parents should be present during the testing probe rather than a soft, flexible one. The former,
in order to settle the child, and to provide the however, is more difficult to advance beyond the
child with a model of cooperative behavior with duodenal bulb due to its acute angle. Moreover,
the physician. The cooperation can also be hard probe may cause great discomfort during
improved by the use of age-appropriate relax- the recording time especially for young children.
ation techniques. For example, infants may relax The addition of a weighted probe tip may facili-
with swaddling and the use of a pacifier. Having tate the placement as it utilizes gravity in addi-
a favorite toy can comfort toddlers. School age tion. The probe can be also advanced through the
and older children benefit when equipment is pylorus using an endoscope and biopsy forceps,
shown and explained prior to the procedure. taking care to use as little air as possible to
ADM manometry is best performed without insufflate the bowel, given over-inflation may
sedation [36]. However, in many children seda- affect gastrointestinal motility and provoke a
tion is necessary, and midazolam has been shown backward movement of the manometric probe. In
to be effective with no or minimal influence on some center the manometric recording is per-
pressure measurement [42]. It is advisable to wait formed the day after the tube placement and fol-
for complete child recovery from any drug effect lowing check radiology to ascertain catheter
before starting the motility tests. Finally, before position with correction if necessary.
starting the procedure it is important to obtain During the manometric recording using a
and verify signed informed consent and neces- water-perfused system, the patients usually main-
sary to check that the fasting period has been of tain the same position (supine), whereas using
adequate duration. In healthy children an over- portable solid state equipment the patients are
night fast is enough, whereas in infants at least encouraged to perform daily activities when pos-
4 h are necessary to avoid nausea, vomiting and sible [35]. Ambulatory manometry is usually per-
aspiration. In children on parenteral nutrition, the formed for 24 h, whereas for stationary
latter should be stopped 12 h before the studies, manometry, recording must be carried out until a
due to the effect of nutrients on hormones, which phase III and/or clear-cut abnormalities are
may affect the intestinal motility [17]. Similarly, recorded. However, it is generally advisable to
blood glucose levels should be carefully assessed, perform a fasting recording for at least 4–6 h (one
since hyperglycemia inhibits gastric emptying or two MMCs), and postpradial recording for at
and reduce the occurrence of phase III [43, 44]. least 90 min [36]. The type and the size of meal
should be adjusted according to patient’s age and
preference. In older children the test meal should
Study Procedure be at least 400 kcal, in order to ensure an ade-
quate postprandial response in the small intestine
The manometric catheter can be placed either lasting at least 90–120 min [25, 36]. In younger
nasally or orally, but there is broad consensus that children the test meal should provide at least
studies are better tolerated when the catheter is 10 kcal/kg. The meal should be balanced with at
introduced through the nose. The catheter can least 30% of calories as fat calories. However, in
9 Antroduodenal Manometry 99

Table 9.1 Manometric features associated with gastroin- removal and algorithms for detection of propa-
testinal motility disorders gated activity offer an improved degree of objec-
Interdigestive or fasting period tivity in the analysis of pressure tracing and can
• Absence of phase III facilitate the quantitative analysis of relevant
• Short intervals between phase III parameters [48].
• Abnormal phase III A normal motility pattern is defined as the
– Stationary presence of at least one MMC per 24 h of record-
– Retrograde
ing (it has been shown that almost 95% of normal
• Non migrating burst of contraction
• Sustained simultaneous cluster of contractions
children have phase III within 4 h fasting study),
• Low amplitude contraction conversion to the fed pattern without return of
Postprandial or fed period MMC for at least 2 h after a 400-kcal meal, distal
• Failure to switch to postprandial period postprandial contractility (MI per 2 h >13.67),
• Postprandial hypomotility small intestinal contraction >20 mmHg, and
– Low frequency of contraction absence of abnormal findings described in
– Low amplitude of contraction Table 9.1 [49]. Therefore, the presence and char-
• Non migrating cluster of contraction acteristics of the MMC and its response to nutri-
ents is used as a marker of enteric neuromuscular
function.
Based on the findings of abnormal manometric
some cases is impossible to give predetermined features different clinic-pathophysiological cate-
volume to a patient, e.g., one with severe gastro- gories of abnormalities can be recognized [35, 49].
intestinal dysmotility and inability to tolerate oral In patients with enteric neuropathy the motor
or enteral feeding. Finally, if no phase III is activity is typically disorganized and/or uncoordi-
recorded during fasting, a drug stimulation test nated. The most compelling finding is represented
should be performed using erythromycin (1 mg/ by the absence of a MMC during a sufficient
kg over a period of 30 min), which is able to recording time (ideally 24 h); however, this sce-
induce a gastric phase III and allows assessment nario is a rare event in patient with enteric neu-
of its migration in the small intestine [46, 47]. ropathy. More common findings include the
presence of retrograde or uncoordinated phase III
activity (Fig. 9.5), increased frequency of phase III
Analysis of Manometric Recording (in adults and older children > 1 MMC cycle per
hour) (Fig. 9.6), presence of non-propagated bursts
Both qualitative and quantitative analysis of the and sustained uncoordinated phasic activity, antral
ADM tracings should be performed. Qualitative hypomotility, inability to establish a fed pattern
analysis includes the recognition of specific after a test meal, and presence of phase III-like
motor patterns as well as the overall characteris- activity in the fed period. In patients with enteric
tics of the fasting period (typical cycling pattern myopathy the normal manometric patterns are usu-
of the MMC, characteristics of phase III activity ally preserved, but the amplitude of contractions in
including the numbers found, migration pattern, both preprandial and postprandial periods do not
mean amplitude, mean peak velocity, and inter- exceed 20 mmHg (Fig. 9.7); however, low ampli-
vals) and fed period (presence of change in motil- tude contractions may also represent a conse-
ity after test meal). Quantitative analysis includes quence of gut dilatation proximal to an obstructive
the calculation of distal antral and duodenal segment. For this reason, the absence of dilated
motility indexes (MI), expressing the contractile loops is a prerequisite for a diagnosis of enteric
activity as the natural logarithm of the area under myopathy. In patients with mechanical obstruc-
the manometric pressure peaks above a threshold tion multiple simultaneous giant contractions as
pressure. Computerized data evaluation, includ- well as the presence of simultaneous DCCs in the
ing wave identification algorithms, artifact postprandial period are frequently reported.
100 O. Borrelli et al.

Fig. 9.5 Abnormal propagation of phase III in a child ing from the antrum (arrow image). The recording was
with chronic intestinal pseudo-obstruction. Note the pres- performed with a 20-channel manometric catheter (side
ence of retrograde contractions in the proximal jejunum holes 2.5 cm apart). The first two channels are localized in
meeting, in the distal duodenum, the activity front migrat- the antrum

In neonates the presence of high amplitude retro- Reference Values

propagated contractions should raise the suspicion
of mechanical obstruction. In children with CNS Before interpreting the recorded data and deciding
abnormalities it has been show an abnormal fre- whether abnormalities of gastric and small intes-
quency and propagation of phase III, increase tine motor activity are present, it should be of
proportion of non-propagated DCCs, antral hypo- pivotal importance to define the limits of normal-
motility, abnormal proportion between periods of ity. Unfortunately, the lack of normal controls is
phase I and II activity, and altered postprandial an important limiting factor for the establishment
pattern duration with the presence of phase III-like of normal motility patterns, making the interpre-
activity [50]. Finally, in adult patients with post- tation of manometric recording data difficult and
vagotomy syndrome the most common manomet- subjective and occasionally leading to over-inter-
ric findings are an increased frequency of MMC, pretation. However, some control data have been
the absence of antral phase III and the presence of published. Although, each center performing
antral hypomotility after test meal, and an altered ADM manometry should have an own set of nor-
postprandial pattern duration with a rapid return of mal values, it is suggested that “normal” ranges
MMC activity. proposed by one group could be used by another
9 Antroduodenal Manometry 101

Fig. 9.6 Short intervals of phase III activity in a child the tonic component within phases III, which are defined
with chronic intestinal pseudo-obstruction. The phase IIIs as an elevation of the baseline more than 10 mmHg for
were separated by intervals of only 10–20 min. Note also longer than 1 min

if the investigation is performed and interpreted motor abnormalities, such as sustained phasic
in the same way. contraction and postprandial simultaneous clus-
ters, is significantly low [51]. Therefore, given
small bowel manometry requires expertise and
Indications dedicated equipment and personnel, it should be
restricted to a limited number of referral centers
Although ADM manometry is well tolerated by with a specific interest in the field.
patients with otherwise undiagnosed gut motility ADM manometry serves to clarify a clinical
disorders unresponsive to conventional therapies diagnosis of abnormal motility or exclude a GI
and whose quality of life is substantially impaired motility disorders. There are only few indications
(by symptom severity and the diagnostic uncer- for the test (Table 9.2). Manometry is indicated in
tainty), it is a rather cumbersome procedure to children with suspected chronic intestinal pseudo-
perform, not always easy to interpret, and practi- obstruction in order to verify the diagnosis, clar-
cally useful in the clinical management of only a ify the pathogenesis and optimize clinical
minority of patients. For instance, it has been management [52]. For instance, the presence of a
shown in children that there is an excellent inter- myopathic pattern is an indicator of a poor
observer agreement for the number of fasting response to enteral feeding, whereas the presence
phase III and their measurement, while the inter- of MMC predicts clinical response to prokinetics
observer agreement for the detection of other therapy and success of enteral feeding [53, 54].
102 O. Borrelli et al.

Fig. 9.7 Manometric tracing in a child with enteric myopathy. Note the low amplitude but normal propagation of the
phase III and the paucity of other contractile activity in the small intestine

Table 9.2 Clinical indication for antroduodenal manometry

1. Clarify the diagnosis in patients with unexplained nausea, vomiting or symptoms suggestive of upper GI
dysmotility
2. Differentiate between neuropathic vs. myopathic gastric or small bowel dysfunction in pts with chronic intestinal
pseudo-obstruction.
3. Identify generalized dysmotility in patients with colonic dysmotility (e.g., chronic constipation), particularly prior
to subtotal colectomy
4. Confirm diagnosis in suspected chronic intestinal pseudo-obstruction syndromes when the diagnosis is unclear on
clinical or radiological grounds
5. Assess for possible mechanical obstruction when clinical features suggest, but radiological studies do not reveal,
obstruction
6. Determine which organs need to be transplanted (isolated vs. multi-visceral transplantation) in patients with
chronic intestinal pseudo-obstruction being considered for intestinal transplantation
7. Confirm a diagnosis of rumination syndrome

Manometric assessment may allow determina- nal motor abnormalities seem to compromise the
tion of the extent of disease (localized or diffuse) postoperative course of the intestinal graft recipi-
and the optimal route for nutritional support (gas- ent. In patients with intractable constipation,
tric, enteric, or parenteral). ADM may be useful ADM manometry should be performed if surgery
in determining the suitability of intestinal trans- is being considered; given patients with small
plantation for children with chronic intestinal bowel dysmotility have generally a poor outcome
pseudo-obstruction [54]. Severe gastric or duode- after the surgery. ADM is also indicated in
9 Antroduodenal Manometry 103

patients with recurrent subocclusive episodes, in 4. Kellow JE, Delvaux M, Azpiroz F, Camilleri M,
order to differentiate a pseudo-obstructive syn- Quigley EM, Thompson DG. Principles of applied
neurogastroenterology: physiology/motility-sensa-
drome from a mechanical obstruction, which is tion. Gut. 1999;45 Suppl 2:17–24.
sometimes overlooked also by an experienced 5. Quigley EM. Gastric and small intestinal motility in
radiologist [55]. Manometry is indicated in the health and disease. Gastroenterol Clin North Am.
investigation of children with severe unexplained 1996;25:113–45.
6. Tomomasa T, Kuroume T, Arai H, Wakabayashi K,
gastrointestinal symptoms, such as vomiting, Itoh Z. Erythromycin induces migrating motor com-
nausea, abdominal distension and abdominal plex in human gastrointestinal tract. Dig Dis Sci.
pain who fail to respond to any therapy, and in 1986;31:157–61.
this context the test helps to differentiate between 7. Lindberg G, Iwarzon M, Stål P, Seensalu R. Digital
ambulatory monitoring of small-bowel motility. Scand
vomiting and rumination [56, 57]. This is cov- J Gastroenterol. 1990;25:216–24.
ered elsewhere in the book. Finally, an entirely 8. Cucchiara S, Bortolotti M, Colombo C, et al. Abnormalities
normal study in children suspected clinically of of gastrointestinal motility in children with nonulcer dys-
having a severe dysmotility syndrome may help pepsia and in children with gastroesophageal reflux dis-
ease. Dig Dis Sci. 1991;36:1066–73.
to redirect the diagnostic effort, and may result in 9. Tomomasa T, Itoh Z, Koizumi T, Kuroume T.
the consideration of other diagnoses such as fab- Nonmigrating rhythmic activity in the stomach and
ricated induced illness (formerly Munchausen’s duodenum of neonates. Biol Neonate. 1985;48:1–9.
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infants. J Pediatr Gastroenterol Nutr.
1992;14:182–6.
Conclusion 11. Ittmann PI, Amarnath R, Berseth CL. Maturation of
antroduodenal motor activity in preterm and term
infants. Dig Dis Sci. 1992;37:14–9.
ADM provides relevant physiological information 12. Piñeiro-Carrero VM, Andres JM, Davis RH, Mathias
on the neuromuscular activity of the foregut and is JR. Abnormal gastroduodenal motility in children and
useful in diagnosing and guiding the management adolescents with recurrent functional abdominal pain.
of enteric neuromuscular disorders. Because of the J Pediatr. 1988;113:820–5.
13. Husebye E, Skar V, Aalen OO, Osnes M. Digital ambu-
complexity in performing and analyzing ADM, it latory manometry of the small intestine in healthy
requires considerable experience and skills that adults. Estimates of variation within and between indi-
may only be available in referral centers with a viduals and statistical management of incomplete
specific interest in the field of GI motility. The MMC periods. Dig Dis Sci. 1990;35:1057–65.
14. Husebye E, Engedal K. The patterns of motility are
development of recording equipment and advanced maintained in the human small intestine throughout
computer analysis that are in progress appear to the process of aging. Scand J Gastroenterol.
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understanding of normal and abnormal foregut 15. Husebye E. The patterns of small bowel motility:
physiology and implications in organic disease and
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16. Sarna SK, Otterson MF. Small intestinal physiology
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 Colonic Manometry
10
Brian P. Regan, Alejandro Flores,
and Carlo Di Lorenzo

Introduction Normal Physiology of Colonic Motility

The main functions of the colon are absorption It has been hypothesized that defecation has two
of water and electrolytes, mixing of contents of phases, the first being an involuntary phase dur-
the colon with distal propulsion, and storage of ing which fecal content is transported to the rec-
fecal waste until a socially appropriate time for tum, followed by a second voluntary phase.
defecation. These functions are achieved through During the voluntary phase, intra-abdominal
slow net distal propulsion, continuous mixing, pressure increases, with descent of the pelvic
and exposure to mucosal surfaces. The process floor and straightening of the anorectal angle.
by which this happens is an organized pattern Rectal pressure then increases, resulting in inter-
with specific actions at different regions of the nal anal sphincter relaxation, followed by expul-
colon. Much is known about in vitro activity on sion of stool when the external anal sphincter
a cellular level of this process; however, there relaxes [1]. Normal colorectal motility involves
are still unanswered questions regarding in vivo the coordinated activity of the muscular struc-
activity, in part due to the lack of a suitable ani- tures, the enteric nervous system, the interstitial
mal model. For many years studies in human cells of Cajal (ICC) and the autonomic nervous
subjects were also limited due to the difficulty to system made up of the sympathetic and parasym-
place manometry catheters into the proximal pathetic nervous systems.
colon. Colonic manometry is the most direct The neural input controlling the function of the
means of assessing colonic motility, and the cur- colon and rectum includes the enteric nervous
rent state of knowledge of this diagnostic tech- system, the autonomic, composed of sympathetic
nique is shared in this chapter. and parasympathetic nervous system, and the
extrinsic spinal sensory nerves. The enteric ner-
vous system affects the majority of the gut neural
function. The autonomic nervous system impacts
B.P. Regan, D.O. (*) • A. Flores, M.D. the gut function primarily through mediation of
Pediatric Gastroenterology, Tufts Medical Center, the enteric nervous system. The myenteric plexus
800 Washington Street, Boston 02111, USA
e-mail: [email protected]
controls the motor function with innervation to
the circular muscle layers and the taeniated longi-
C. Di Lorenzo, M.D.
Division of Pediatric Gastroenterology, Nationwide
tudinal muscle layers of the colon. Sensory input
Children’s Hospital, The Ohio State University, affecting motility is accomplished via intrinsic
Columbus, OH, USA sensory neurons which are activated by stretch

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 107

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_10, © Springer Science+Business Media New York 2013
108 B.P. Regan et al.

and by muscle tension and via input from chemical Solid state catheters include multiple micro-
and mechanical receptors within the mucosal epi- transducers linked to a flexible, pressure sensi-
thelium, reacting to intraluminal chemical stimuli tive diaphragm. They have been shown to give
[2, 3]. The autonomic nervous system, via the higher readings in the presence of amplitudes
sympathetic nervous systems, directly innervates <100 mmHg and lower reading with ampli-
smooth muscle but large amount of its influence is tudes >100 mmHg. An opposite trend was
indirectly mediated by influences on enteric neu- found for the duration of contractions when
ronal circuits. Norepinephrine acts via alpha-2 compared with the more traditional water per-
receptors causing presynaptic inhibition of enteric fused assembly [7]. Using solid state catheters,
motor reflexes [4]. The parasympathetic nervous the transmitted signals can be recorded by a
system is influenced primary by vagal efferents to portable digital recorder allowing ambulatory
the upper colon. There is little or no vagal effect studies to capture more representative time
beyond in the distal colon where sacral parasym- periods for analysis. Disadvantages include
pathetic influences come into play. The sacral the higher cost and the relative fragility of
parasympathetic pathways are identified as being the transducers.
responsible for the distal colonic activity in defe-
cation [5].
Catheter Placement

How to Perform the Study Placement of colonic catheters constitutes one

of the most challenging portions of the testing
Colonic contractile function in children tradition- in children. In pediatrics, the placement is
ally has been measured using catheters located always done transanally, in a retrograde fash-
within the colonic lumen, with pressure sensitive ion, except in the presence of ostomies which
ports placed along the catheter length. Most pedi- may allow placement of the catheter from the
atric studies have been done using water perfused ostomy in an antegrade fashion into the more
catheters; however, solid state probes are avail- distal colon. Colonoscopic placement requires
able as well. The spacing between recording sites bowel preparation which some studies have
on the catheter is variable but usually ranges suggested may affect basal motor activity [8, 9].
5–15 cm, based upon the age of the child and the Different endoscopic techniques can be used
length of the colon to be studied. Each port is for the placement. A biopsy forceps can be
connected via a separate lumen (channel) to indi- passed through the biopsy channel grasping the
vidual strain gauge pressure transducers allowing manometry catheter via a suture loop placed at
multichannel studies. Perfusion is at a constant the catheter tip. The catheter is advanced along
flow rate and is achieved by use of distilled water with the colonoscope to the desired location,
at constant pressure [6]. Contraction of the the forceps is opened, and the scope is then
colonic wall occludes the manometric ports and slowly retracted suctioning as much air as pos-
impedes the flow of water. Resistance to flow at sible. Recently, it has been suggested that the
each port is measured as pressure changes. The catheter is clipped to the colonic mucosa, mak-
advantages of this system include its simplicity ing it less likely to be dislodged during the
and the relatively inexpensive components. The manometry testing (Figs. 10.1 and 10.2) [10].
catheters are fully autoclavable, allowing easy This can be easily accomplished grabbing the
sterilization. The major disadvantage of this sys- suture loop with a hemostasis clipping device
tem is the need to be linked to an infusion pump that is then deployed when the catheter is
and recording equipment which precludes ambu- released. Once the test is complete, a gentle
latory studies. The amount of water infused dur- pull allows the easy removal of the catheter. An
ing prolonged studies needs to be monitored alternate trans-rectal placement technique uses
carefully especially in small infants in order to a guidewire passed though the biopsy channel,
reduce the risk for water intoxication. and left in place with removal of the colonoscope.
10 Colonic Manometry 109

subjects provide more physiologic data. Most

of the pediatric literature has been generated
using the shorter duration studies with water
perfused catheters. Short duration tests, also
known as provocation studies, are used to
assess response to stimuli such as food, sleep,
and medications. Response to food is the most
powerful physiologic stimulus. After eating,
there is an increase in phasic and tonic motor
activity, known as the gastro-colonic response.
The early response is most intense in the distal
colon. A second peak in motility is seen after
50–110 min lasting up to 3 h. Increased motor
activity following a meal may be regarded as
an indication of the integrity of the neurohu-
moral control of colonic motility. Intraluminal
bisacodyl instillation is typically done after the
postprandial portion of the testing and it
induces high amplitude propagated contrac-
tions (HAPC) in normal individuals [12, 13].
Fig. 10.1 Abdominal radiograph showing a colonic
motility catheter placed with its tip in the ascending colon. Absent response has been associated with
The arrow shows an endoscopic clip holding the catheter colonic inertia and myenteric plexus damage in
in place adults and children [14, 15]. Stimulation with
other drugs, such as neostigmine, is not rou-
The manometry catheter is then advanced over tinely done in children.
this guidewire with fluoroscopic assistance. It Pediatric studies are initiated after the effect
should be emphasized that in children the of the sedation or the anesthesia used to the
endoscopic placement is always done under place the catheter has resolved. Typical proto-
sedation or general anesthesia and the endos- cols in pediatrics start with fasting unstimu-
copies are often very challenging due to the lated motility testing for 1 h. The child is then
presence of very dilated colons, at times poorly offered a large, age-appropriate meal, and post-
cleansed, especially when performed in chil- prandial motility is measured for at least one
dren with years of severe constipation. more hour. Changes with sleep and wake and
Fluoroscopic placement of the catheter in the symptoms experienced by the child are noted if
proximal colon may also be achieved by skilled occurring during the study. Pharmacologic
interventional radiologists, obviating the need provocation is then performed with 0.2 mg/kg
for general anesthesia but exposing the patient of bisacodyl (max 10 mg), infused through the
to more radiation [11]. motility catheter into the most proximal por-
tion of the colon. It is particularly informative
to observe the child’s reaction to the onset of
Study Protocol the urge to defecate associated with the admin-
istration of bisacodyl. At times, the child’s
There is variability in study protocols with no attempts to withhold are finally recognized as
prospective data indicating superiority of any such by the parents once the experienced medi-
specific one. Studies of relatively short dura- cal providers observing the study point out that
tion, approximately 4–8 h, are usually adequate behavior to the parents. Thus, it is imperative
to evaluate response to stimuli; however, more that a nurse or a physician is in the room with
physiologic studies lasting 24 h in ambulating the child undergoing the test at all times.
110 B.P. Regan et al.

Fig. 10.2 Endoscopic image of a colonic motility catheter clipped to a fold in the cecum. The suture material tied to
the tip of the catheter is shown attached to an endoscopic clip

ing an amplitude of less than 50 mmHg. They

Identifiable Motility Patterns occur 45–120 times per 24 h and are typically
5–40 mmHg in amplitude. They occur
High amplitude propagating contraction significantly more during the day than at night,
(Fig. 10.3) constitute a motor pattern found in and much like HAPC, increase following meals
patients with normal colonic motility and are and after waking [20, 21]. The function of LAPC
defined as contractions with an amplitude greater is poorly understood. They are likely to be asso-
than 80 mmHg, have a duration greater than 10 s, ciated with lesser propulsive movement of
and propagate over at least 30 cm, stopping at the intraluminal contents, and have been reported to
junction between sigmoid colon and rectum. be involved with the transport of less viscous
They typically occur following meals, upon colonic contents, such as fluid or gas [22].
awakening, and can be induced by bisacodyl, An increase in colonic motility, often mea-
glycerin and other colonic irritants. They are sured as the “motility index” (a parameter which
more common in younger children [16] and in takes in account both frequency and amplitude
patients who have had a distal colonic resection, of contractions), is expected after ingestion of a
such as in patients after surgery for Hirschsprung’s meal. Such contractions are both tonic and pha-
disease [17]. Recent studies have also shown that sic in nature and may be difficult to quantify
propagated contractions of varied amplitude can especially when the postprandial period is asso-
also be induced by saline infusion and distention ciated with motion artifacts. Evaluation of post-
of the right colon [18, 19]. prandial changes in colonic tone using the
Low amplitude propagating contractions electronic barostat, a frequent feature of colonic
(LAPC), in contrast to HAPC, are defined as hav- manometries performed in adults, is not
10 Colonic Manometry 111

Fig. 10.3 Example of a cluster of six high amplitude propagating contractions (HAPC), indicated with asterisks, asso-
ciated with the urge to defecate

commonly done in the pediatric patient [23]. (b) Guide surgical interventions including
Visual interpretation of the gastrocolonic placement of diverting stoma, resection of a
response produces the maximum variability in portion of the colon, or formation of a
interindividual interpretation of the test. On the conduit for administration of antegrade
other hand, there seems to be great concordance enemas.
among different investigators in the recognition (c) Evaluate the function of the disconnected
of the HAPC pattern. The median agreement colon before possible closure of a divert-
regarding the overall interpretation of the ing ostomy.
colonic manometry in children being either nor- 2. Chronic intestinal pseudo-obstruction
mal or abnormal is 87% [24]. (a) Evaluation if the colon is involved in the
disease.
(b) Help plan which organs to transplant
Indications the Study [23] before a small bowel transplant.
3. Hirschsprung’s disease and repaired imperfo-
1. Intractable constipation rate anus
(a) Assessment of patients with severe con- (a) Clarify the pathophysiology of persistent
stipation, unresponsive to medical ther- symptoms after removal of the agangli-
apy, with no evidence of an evacuation onic segment and repair of anorectal
disorder. malformations.
112 B.P. Regan et al.

positive response to antegrade enema.

Intractable Constipation Retrospective studies have indicated that patients
with HAPC and an intact gastrocolonic response
Most children with constipation suffer from are more likely to do well when receiving ante-
functional constipation, a condition related to grade enemas [33, 34]. The propagated contrac-
a maladaptive response to a painful or fright- tions seem to be essential to propel colonic
ening defecation. A small proportion of chil- contents during antegrade irrigation. However,
dren with constipation have symptoms which the motor response is still not a guarantee for suc-
are severe and unresponsive to aggressive cess, as even some patients with HAPC have had
medical and behavioral therapy. The lack of a poor outcome, indicating that motility pattern is
response can lead to frustration, distrust with important, but there are additional factors, such
the medical team and loss of self-esteem for as compliance with the infusion schedule and
the child. Colonic manometry is indicated for anorectal and pelvic floor function, possibly play-
the evaluation of such children in order to dis- ing a role.
criminate normal colonic motility from abnor-
mal colonic motor function [25, 26 ] which
may be associated with colonic neuromuscu-
lar disease. This information can then be used Chronic Intestinal Pseudo-Obstruction
to guide management [27]. Resection of
colonic segments found to have abnormal Chronic intestinal pseudo-obstruction (CIPO)
motor function leads to improvement in symp- is a heterogeneous group of disorders what
toms [28, 29 ]. Interestingly, there seems to be vary in cause, severity, course, and response
little or no correlation between manometric to treatment. Di Lorenzo et al. studied patients
findings and histopathologic abnormalities, with CIPO, and found a subgroup of patients
suggesting that our current ability to study the with chronic constipation as part of their
morphology and function of the enteric neuro- CIPO symptomatology had abnormal HAPC,
musculature is limited [30] . absent gastrocolonic response or total lack of
A study by Villareal et al. used HAPC as a identi fi able colonic motor activity [ 35 ] . A
marker for intact neuromuscular colonic function thorough manometry evaluation including
[31]. The colonic manometry pattern, namely the colonic manometry needs to be performed
failure to demonstrate colonic HAPC, directed during the evaluation for possible isolated
the providers to the formation of a defunctioning small bowel or multivisceral transplantation
ostomy (ileostomy or colostomy). In patients in children with CIPO, in order to assess
who had evidence of a dilated colon with abnor- which organs need to be transplanted and if a
mal motility patterns, repeat manometry testing permanent diverting ileostomy needs to be
after a period of decompression (5–30 months) planned [36] .
led to an improved motor function. Aspirot et al.
evaluated the effect of chronic use of antegrade
enemas on colonic motility in children and ado- Hirschsprung’s Disease and Anorectal
lescents with severe constipation [32]. Although Malformations
only few patients were included in the study, all
those with abnormal manometry prior to cecos- After resection of the abnormally innervated
tomy placement showed improvement in colonic bowel in Hirschsprung’s disease, a large per-
motility after using antegrade enema for at least 1 centage of patients continue to struggle with
year. The patients evaluated were selected due to abnormal defecation patterns [37] . Colonic
consideration of removal of their cecostomy manometry testing allows classi fi cation of
tubes, in view of their clinical improvement. symptomatic patients post-Hirschsprung’s
Colonic manometry may be also used to predict surgery into four groups, each with different
10 Colonic Manometry 113

Fig. 10.4 Example of non-propagating HAPC, indicated by asterisks. The contractions appear to be propagating only
in the proximal colon (top two recording channels)

physiology [38]. Each category and physio- in pressure in the distal colon (Fig. 10.5) may
logic process directs different therapy: (1) be due to a neuropathic motility disorders
The first group of patients has HAPC which proximal to the aganglionic segment, possibly
progress through the neorectum all the way to associated with intestinal neuronal dysplasia
the anal verge. The amplitude of the HAPC [ 39 ] , or to a common cavity phenomenon. (4)
exceeds that of the voluntary contraction of Finally, a small number of patients with
the external anal sphincter. The result is defecation disorders post-surgery for
incontinence or rectal pain as the patient Hirschsprung’s disease have normal colonic
attempts to retain the stool. (2) The second motility and a hypertensive anal sphincter.
group has normal colonic motility with fear of Successful treatment options for this subset of
defecation and stool withholding. The nega- patients have included myectomy, which leads
tive experience related to attempting defeca- to irreversible destruction of the internal anal
tion before surgical removal of the aganglionic sphincter, and botulinum toxin injection to
segment may result in fecal retention after the hypertensive anal sphincter [40–42 ] .
surgery. Identification of normal colonic Similar findings have been reported in chil-
manometry pattern in these children provides dren with continence disorders after anorectal
reassurance in the diagnosis and more malformations repair. Heikenen et al. have
confidence in the behavioral and medical reported that propagation of excessive numbers
treatment plan. (3) Abnormal colonic manom- of HAPCs into the neorectum as well as internal
etry with lack of HAPC, poorly propagating anal sphincter dysfunction can contribute to fecal
HAPCs (Fig. 10.4) or simultaneous increases incontinence in these children [43].
114 B.P. Regan et al.

Fig. 10.5 Example of simultaneous increases in pressure in the distal colon, indicated by asterisks

Variations on Colonic Manometry continuous manometric measurement. It is unclear

Testing how much the additional information collected
during a 24-h study changes clinical management
Ambulatory 24 h Colonic Manometry compared to a shorter study with meal ingestion
and pharmacological stimulation.
A limitation of traditional colonic manometry
studies is the duration of the study. There is a well-
established circadian variation in colonic manom- Wireless Motility Capsule
etry which is missed during short studies [21,
44–46]. Twenty-four hour colonic manometry has This tool has been approved by the US Food and
been proposed as a better test which evaluates a Drug Administration (FDA) for measurement of
time period felt to be more representative of the gastric emptying and whole gut transit time. Once
patient’s environment, eating and sleeping pat- swallowed, this fairly sizable capsule is capable
terns. It has been performed in children using of measuring intraluminal pH, pressure and tem-
water perfused probes [47] but it is best done using perature throughout the entire gastrointestinal
solid state probes which do not confine the patient tract. Data is transmitted to a data receiver and
to a restricted environment. Solid state probes have downloads to a computer for analysis. Gastric
been placed via colonoscopy with clips adhering emptying is measured by timing the point from
to multiple sites of colonic wall. The probe is then ingestion to the point where the pH rises above
taped to the gluteal region and connected to a por- pH 6, indicating the capsule has left the acid
table recorder. The patient is allowed to ambulate, environment of the stomach and has entered the
eat and defecate in a hospital setting for 24-h with more neutral pH of the duodenum [48]. Because
10 Colonic Manometry 115

it has a single pressure measurement, propaga- gators with a special expertise in motility and who
tion of motor activity cannot be defined. In addi- are comfortable in evaluating children with com-
tion, the gastric emptying time for the capsule plex biopsychosocial disturbances. Better under-
most probably reflects the gastric emptying of a standing on how to perform and interpret the test
large non-digestible solid, which is different from continues to occur and new techniques, such as
the emptying of a digestible solid [49]. Wireless high resolution fiber optic manometry and wire-
pH motility capsule has been found to be useful less motility capsule [54], are emerging which will
in evaluating colonic transit, and has been vali- hopefully continue to increase knowledge in the
dated in adults as an alternative to radiopaque field of colonic motility disorders.
markers as a tool to assess colonic transit [50].
The exact role of the wireless pressure capsule in
the evaluation of children with possible colonic
dysmotility is still under investigation.
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 Anorectal Manometry
11
Minou Le-Carlson and William Berquist

patients and their families constituting approxi-

Introduction mately 3% of all pediatric outpatient visits [3].
However, given the significant overlap of symptom-
Fecal continence and defecation are achieved atology among the different functional and non-
through a coordinated sequence of events involving functional causes of anorectal dysfunction, diagnosis
the relaxation and contraction of abdominal muscu- is often not possible based on history and exam
lature, as well those muscles that form and surround alone. Indeed, anal achalasia, Hirschsprung’s dis-
the anorectal canal. Anorectal manometry (ARM) ease (HD), and pelvic floor dyssynergia can all
is an objective way to assess the function of such present similarly with constipation but can require
muscles, thereby allowing the diagnosis of abnor- highly varied forms of therapy—botulinum toxin
malities and the subsequent application of appropri- injection, surgery, and biofeedback, respectively.
ately tailored treatments. Pediatric patients typically By characterizing the underlying pathology of simi-
referred for ARM testing include those with severe larly presenting symptoms through ARM, appropri-
constipation refractory to medical management, ate forms of management can be applied to help
anorectal pain especially with defecation and/or patients gain normal or near normal stool function.
fecal incontinence. Constipation in children is gen- Equally as important, ARM also offers providers an
erally characterized by less than 3 bowel move- objective way to educate patients and families
ments weekly, as well as hard, often painful stools regarding the underlying pathophysiology of these
that are difficult to pass [1, 2]. Fecal incontinence is often chronic and consuming conditions.
the inappropriate leakage of stool which is often
secondary to stool withholding, although can be
non-retentive in nature. Constipation and inconti- Anatomy/Physiology
nence can be highly distressing conditions for
The major structures of the anorectal canal
M. Le-Carlson, M.D. (*)
include the internal anal sphincter (IAS), external
Pediatric Gastroenterology, Hepatology and Nutrition, anal sphincter (EAS) and the levator ani complex
Pediatrics Department, Stanford University Medical including the puborectalis sling (Fig. 11.1a). The
Center, Lucile Packard Children’s Hospital, IAS, located proximally and most medial to the
750 Welch Road, Suite 116, Palo Alto, CA 94304, USA
e-mail: [email protected]
central lumen, envelopes the canal and is involved
in involuntary or reflexive muscular contraction.
W. Berquist, M.D.
Gastroenterology Division, Pediatrics Department,
Distal and lateral to the IAS, the skeletal muscles
Stanford University, Lucile Packard Children’s Hospital, of the EAS form an additional layer of circumfer-
Stanford, CA, USA ential musculature that is under voluntary control

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 119

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_11, © Springer Science+Business Media New York 2013
120 M. Le-Carlson and W. Berquist

Fig. 11.1 (a) Anterior–posterior view of the anorectal canal with ARM catheter and inflated balloon in place.
(b) Lateral view with puborectalis sling angulating anorectal canal. Figures drawn by Minou Le-Carlson

[4–6]. There is considerable overlap of the two Methods/Technique

anal sphincters such that differentiation on ARM
often is not possible, particularly in younger chil- There are several forms of ARM available includ-
dren as the anorectal canal does not extend ing conventional water perfusion, sleeve catheter,
beyond a few centimeters in length [7]. The leva- water and air filled balloon catheter, as well as
tor ani complex is composed of a group of mus- high-resolution or solid-state manometry. The
cles that acts to support and lift the pelvic floor. more widely used water-perfusion manometry
Part of this complex, the puborectalis, loops pos- (WPM) and high-resolution manometry (HRM)
teriorly around the rectum forming a sling that will be reviewed here. WPM involves a flexible
angulates the anorectal canal. The degree of this catheter with multiple side-holes either circum-
angle, typically 85–105° at rest, plays an impor- ferentially or spirally arranged along the length
tant role in controlling anorectal function by nar- in a staggered configuration to permit continuous
rowing to support continence and widening to perfusion of water typically at rates of 0.1–
permit the passage of stool (Fig. 11.1b) [4]. 0.5 mL/min (Fig. 11.2a) [5]. HRM involves a
During normal function, the passage of stool catheter with channels positioned several milli-
into the rectum leads to the involuntary relaxation meters apart, each composed of multiple sensing
of the IAS to accommodate the stool burden, points arranged in a circumferential pattern which
referred to as the rectoanal inhibitory reflex accumulatively allow retrieval of more than a
(RAIR), as well as to the urge to defecate. hundred of data points (Fig. 11.2b, see also
Simultaneous contraction of the EAS and pub- Fig. 11.4a). Newly emerged is the high resolu-
orectalis muscles counters this action to increase tion, three-dimensional ARM which configures a
distal anorectal pressures, decrease the anorectal multidimensional view of the anorectal canal
angle and ultimately, prevent forward propulsion (Fig. 11.2c) [8]. The utility and practical advan-
of stool and dissipate the urge to defecate. When tages of this method over other forms of ARM,
defecation is permissible in both a practical and however, have yet to be well established clini-
appropriate social context, an increase in intra- cally. All methods include an inflatable balloon
abdominal pressure coupled with the relaxation positioned at the tip for measurement of rectal
of the EAS and puborectalis muscle allows for- distention and balloon expulsion. The compara-
ward propagation and evacuation of stool and ble advantages and disadvantages of each system
ultimately, the urge to defecate is relieved [4–6]. are debatable. Generally, the simplicity and cost
11 Anorectal Manometry 121

Fig. 11.2 (a) Water-perfusion catheter (Medical high-resolution catheter (Sierra Scientific Instruments).
Measurement Systems). (b) High-resolution catheter Printed with permission from Medical Measurement
(Medical Measurement Systems). (c) Three-dimensional Systems

are major advantages of WPM, while mainte- mands. If possible, any home medications with
nance of the narrow fluid channels—susceptible the potential to modify muscle activity should be
to leakage and occlusion—can be a drawback. held including opioids and anticholinergics.
Meanwhile, HRM offers substantially higher Ideally, patients should be in the lateral position
anatomic detail of the anorectal canal allowing with knees flexed slightly towards the chest,
some differentiation between internal and exter- awake and actively participating in the study par-
nal rectal sphincters and increased appreciation ticularly to evaluate rectal sensitivity and defeca-
of asymmetric anatomy—potential advantages tory dynamics. While most ARM procedures are
when surgical intervention is being considered. done without anesthetics, when they cannot be
Additionally, given its circumferentially located avoided the provider must always factor the
sensors, HRM requires less catheter manipula- potential impact of such drugs towards the inter-
tion after placement in the canal, thereby mini- pretation of study outcomes. Limited studies have
mizing sensor migration. The major downsides to demonstrated that ketamine and midazalom do
HRM are most notably the cost and cleaning, as not significantly impact resting anal pressure or
well as temperature sensitivity and potentially RAIR [11, 12]. Propofol has also been shown to
longer downtime when repairs are needed. have no effect on RAIR, but there is evidence to
Prior to the procedure, children should attempt suggest an alteration of resting pressures in an
to defecate or if concerns for large rectal burden, adult study [13]. As with all studies of motility,
an enema or suppository should be administered the impact of anesthesia on ARM is not fully
several hours prior to the study. For younger characterized. Additionally, some providers con-
babies, no bowel preparation is required [9, 10]. currently perform ARM and electromyography
A digital rectal exam should precede the ARM (EMG) for an enhanced investigation of pelvic
study to assess stool content, as well as overall floor activity. During EMG, external surface elec-
anatomy and patient’s ability to follow com- trodes are placed near the anus to capture the
122 M. Le-Carlson and W. Berquist

Fig. 11.3 (a) Normal RAIR. (b) Absent RAIR in an HD patient. (c) Normal balloon expulsion with normal EAS relax-
ation. (d) Dyssynergia with abnormal EAS contraction

electrical activity of the striated muscles of the pressure (or the average of at least three of the
region (EAS and levator ani) and to highlight the highest pressures).
ability of such muscles to relax and contract 3. Anal canal length—The length of the anal
appropriately [14]. canal is determined by the distance between
Some of the key measurable values of routine the anal verge and the location of ³5 mmHg
ARM in pediatrics include the following: basal or pressure increase above rectal pressure.
resting anal pressure, maximal squeeze pressure, 4. RAIR—It is the reflexive relaxation of the
anal canal length, RAIR, conscious rectal sensa- IAS with stimulation with either stool accom-
tion, initial urge to defecate, and defecatory modation or balloon inflation. To obtain the
dynamics: RAIR, the balloon is rapidly inflated and either
1. Basal or resting anal sphincter pressure—A rapidly deflated or left distended for a short
measure of the canal at rest which is reflective period (10–20 s). No clear standard has been
of overall muscle tone from both the EAS and accepted as the criteria qualifying an intact
IAS, with a >75% contribution from the latter reflex, although both a drop of ³5 mmHg or
[15]. There are several techniques for obtain- ³15% from resting pressure have been pro-
ing the anal resting pressure in WPM, includ- posed (Fig. 11.3a, also see Fig. 11.4b) [5]. A
ing the station pull-through for circumferentially dose response should be observed with both
arranged and continuous withdrawal for spi- the overall degree and duration of such reflex
rally arranged catheters [5, 15]. increasing with increasing volumes of balloon
2. Maximal squeeze pressure—By maximally inflation. Patients should be instructed not to
squeezing or tightening the anal sphincter provide voluntary squeeze during balloon
when directed, the patient produces a force on inflation, as it may artificially affect the degree
the catheter called the maximal squeeze pres- of the RAIR. Careful consideration must be
sure. Specifically, it is defined as the highest made to ensure stable position of the catheter
pressure increase over the average resting during this particular test, as movement within
11 Anorectal Manometry 123

Fig. 11.4 High resolution ARM. (a) Normal at rest. (b) Normal RAIR. Printed with permission from Medical
Measurement Systems
124 M. Le-Carlson and W. Berquist

the canal can lead to a drop in pressure and uses, which in ARM is manifested by an absent
subsequently, an inaccurate interpretation of RAIR (Fig. 11.3b) [18]. The absence of RAIR is
an intact reflex. Of note, such catheter move- suggestive but not diagnostic of HD. Such patients
ment can be detected in HRM but may be should then undergo a full-thickness rectal biopsy
missed with WPM. to detect the absence of ganglion cells, the uni-
5. Conscious rectal sensation and initial urge to versally accepted standard to confirm the diagno-
defecate—Conscious rectal sensation has sis of HD. A systematic review by Lorijn et al.
many variations in the literature including analyzed 22 studies of the three commonly used
transient rectal sensation or conscious sensi- diagnostic studies to workup HD including rectal
tivity threshold. Essentially, it is the smallest suction biopsy, ARM, and contrast enema, and
balloon volume that elicits a sensory response found the sensitivity and specificity of the former
by the patient. In relation, the initial urge to to be 93% and 98%, respectively. In this study,
defecate is the minimal balloon volume that ARM reached diagnostic accuracy similar to rec-
the patient perceives as a need to defecate. tal suction biopsy with a sensitivity of 91% and
6. Balloon expulsion or defecatory dynamics— specificity of 94% with both being far superior to
As the patient attempts to expel the balloon, contrast enema with a sensitivity of 70% and
often at varying volumes, the dynamic coordi- specificity of 83% [19]. There exists data that
nation of muscle contraction and relaxation suggests detecting HD through ARM in younger
can be assessed for evidence of dyssynergia children is inconsistent and unreliable with a 26%
by the balloon expulsion test [9, 10, 15]. error rate in neonates in one study [20]. Such
Noticeably lacking are age-specific, norma- findings may reflect the technical challenges of
tive ranges for the above measurements in the choosing an appropriate catheter in terms of size
pediatric population. Table 11.1 lists several ref- and type, and of correct positioning of such a
erences for key measurements for various age probe within the short, developing anorectal canal
groups using WPM, although differences in of neonates. Studies have suggested that the
methodology and equipment certainly need to be sleeve catheters, and air rather than balloon
acknowledged. HRM data in healthy pediatric insufflation, yield the most reliable results in this
subjects has not been published. Although there younger age group [21, 22]. Based on the above
appears to be good correlation between methods, information, ARM is considered an accurate,
the absolute values obtained in HRM have been noninvasive screening test for HD particularly in
suggested to be relatively higher than those of children >1 year [23]. Beyond playing a role in
WPM [16, 17]. Ultimately, given the lack of just the initial diagnosis, ARM can be useful in
sufficient pediatric control data or standards, as patients with HD who have undergone surgery by
well as the wide range of techniques and equip- characterizing the activity of the anorectal canal
ment, it is essential to always correlate data following pull-through surgery, which can vary
obtained by ARM with patient symptoms. among the different surgical techniques depend-
ing on the residual aganglionic rectum and IAS
[24]. ARM can also help guide various treatment
Diseases of the Anorectal Canal options such as sphincter myectomy or botuli-
num toxin injection [25, 26].
Hirschsprung’s Disease

Any patient with severe constipation presenting Anal Achalasia

in infancy, constipation refractory to standard
medical interventions, and of course, intestinal ARM can also help in the diagnosis of anal acha-
obstruction should be considered for HD. In HD, lasia. Patients with anal achalasia can present simi-
neural crest cell migration abnormally arrests larly to HD both clinically with intractable
leading to aganglionosis of the distal enteric plex- constipation and incontinence, and in ARM test-
 11

Table 11.1 References for normal manometric measurements

Maximal
Anorectal Manometry

squeeze
Healthy Anal resting Rectal pressure Anal canal Threshold of Sensation Critical pressure
Technique controls, N= Ages tone (mmHg) (mmHg) length (cm) RAIR (mL) threshold (mL) volume (mL) (mmHg)
Benninga [40] WPM 13 8–16 years 55 ± 16 18 ± 10 19 ± 12 131 ± 31 182 ± 61
Hyman [5] Not 20 5–16 years 67 ± 12 3.3 ± 0.8 140 ± 52
specified 16 >5 years 11 ± 5 14 ± 7 101 ± 39
Kumar [7] WPM 30 <1 month (GA 31 ± 11 1.7 ± 0.3 10 ± 4
34–39 weeks)
30 1–16 months 42 ± 9 1.9 ± 0.6 14 ± 10
30 18 month to 43 ± 9 3.0 ± 0.5 25 ± 12
12 years
Li [41] Not 10 5–15 years 28 ± 11 117 ± 46
Specified
Sutphen [42] WPM 27 ~7–12 years 30 ± 12 96 ± 38 142 ± 47
Benninga [21] Sleeve, 22 Neonates 32 ± 4a 9±2 1.6 ± 0.3b
WPM (PMA
30–33 weeks)
De Lorijn [22] Sleeve, 16 Neonates 25 ± 11a 7±5 3.4 ± 1.6b
WPM (PMA
27–30 weeks)
GA gestational age, PMA postmenstrual age
a
Anal sphincter pressure
b
Air insufflation
125
126 M. Le-Carlson and W. Berquist

ing with the absence of an intact RAIR. Anal acha- tion may be at increased risk of spinal cord lesions
lasia is differentiated from HD, however, by the requiring further investigation with MRI [32].
presence of ganglion cells on rectal biopsy. In Lastly, ARM can be helpful in the management
patients with anal achalasia, also referred to as of patients with imperforate anus by assessing
ultrashort HD, the IAS fails to properly relax for postsurgical sensory and functional capabilities.
reasons that are not well characterized [27]. Similar Successful management can be challenging for
to postsurgical HD patients above, treatment patients with neuromyopathic disease. Stool soft-
approaches are geared towards inducing IAS eners, though helpful in improving constipation,
relaxation either through the injection of botuli- have the tendency to worsen incontinence.
num toxin or internal sphincter myectomy. Both However, establishing a scheduled toileting regi-
approaches have demonstrated good outcomes in men in conjunction with intermittent stimulants
pediatric studies [25, 28]. An interesting subset of or enemas to empty bowel contents can be an
anorectal motility dysfunction is found in patients effective approach for patients with neuromuscu-
with food-allergy related constipation. Studies lar disease [5].
have shown hypertensive resting anal pressures
and partial relaxation on rectal distention, some-
what similar to anal achalasia, which improves Dyssynergic Defecation
with allergen food elimination [29].
Chronic functional constipation is a common
problem in the pediatric population and is
Neuromuscular Disease believed to represent up to 95% of all cases of
constipation in children [3]. Dyssynergia, per-
Neuromuscular disease can also be associated haps the most prevalent form of pediatric func-
with anorectal dysfunction. Patients with condi- tional constipation, occurs when the abdominal,
tions such as myotonic dystrophy, Duchenne anorectal and pelvic floor muscles are not prop-
muscular dystrophy and congenital myopathy erly coordinated during attempted defecation.
commonly present with constipation, fecal incon- Again, in order for effective stooling to occur, a
tinence and fecal impaction which can even prog- rise in the propulsive forces of the rectum must
ress to megacolon and/or chronic intestinal be countered by the relaxation of the EAS and
obstruction. While there are no specific findings subsequent drop in anal pressures to permit for-
on ARM that can diagnosis neuromuscular dis- ward passage of stool (Fig. 11.3c). Typically,
ease, there are several patterns that can be sup- dyssynergia is a learned behavior resulting from
portive of such a diagnosis. Consistent with the withholding tendencies of constipated children
overall presentation of weakness, patients with with a history of painful, dry bowel movements—
neuromuscular disease often demonstrate low in children most commonly characterized by a
anal resting and squeeze pressures [5]. paradoxical tightening of the EAS with defeca-
Additionally, patients with neuromyopathy often tion (Fig. 11.3d) [33]. Dyssynergia describes the
have an intact RAIR but will often lack a normal pathophysiologic correlate of functional retentive
dose response, as the degree and duration of the constipation where such withholding behavior
relaxation will fail to increase with increasing initiates a vicious cycle of firm stool accumula-
balloon volumes [30]. Also notable in this subset tion, impaction, over flow incontinence and ulti-
of patients is an exaggerated rebound contraction mately, worsening intractable constipation.
following the RAIR [31]. Patients with spinal Pediatric dyssynergic defecation is identifiable
cord lesions such as tethered cord have notable by ARM through the balloon expulsion test,
variations in ARM such as anal spasms with bal- which evaluates the dynamic defecatory process.
loon dilatation and a left-shifted RAIR dose– Four distinct patterns of dyssynergia have been
response curve. Thus, ARM may be helpful to identified, each defined by two parameters: rectal
identify which patients with intractable constipa- pressures (appropriate versus insufficient
11 Anorectal Manometry 127

increase) and anal sphincter pressures (anal con- and offers customized treatment interventions to
traction versus incomplete relaxation). Additional help patients gain normalized stool function.
ARM findings often associated with dyssynergia
include evidence of sensory dysfunction with
elevated minimal sensory and urge to defecate
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23. de Lorijn F, Reitsma JB, Voskuijl WP, et al. Diagnosis normal transit constipation due to pelvic floor dyssyn-
of Hirschsprung’s disease: a prospective, comparative ergia. Gastroenterology. 2006;130(3):657–64.
accuracy study of common tests. J Pediatr. 37. Chiarioni G, Salandini L, Whitehead WE. Biofeedback
2005;146(6):787–92. benefits only patients with outlet dysfunction, not
24. Mishalany HG, Woolley MM. Postoperative functional patients with isolated slow transit constipation.
and manometric evaluation of patients with Hirschsprung’s Gastroenterology. 2005;129(1):86–97.
disease. J Pediatr Surg. 1987;22(5):443–6. 38. Heymen S, Scarlett Y, Jones K, et al. Randomized,
25. Chumpitazi BP, Fishman SJ, Nurko S. Long-term controlled trial shows biofeedback to be superior to
clinical outcome after botulinum toxin injection in alternative treatments for patients with pelvic floor
children with nonrelaxing internal anal sphincter. Am dyssynergia-type constipation. Dis Colon Rectum.
J Gastroenterol. 2009;104(4):976–83. 2007;50(4):428–41.
26. Blair GK, Murphy JJ, Fraser GC. Internal sphinctero- 39. van der Plas RN, Benninga MA, Büller HA, et al.
tomy in post-pull-through Hirschsprung’s disease. J Biofeedback training in treatment of childhood con-
Pediatr Surg. 1996;31(6):843–5. stipation: a randomised controlled study. Lancet.
27. Doodnath R, Puri P. Internal anal sphincter achalasia. 1996;348(9030):776–80.
Semin Pediatr Surg. 2009;18(4):246–8. 40. Benninga MA, Wijers OB, van der Hoeven CW, et al.
28. De Caluwé D, Yoneda A, Akl U, Puri P. Internal anal Manometry, profilometry, and endosonography: nor-
sphincter achalasia: outcome after internal sphincter mal physiology and anatomy of the anal canal in
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1999;44(6):1090–9. 1997;40(9):1051–5.
 Esophageal pH and Impedance
Monitoring 12
Rachel Rosen and Eric Chiou

quent evolution to newer diagnostic techniques.

Introduction Wireless methods to detect acidic contents in the
esophagus have now become available (Bravo pH
Gastroesophageal reflux disease (GERD) is capsule) and pharyngeal probes have recently
defined by the reflux of gastric contents into the been introduced (Restech). Additionally, multi-
esophagus resulting in well-defined symptoms and channel intraluminal impedance with pH (MII-pH)
complications [1, 2]. In many cases, GERD can be has been introduced as a novel method to mea-
diagnosed based on history alone; however, when sure acid and non-acid reflux. In the present
patients present with atypical complaints or do chapter, we will discuss the technical details,
not respond to medical therapy, objective testing clinical indications and applications of these
may be necessary to assess the frequency and diagnostic techniques for the dynamic detection
duration of acid reflux, or to document the asso- of reflux episodes.
ciation between gastroesophageal reflux (GER)
and specific symptoms. Diagnostic techniques
designed to discriminate between physiologic and
pathologic reflux have been developed. Catheter-Based Esophageal
Esophageal pH monitoring, which employs a pH-Monitoring
pH electrode to detect acid reflux in the distal
esophagus, was first introduced in 1969 [3]. Over Catheter-based esophageal pH monitoring is the
the years the advantages and limitations of tradi- most widely available and commonly used
tional, catheter-based esophageal pH monitoring method to document abnormal acid exposure
have become better understood, with a subse- and correlate symptoms with acid reflux epi-
sodes. Testing quantifies the frequency and
duration of acid reflux episodes, usually over an
18–24 h period. Most ambulatory catheter-based
R. Rosen, M.D., M.P.H. (*)
Harvard Medical School, Center for Motility and pH probes contain a small antimony electrode
Functional Gastrointestinal Disorders Children’s connected to a portable data logger that records
Hospital Boston, 300 Longwood Avenue, Boston, intraesophageal pH, as well as events during the
MA 02115, USA
study, such as symptoms, meals, position
e-mail: [email protected]
changes, and activity. The methodology of
E. Chiou, M.D.
esophageal pH monitoring has become rela-
Center for Motility and Functional Gastrointestinal
Disorders Children’s Hospital Boston, tively standardized with specific guidelines for
300 Longwood Avenue, Boston, MA 02115, USA use in children [4, 5].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 129

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_12, © Springer Science+Business Media New York 2013
130 R. Rosen and E. Chiou

Electrode Placement Documentation of patient position and activity

during the study should also be recorded since
Appropriate placement of the pH electrode the effect of body position on different patterns
relative to the lower esophageal sphincter of GER has been well reported; acid reflux is
(LES) is very important in order to gather accu- more common in the supine and right lateral
rate data. At higher distances above the LES, positions than the prone or left lateral positions
there is a linear decrease in acid exposure time, [4, 12]. Depending on the aim of the study, H2-
which decreases the sensitivity of the test. blockers and proton-pump inhibitors should be
Adult protocols typically recommend that the stopped at least 3 or 7 days prior to the study,
pH electrode be positioned 5 cm above the respectively. Adult data in healthy volunteers
superior margin of the LES in order to decrease suggests that intragastric pH returns to base-
the risk of slipping into the stomach during line within 2–4 days after stopping acid sup-
swallow-induced shortening of the esophagus pression [13].
[6]. Stationary esophageal manometry, usually
performed as a separate procedure, is optimal
for determination of LES location. In children Definitions and Criteria
however, this additional invasive procedure is
not routinely performed. Strobel’s formula may After the study is completed, data is down-
be used to approximate the esophageal length loaded from the data logger and analyzed with
for initial placement of the pH electrode computer software. A reflux episode is usually
above the LES [length from nares to LES defined as a drop in pH below 4 that lasts for
(cm) = 5 + 0.252(height)] [7]. In the absence of more than 5 s [14]. The reflux index, which is
manometry however, fluoroscopy should be the percentage of time of the entire duration of
used to confirm placement of the sensor at the the investigation with pH <4 is generally con-
level of the third vertebral body above the dia- sidered the single most important variable in
phragm, according to recommendations from clinical practice for both adults and children
the Working Group of the European Society of [4, 6]. A pH of 4 is generally accepted as the
Pediatric Gastroenterology and Nutrition [5]. optimum cutoff in both children and adults,
based on early studies of correlating acid expo-
sure with heartburn [15–17]. The threshold of
Recording Conditions pH < 4 also provides the best discrimination
between subjects with proven reflux disease
The optimal duration of monitoring should be (the presence of esophagitis) and asymptom-
at least 18 h, including a day and a night period atic controls [6, 18, 19]. However, there is
[5]. Shorter studies have been proposed significant overlap between the reflux profiles
(30 min, 2 h, 8 h, and 12 h studies) but no study of patients with and without symptoms and in
period has been found to be sufficiently sensi- patients with and without esophagitis because
tive or reproducible to replace the 24 h studies there are many possible criteria that define
[8, 9]. Instructions for feeding and activity dur- pathologic reflux, including the number of epi-
ing the study should represent a balance sodes greater than 5 min, the longest reflux
between maintaining a degree of standardiza- episode, the percentage of time pH < 4, and the
tion and recreating a normal lifestyle with min- total number of reflux events. Several scores
imal restrictions. Although a strict standardized have been proposed, including the DeMeester
diet is generally not necessary, a minimum of score and the Boix-Ochoa score, but the cur-
three meals should be included. Meal periods rent gold standard for reporting pH monitoring
are routinely excluded from the analysis results is the reflux index, which is the percent-
because the pH probe cannot differentiate swal- age of time of the entire duration of the inves-
lowed acidic contents from refluxate [10, 11]. tigation with pH < 4 [4, 6].
12 Esophageal pH and Impedance Monitoring 131

number of reflux episodes between day 1 and

Normal Ranges day 2 were 0.95 and 0.98, respectively [28]. In
contrast, the correlation coefficient for the reflux
Normative data are essential to guide interpreta- index reported by Mahajan and colleagues was
tion of pH monitoring results and distinguish only 0.62 between day 1 and day 2 [29]. In
between physiologic versus pathologic reflux. another study, 9 out of 30 children had discor-
Published pediatric data is rather limited, how- dant (normal versus abnormal) results between
ever, due to the difficulty in obtaining data from the two recording days, yielding an overall
truly healthy and asymptomatic volunteers. In reproducibility of 70% [30]. Hampton et al
some studies, “normals” were obtained from found that there was discordance between day 1
children hospitalized for GER evaluations who and day 2 studies in 62% of infants. An addi-
turned out to be asymptomatic during the time of tional study was done in the pediatric popula-
pH monitoring [20] or were found to have other tion comparing the amount of reflux in children
causes for their gastrointestinal symptoms [21]. who has pH monitoring with and without anes-
Overall, studies suggest that physiologic acid thesia; Hampton et al found that there was dis-
reflux is a common occurrence in infants during cordance between day 1 and day 2 studies in
the first year of life, with decreased acid exposure 62% of infants. An additional study was done in
found in older children and adults [20–24]. Based the pediatric population comparing the amount
on the available data, the North American Society of reflux in children who has pH monitoring
for Pediatric Gastroenterology, Hepatology, and with and without anesthesia; McCallion et al
Nutrition (NASPGHAN) has established guide- found that the reproducibility of the percent
lines that define the upper limit of normal of the time pH<4 was 85%. [31, 32]. Overall, there
reflux index up to 12% in the first year of life and appears to be some degree of day-to-day vari-
up to 6% thereafter [4]. ability among patients; whether these differ-
ences are clinically significant is debatable.
When the clinical picture is unclear, consider-
Diagnostic Accuracy and ation should be given for repeat testing.
Reproducibility The next question to ask is whether obtaining
pH probe results translate into improvement in
The estimated sensitivity of pH monitoring for clinical outcome. Malfroot et al. found that 75%
predicting esophagitis in children is good, rang- of patients with abnormal pH monitoring experi-
ing from 83 to 100%, but the severity of reflux as enced symptomatic improvement in their pulmo-
measured by pH monitoring has not been found nary symptoms suggesting that it accurately
to necessarily correlate with the severity of symp- measures pathologic reflux [33]. A randomized
toms [15, 25]. For children with non-erosive control trial of acid suppression in children with
reflux disease (NERD), the clinical utility of pH pathologic reflux by pH monitoring showed that
monitoring has not been well studied. In adults, between 69 and 74% of patients with pathologic
there is significant overlap between patients with reflux experience symptomatic improvement
NERD and normal patients; approximately 40% with acid suppression, suggesting that pH probe
of adults with NERD had pathologic reflux but accurately predicts clinical response [34]. There
60% did not, making the differentiation of nor- is very limited data on the impact of this test on
mal patients from NERD patients difficult based clinical outcome; the majority of data is on the
on reflux burden alone [26, 27]. correlation of esophagitis with clinical outcome
Reports on intrasubject reproducibility of and since there is a correlation between esophagi-
esophageal pH results in children have had var- tis and pH abnormalities, it may be reasonable to
ied results. Vandenplas et al. studied infants and assume that there is a correlation between reflux
children over two consecutive 24-h periods; the burden and symptom improvement but there are
correlation coefficients for the reflux index and few studies to support this directly.
132 R. Rosen and E. Chiou

Symptom Correlation and surgical therapy, further prospective validation

studies are needed [40, 41]. Unfortunately, all of
In addition to the quantification of reflux, 24-h these indices rely on the patient to accurately
esophageal pH monitoring also provides the record symptoms immediately as they occur.
opportunity to assess the temporal relationship Additionally, while these may suggest a temporal
between episodes of reflux and onset of symp- association, they do not always prove causality.
toms. This may be especially helpful for patients
with nonspecific or extraesophageal symptoms.
Lam et al. found that using a two minute time Pharyngeal pH Monitoring
window was best for correlation of chest pain
with reflux, although the optimal time window Proving causality is even more difficult in the
for symptom–reflux association may vary depend- patient with extraesophageal manifestations of
ing on the particular symptom of interest [35]. reflux (hoarseness, recurrent pneumonia, otitis
Several statistical methods have been devel- media, and sinusitis) as there is an often unsatisfac-
oped to better quantify the association of symp- tory correlation between esophageal reflux and
toms and reflux episodes but there is no conclusive extraesophageal symptoms. As a result, the mea-
data proving one index to be superior to the oth- surement of oropharyngeal acidification has
ers. The symptom index (SI) is defined as the per- been proposed as a more accurate indicator of
centage of symptom episodes that are related to proximal reflux than dual channel pH probes. The
reflux, with a score of ³50% suggesting a posi- Restech Dx-pH probe (Respiratory Technology
tive relationship between symptom and reflux Corp., San Diego, CA) is a recently introduced,
[36, 37]. A second approach is the symptom sen- transnasal, oropharyngeal pH sensor. Besides being
sitivity index (SSI), which divides the number of less invasive than traditional catheters, the anti-
reflux episodes associated with symptoms by the mony-based sensor is also designed to measure the
total number of reflux episodes [38]. An arbitrary pH of both liquid and aerosolized droplets in the
cutoff of 10% or higher is commonly used to posterior oropharynx. Investigators have recently
indicate a significant association between symp- proposed the use of less acidic pH thresholds or
toms and reflux episodes. The SI may overesti- relative drops in pH to identify episodes of reflux in
mate the relationship between reflux and the posterior oropharynx, based on the hypothesis
symptoms when there are a high number of reflux that the threshold of pH <4 may be too stringent
episodes, and the SSI is more likely to be positive and insensitive and that pH changes above 4 may
when the number of symptom episodes is high. be damaging to laryngeal tissue [42, 43].
More recently, the symptom association proba- The clinical validity of these alternative cri-
bility (SAP) has been introduced. Using Fisher’s teria, however, is not yet established. A previous
exact test, this method expresses the statistical study which employed pharyngeal pH monitor-
likelihood that the patient’s symptoms are related ing found that 92% of pharyngeal pH decreases
to reflux [39]. By statistical convention, SAP of 1–2 pH units and 66% of pH <4 events were
³95% indicates that the probability that the artifactual or independent of esophageal
observed association between reflux and the acidification [44]. Moreover, recent studies
symptom occurred by chance is <5%. which combined the Restech oropharyngeal pH
While these indices are helpful for research, it probe with concurrent esophageal pH monitor-
is essential to determine if these indices predict ing in adults have also found inconsistencies
symptom response to acid suppression. Taghavi between oropharyngeal and distal esophageal
et al. found that the SSI and the SAP predicted a pH data, with higher numbers of non-correlating
response to acid suppression but this was an imper- oropharyngeal pH events during sleep and
fect relationship. Although patients with a positive supine periods [45, 46].
relationship between symptoms and reflux have Chiou et al., who used the Restech probe in
been shown to more likely to respond to medical children, found that a high proportion of
12 Esophageal pH and Impedance Monitoring 133

oropharyngeal pH events did not correlate with longed recording, using this technique there is
distal reflux by pH-MII, especially with the use of additional opportunity for the correlation of
alternative pH criteria and during supine periods symptoms with reflux, particularly symptoms
[47]. One reason for this finding may be that that do not typically occur on a daily basis.
decreased salivary flow during sleep leads to dry- Only one study to date has compared the
ing of the oropharyngeal pH electrode and subse- Bravo capsule side-by-side with a simultaneous
quently false readings. This phenomenon was transnasal pH catheter in children. Croffie and
initially described by Wiener et al. as “pharyngeal colleagues found no significant difference in the
pseudo-reflux” in reference to artifacts with a reflux index obtained by the two devices on day
gradual descent to pH <4 without a corresponding 1; on day 2, however, the median reflux index
fall in esophageal pH [48]. The utility of pharyn- recorded by the Bravo capsule was significantly
geal monitoring is still questionable and addi- higher compared to day 1 of both the capsule and
tional studies are underway to validate its use. catheter [54]. The clinical significance of this is
unclear, with only one patient having discordant
(abnormal versus normal) results between the 2
Wireless pH Monitoring days of recording.
Several pediatric studies have compared the
One of the main limitations to all of the catheter- pH results between day 1 and day 2 of the Bravo
based tests is that patient discomfort can be studies. In a study of Bravo in 23 children,
significant, such that their typical eating and activ- Gunnarsdottir et al. found no statistically
ity patterns are altered to the point that the study significant differences in the reflux profiles
may not be representative of a “typical” day for the between the first 24 h and the entire 48-h record-
patient. To overcome this limitation, a wireless ing but 7 children received a different classification
method has recently been devised. The Bravo pH (normal versus abnormal) between day 1 and 2
system (Medtronic, Shoreview, MN) consists of an [55]. In a series of 145 Bravo studies in children,
antimony electrode contained within a small cap- there were significantly more long duration
sule which is pinned to the mucosal wall of the events and a higher percentage of time that the
distal esophagus during an upper GI endoscopy pH was less than 4 in the upright position on day
and transmits pH data wirelessly to a portable 1 compared to day 2 [52]. Currently, there is no
receiver using radiotelemetry. The capsule can consensus on whether the interpretation of the
remain in place for up to 4 or more days but typi- results should rely on the first or the second day
cally is in place for at least 2 days allowing for or average of the days; outcome studies are
extended recording. In adults, the capsule is placed needed to make this determination.
6 cm above the squamocolumnar junction, with Currently, Bravo is a reasonable alternative for
placement confirmation by endoscopy [49]. There patients that cannot tolerate a catheter-based sys-
are currently no specific guidelines for placement tem, but the need for anesthesia for placement
in children. Adult series have reported significant (and the resultant associated costs) combined
chest discomfort, early detachment of the capsule, with the need to stop acid suppression therapy
perforation, and the need for endoscopic removal may limit its utility in becoming the gold stan-
of the capsule but because of the small case series dard reflux tool [51, 56].
in pediatrics, the extent of Bravo complications in
children is still largely unknown [49–51].
In published studies of children older than Proximal Esophageal pH Monitoring
4 years old, pH monitoring with the Bravo cap-
sule was better tolerated than the transnasal cath- Proximal esophageal pH monitoring is designed to
eter in terms of appetite, activity, and satisfaction, assess the proximal extent of acid reflux and its
with no significant complications other than mild relationship with oropharyngeal and respiratory
chest discomfort [52–54]. Because of the pro- symptoms. Studies employing dual-probe pH
134 R. Rosen and E. Chiou

monitoring of both the distal and proximal esopha- esophagus at different spacing depending on the
gus have provided mixed results in terms of sen- size of the catheter that is used (infant for ages 0–2,
sitivity and specificity for extra-esophageal pediatric for ages 2–10 and adult for children older
manifestations of reflux, intra-subject reproduc- than 10). Since the impedance sensors cannot dif-
ibility and prediction of response to therapy [57, ferentiate between acid versus non-acid material, a
58]. Additionally, there is poor correlation between distal pH sensor has been added to the catheter
the acidification in the proximal sensor with the allowing the clinician to determine whether the
acidification in the distal esophagus raising the flow across the catheter is acidic, weakly acidic, or
question of whether the proximal acidification has non-acidic, depending on the pH value.
any significance in the absence of distal The pH-MII catheter is inserted through the
acidification. In pediatrics, because there are a lim- nose and the catheter is positioned so the distal
ited number of catheter sizes and a wide range of pH sensor is at the third vertebral body above the
esophageal lengths, it is difficult to ensure that the diaphragmatic angle (Fig. 12.2) [5]. Studies are
proximal sensor is uniformly in the same location performed for 24 h and, as with pH studies, meals
without compromising distal sensor location. are conventionally excluded from analyses.
Furthermore, it is unclear which pH level produces Typically, when performing pH studies, acid sup-
damage to bronchial, laryngeal and pharyngeal tis- pression medications are stopped a minimum of
sue and while the literature is based on a pH cut- 48 h prior to testing because the pH probe cannot
off of 4, non-acid reflux with pH 4–7 may also detect non-acid reflux, which is prevalent in the
play a clinically significant role in aerodigestive acid suppressed patient [64]. Since the pH-MII
diseases [59, 60]. At the current time however, the catheter can detect acid and non-acid reflux, the
clinical advantage of proximal esophageal pH studies can be performed off or on acid suppres-
monitoring in children is not yet clearly proven sion therapy, although adult studies suggest that
and more studies are needed to validate their use. symptom correlation may be improved if medica-
tions are stopped prior to pH-MII testing [65].

Multichannel Intraluminal
Impedance (pH-MII) Definitions

MII-pH uses sensors distributed throughout the A liquid episode is defined as a drop in imped-
esophagus to measure resistance to flow rather ance to 50% of the baseline value or below, with
than pH changes alone. The advantages of pH- a subsequent recovery back to 50% of the base-
MII are the following: (1) the sensors are able to line value. This drop in impedance needs to be
determine the directionality of flow so that reflux visualized in at least the distal two channels to be
events can be distinguished from swallows; considered “reflux.” Gas reflux is defined as
(2) multiple sensors throughout the esophagus simultaneous increases in impedance to greater
allows for accurate determination of refluxate than 8,000 W in two or more channels. Mixed
height; (3) the sensors, which do not rely on pH, reflux has components of both liquid and gas.
are able to detect non-acid reflux which is com- There are three types of reflux episodes that can
mon in the pediatric population, in the acid sup- be detected: (1) acid reflux events detected by
pressed patient and in the postprandial period both the impedance and the pH-sensor, (2) non-
[61–63]; and (4) because liquid and gas have dif- acid reflux events, which are detected only by the
ferent impedances, the sensors can differentiate impedance sensors, and (3) pH-only events, which
the composition of the refluxed material. are detected only by the pH sensor, without any
Traditionally, there are seven impedance sen- impedance changes. In some studies, non-acid
sors placed in series which generate six impedance reflux is further subdivided into weakly acidic
waves, one for each pair of adjacent sensors reflux (pH 4–7) and alkaline reflux (pH > 7). The
(Fig. 12.1). Sensors are distributed throughout the importance of pH-only events is still questionable
12 Esophageal pH and Impedance Monitoring 135

Fig. 12.1 Examples of retrograde bolus movement up are categorized as acid or non-acid depending on if there
the esophagus across six areas of the esophagus indicating is a pH drop to less than 4 during the impedance-detected
an acid (a) and non-acid (b) reflux episode. The episodes episode
136 R. Rosen and E. Chiou

symptoms and non-acid reflux events [66].

Hemmink et al. determined the sensitivity of the
automated software (Medical Measurement
Systems) and found that sensitivity of the soft-
ware was 73 ± 4%. Additionally, the automated
software incorrectly determined a symptom asso-
ciation 16–20% of the time, depending on the
symptom index used [67]. There are selected
populations where the impedance software is
particularly inaccurate; manual interpretation is
critical in the presence of esophagitis or if there is
a motility disorder, such as achalasia or esopha-
geal atresia, all of which lower impedance base-
lines. The low impedance baseline results in
significant underestimations of the amount of
reflux present.

Sensitivity
Fig. 12.2 Chest X-ray showing placement of an imped-
ance catheter. The catheter is positioned such that pH Impedance sensors have been shown to accu-
electrode is at the third vertebral body above the diaphrag- rately detect boluses in the esophagus down to
matic angle 0.1 ml using fluoroscopy [68, 69]. The difficulty
in determining the sensitivity of pH-MII is which
and the current theory is that pH only episodes gold standard technique should be used as the
represent very distal reflux that does not meet cri- basis for comparison; the pediatric studies have
teria for an impedance detected event (i.e., the used reflux detected by any device (pH-MII and
reflux does not reach the required three imped- pH probe) as the gold standard. Rosen et al. found
ance sensors). that the sensitivity of pH-MII was 76 ± 13% com-
pared to the pH probe whose sensitivity was
80 ± 18%. When patients taking acid suppression
Interpretation were studied, the sensitivity of the pH probe
dropped to 47 ± 36% whereas the sensitivity of
The interpretation of impedance tracings is time- pH-MII in medicated patients was 80 ± 21% [70].
consuming and in most research laboratories is Francavilla et al. found that the sensitivity of pH-
still done by hand even though there is commer- MII was 86 ± 12%, that this sensitivity was higher
cially available analysis software. Roman et al. in infants compared to children as infants have
studied the concordance of the automated soft- more non-acid reflux events, and that impedance
ware (Sandhill Scientific) to detect reflux events resulted in a higher symptom index, symptom
compared to a manual scoring of the events. sensitivity index, and symptom association prob-
Agreement between visual and automated analy- ability than the pH probe [71]. Wenzl et al. found
sis was good (Kendall’s coefficient W > 0.750, that in untreated infants, the sensitivity of pH-
P < 0.01) for all parameters. They also analyzed MII to detect acid reflux events was 54% com-
symptom detection, and concluded that despite pared to the pH probe [72]. Failure of pH-MII to
good agreement with manual analysis, automatic report reflux events detected by pH probe primar-
analysis overestimated the number of non-acid ily occurs when (1) there is a persistent drop in
reflux events [66]. Manual analysis remains the pH less than 4 even after the bolus had been
gold standard to detect an association between cleared by impedance, (2) the pH hovers around
12 Esophageal pH and Impedance Monitoring 137

4 with multiple drops to less than 4, or (3) pH 52% can be acid and up to 98% can be non-acid
drops are associated with swallows. [61]; the study, however, was performed with
nasogastric tubes in place which can stent open
the Lower Esophageal Sphincter and increase the
Reproducibility number of reflux events by more than 50%, sug-
gesting that these values may be artificially high
Dalby et al. performed 48 h impedance studies in [77]. In contrast, in a small study of older chil-
30 children to determine the degree of variability dren (n = 10, patients with normal pH recording
between the first and second day of recording and normal esophageal biopsies and no gastroin-
[73]. The authors found that the reproducibility testinal symptoms), the 95th percentile for total
for the total number of reflux events in each events was 69, a value very similar to adult data
patient between different days was better than the [78]. Obviously, larger studies are needed to
reproducibility for the number of acid or non- confirm the range of normal values in children.
acid events individually. On a population basis, Because normal cut-off values are not available
there was no significant difference between the in pediatrics, the main role of impedance is to
median total number, acid or non-acid events correlate symptoms with reflux events.
between day 1 and day 2 [73]. Results from adult
studies support this pediatric study. Aanen et al.,
in a study of 21 adults, found that the number of Symptom Association
acid, weakly acidic, and total events was similar
between the 2 days with a Kendall’s W value Given the lack of normative data to determine
ranging from 0.9 to 0.92, where a value of 1 indi- normal pH-MII in children, the most important
cates perfect concordance. Additionally, the use of the technique has been to study the tempo-
reproducibility of symptom indices using the ral association between symptoms and reflux.
SAP, SI and SSI was 0.9, 0.73, and 0.86 respec- There is significant debate in the adult literature
tively [74]. Similarly Zerbib et al. found, in 27 about the optimal way to correlate reflux with
adults, that there was good reproducibility for the symptoms but the literature is clear that pH-MII
number, acidity and composition of reflux events is superior to pH monitoring alone when evaluat-
(Kendall’s W-values = 0.72–0.85) [75]. ing symptom correlation [59, 65, 79, 80]. The
rates of symptom index (SI), symptom sensitivity
index (SSI), and the symptom association proba-
Normal Values bility (SAP) positivity have been studied using
MII-pH. In adults, Aanen et al. found that the
One of the current limitations to pH-MII moni- SAP and the SSI were the most reproducible
toring is the lack of normal pediatric values to indices in patients who had two impedance stud-
differentiate physiologic from pathologic reflux. ies separated by a minimum of 1 week [74].
Adult normal values have been published. Shay Similarly, Brendenoord et al. found that the SAP
et al. conducted a multicenter study of 60 healthy was the most frequently positive index followed
volunteers and found that the upper limit of nor- by the SI and then the SSI. They also found that
mal for total, acid, weakly acid, and non-acid the addition of pH-MII over a standard pH probe
reflux were 73, 55, 26, and 1, respectively [76]. increased the number of patients with a positive
Zerbib et al. found similar numbers in normal SI and SAP but did not increase the number of
adults with the upper limit of normal for healthy patients with a positive SSI [79].
adults for total, acid, weakly acid, and non-acid In pediatrics, Rosen et al. studied 28 children
reflux were 75, 50, 33, and 15, respectively [75]. taking acid suppression therapy for intractable
Normal preterm infant values differ respiratory symptoms; in these patients, more
significantly from adults; the upper limit for total patients had a positive SI for respiratory symp-
number of reflux events was 100 of which up to toms using MII-pH than pH probe alone but there
138 R. Rosen and E. Chiou

was no difference in the number of patients with Proximal Reflux

a positive SSI when MII-pH was used compared
to a standard pH probe [59]. In contrast, Thilmany One of the advantages of MII-pH is that the mul-
et al. found that the rate of positivity for the SI tiple sensors can detect full column reflux which
was higher for acid reflux episodes whereas the is extremely important when determining the
rate of positivity of SSI was higher for non-acid impact of reflux on the airways. Rosen et al.
reflux episodes suggesting that the value of pH- found that, in children with severe respiratory
MII may differ depending on what symptom symptoms, full column reflux is more highly
index is used [81]. Loots et al. studied 50 chil- associated with respiratory symptoms than distal
dren undergoing pH-MII testing and found that reflux [59]. The importance of full column reflux
uniformly pH-MII resulted in a higher symptom in the generation of symptoms is further sup-
association, regardless of the index used, com- ported by Jadcherla et al. who found that acid
pared to pH probe and that the SAP was the most reflux events reaching the proximal esophagus
frequently positive symptom index [82]. were four times more likely to be associated with
One of the limitations of symptom indices is that symptoms that distal events [85]. The next step is
they only represent a significant temporal relation- to determine whether full column reflux predicts
ship rather than a true cause and effect relationship. clinical outcome. Rosen et al. found that full col-
The normal cut off values, therefore, represent sta- umn reflux events, rather than total reflux burden,
tistical definitions and are not linked to clinical out- predicted a positive surgical outcome after fun-
comes; the normal values of 50% for the SI, 10% doplication [86]. In other studies, the relationship
for the SSI and 95% for the SAP were not gener- between full column reflux and symptoms is less
ated by investigating clinical outcomes. Rosen et al. clear. Condino et al. found that, in asthmatic chil-
looked at the value of the SI and the SSI in predict- dren, proximal reflux was not a predictor of
ing fundoplication outcome. They found that nei- symptom generation [80]. Because extraesopha-
ther a positive SI nor an SSI predicted fundoplication geal symptoms represent the consequences of a
results and, using ROC curves, there was no clear heterogeneous grouping of diseases, it is often
cut off value for either index predicting outcome difficult to determine a definitive relationship
[83]. These data suggest that a temporal association between full column events and symptoms, but it
alone does not prove causality which is the key is becoming increasingly clear that full column
limitation to all of the symptom indices. A second reflux may be an important component of a pH-
limitation of the symptom indices is the time lag MII report.
between when a symptom occurs and when the
patient actually records the symptom. In a study by
Sifrim et al., there was an average delay of 28 s Impedance and Clinical Outcome
between the time when a patient coughed and when
they actually recorded a cough on the symptom log The role of impedance in improving clinical out-
[84]. Furthermore, patients only recorded, on aver- comes is uncertain at this time. Several adult
age, 38% of coughs on the log [84]. To address this studies have shown that pH-MII may predict a
limitation, impedance sensors can be paired with clinical response to therapy [87, 88]. There is
pressure sensors which measures esophageal pres- only a single pediatric study which investigated
sure spikes occurring when a patient coughs. the role of how pH-MII testing changed clinical
Coughs appear as simultaneous high pressure outcome. For each pH-MII done for clinical rea-
spikes in the esophagus and this allows for precise sons, Rosen et al. gave the results of the pH por-
correlation between reflux and cough without the tion of the test and asked the referring
possibility for recording error. Because the place- gastroenterologist how the pH results changed
ment of two catheters can be uncomfortable, new management. The MII portion of the test was
technologies are on the horizon to measure cough- then given to the ordering clinician who was
reflux associations less invasively. again asked how this result changed clinical
12 Esophageal pH and Impedance Monitoring 139

management. Out of 50 impedances ordered by tion to the Tuttle test without prior esophageal
23 attendings, the MII portion of the test changed manometry. J Pediatr. 1979;94:81–4.
8. Jolley SG, Tunell WP, Carson JA, Smith EI, Grunow
the clinical management of the patient 22% of the J. The accuracy of abbreviated esophageal pH moni-
time. Whether this change in management results toring in children. J Pediatr Surg. 1984;19:848–54.
in patient improvement is unknown. 9. Tolia V, Kauffman RE. Comparison of evaluation of
gastroesophageal reflux in infants using different
feedings during intraesophageal pH monitoring.
J Pediatr Gastroenterol Nutr. 1990;10:426–9.
The Future for MII 10. Wo JM, Castell DO. Exclusion of meal periods from
ambulatory 24-hour pH monitoring may improve
Currently, evidence indicates that pH-MII has diagnosis of esophageal acid reflux. Dig Dis Sci.
1994;39:1601–7.
replaced the gold standard pH-only monitoring 11. Ter RB, Johnston BT, Castell DO. Exclusion of the meal
for the evaluation of reflux in a research setting. period improves the clinical reliability of esophageal pH
It also seems to be the new gold standard for the monitoring. J Clin Gastroenterol. 1997;25:314–6.
evaluation of patients with persistent symptoms 12. Tobin JM, McCloud P, Cameron DJ. Posture and gas-
tro-oesophageal reflux: a case for left lateral position-
in the postprandial period and for patients with ing. Arch Dis Child. 1997;76:254–8.
persistent symptoms despite acid suppression 13. Bell N, Karol MD, Sachs G, Greski-Rose P, Jennings
therapy. The utility of the technology is limited DE, Hunt RH. Duration of effect of lansoprazole on
by the time-consuming nature of the study inter- gastric pH and acid secretion in normal male volun-
teers. Aliment Pharmacol Ther. 2001;15:105–13.
pretation and a paucity of evidence to prove that 14. van Wijk MP, Benninga MA, Omari TI. Role of the
it improves clinical outcomes over a standard pH multichannel intraluminal impedance technique in
monitoring. infants and children. J Pediatr Gastroenterol Nutr.
2009;48:2–12.
15. Cucchiara S, Staiano A, Gobio Casali L, Boccieri A,
Acknowledgment This work was supported in part by Paone F. Value of the 24 hour intraoesophageal pH
NIH NIDDK073713 (R.R.). monitoring in children. Gut. 1990;31:129–33.
16. Vandenplas Y, Franckx-Goossens A, Pipeleers-
Marichal M, Derde M, Sacre-Smits L. Area under pH
4: advantages of a new parameter in the interpretation
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 Barostat and Other Sensitivity Tests
13
Christophe Faure

(Fig. 13.1). The principle of the barostat is to

Introduction maintain a constant pressure within the air-filled
bag inserted in the organ: when the organ relaxes,
Visceral sensitivity is a complex phenomenon the air-pump inflates the balloon to compensate for
that is regarded as a key pathophysiological fac- the decrease in pressure; when the organ contracts,
tor in children with functional gastrointestinal the system withdraws air and deflates the balloon
disorders. In recent years, novel techniques have so that the intraballoon pressure does not change.
been developed in adults and adapted to children Because in barostat studies the function of the bag
allowing the measurement of visceral sensory is to isolate a segment of the digestive tract without
thresholds of stomach and colon. This chapter interfering with its function and its motility, the
reviews the barostat technique and the satiety compliance of the balloon or bag should be
drinking tests. Functional cerebral imaging and “infinite” and its volume must be greater than the
other chemical stimulations that have not been range of volumes used during the study (rectal
yet used in pediatric subjects are not discussed. bags: length 11 cm, maximal capacity: 600 mL,
gastric bags: maximal diameter 17 cm, maximal
capacity: 1,200 mL). Polyethylene bags rather
Barostat than latex balloons are recommended.
Because visceral sensitivity relies on wall
Principles pressure and not on volume of the organ [1, 2],
sensory thresholds should be expressed as pres-
The barostat is a computer-driven air pump con- sure. Moreover, reproducibility of pressures mea-
nected to a double-lumen catheter on which a surements between laboratories and between
highly compliant balloon or bag is securely fixed. subjects is higher than volumes because the pres-
The balloon is introduced in a hollow organ (in sure scale compensates for differences in bag
children rectum or stomach) and is used to mea- shape, smooth muscle compliance, and contrac-
sure tone, compliance and sensory threshold tile activity of the organs [3].

C. Faure, M.D. (*) Procedure

Division of Pediatric Gastroenterology, Department of
Pediatrics, Sainte-Justine University Health Center,
Technical recommendations for measurements of
Université de Montréal, 3175 Côte Sainte-Catherine,
Montréal, H3T1C5, QC, Canada sensory threshold and compliance have been
e-mail: [email protected] published in adults and the general principles also

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 143

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_13, © Springer Science+Business Media New York 2013
144 C. Faure

Fig. 13.1 Schematic diagram of a

Computer Pressure
barostat and catheter
Sensor

Pressure Line

Reservoir
Air
Motor/Pump Inflation Line

Balloon

apply to practice in children [3]. However, sensory individual operating pressure (IOP) also called
threshold assessment requires an adequate the minimal distending pressure (MDP) which is
cooperation for the report of sensations and feel- the minimum pressure required to overcome sur-
ings by the subject. Children younger than rounding mechanical forces and inflate the bag
7–8 years may not be able to relate adequately with 30 mL of air.
their sensations during the test. Age appropriate Various distension protocols have been
explanation about the equipment and sequence of described [3]. In children the ascending method
the procedure must be offered to the child. Because of limits (AML) without [5–7] or with [8–13]
psychological state modulation results in changed tracking has been the most applied. In the AML
sensation at a given stimulus in healthy adult sub- the barostat is programmed to deliver phasic
jects [4], environment during the barostat study intermittent stimuli starting at the IOP progres-
should be as quiet as possible in order to minimize the sively increased in 2–4 mmHg steps lasting 60 s
external influences and standardize the procedure. followed by 60 s deflation. When the first sensa-
For rectal sensitivity studies in children, most tion of pain is reported, the study can be stopped
authors do not clean extensively the colon but rather (the sensory threshold is determined) or can be
suggest to the child to go to the bathroom before the prolonged (tracking) by subsequent distensions
study. When studying rectal compliance in children randomly adjusted up or down depending on the
with constipation, cleansing of the rectum with an response to the previous distension (if the subject
enema should be done on the day before the barostat reports pain, the next distension will be decreased
study. Because meals may interfere with colonic or kept the same; if the subject reports no pain,
and gastric tone, a 4–6-h fasting period prior to the the next distension will be increased or kept the
study is recommended. All medications affecting same). The threshold is determined by averaging
pain or gastrointestinal motility should be discon- the pressures at which pain had been indicated
tinued at least 48 h prior to the test. after a series of measures (usually 3) (Fig. 13.2).
For rectal studies, the patient lies in the left A 4–5-point scale [6, 10] is used as a verbal
lateral position and the catheter is gently inserted descriptor for sensations felt during the barostat
into the rectum. For gastric studies, the device is procedure. The AML is vulnerable to psycho-
inserted orally. The catheter is then secured with logical biases (fear of pain) because the stimuli
tape and 5–10 min is allowed for adaptation are predictable to the subject. The tracking tech-
before beginning the procedure. The barostat bag nique is believed to be more reliable because it is
is slowly inflated with 30 mL of air and the pres- less vulnerable to psychological bias (the stimuli
sure is allowed to equilibrate for 3 min. The aver- is unpredictable) and because there are multiple
age bag pressure during the last 15 s defines the determinations of the threshold. On the other
13 Barostat and Other Sensitivity Tests 145

Pressure, mmHg
30
4 4 4
25 1 3 3
3
20 3
3 3
15 3
1 1
10 1
5
0
99 200 300 400 500 600 700 800 900 1000 1100 1200 1300 Pain
Corrected Volume mL
200
150
100
50
0
-50
-90
99 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700

Fig. 13.2 Ascending method of limits with tracking. Rectal barostat tracing in an 11-year old girl with IBS. Verbal
scale: 1—gas or first sensation, 2—need to go to the bathroom, 3—urge to go to the bathroom, 4—pain

hand, the tracking technique necessitates deliver- surement is responsive to changing environments or
ing multiple painful stimuli, making it less suit- perturbations and psychological modulation result-
able for use in children. Nevertheless, the tracking ing in changed sensation at a given stimulus in
method has been used successfully without any healthy subjects [4]. In children, there are few data
adverse event by several pediatric groups [8–13]. regarding the influence of psychological state or
Of note the majority of children tested report that trait on sensory threshold assessment. One pediatric
the pain sensation felt during the barostat is nota- study found that rectal sensory threshold did not
bly lower than the pain felt in the real life. correlate with the state of anxiety, suggesting that
the anxiety generated by the procedure itself is not
sufficient to bias the child’s response to distension
Measurements [10]. Results can be expressed as sensory thresh-
olds, i.e., the first pressure that triggers a given sen-
Sensory Thresholds sation (urge to defecate, pain), or in intensity of
The visceral sensory threshold can be separated into sensation triggered by stimuli at fixed pressure.
two components: the perceptual sensitivity (the
ability to detect intraluminal distension) and the Compliance
response bias (how the sensation is reported). The The compliance reflects the ability of a hollow
perceptual sensitivity allows discrimination between organ to adapt to an imposed distension. It is
two distensions and reflects the ability of the organ expressed in mL/mmHg. It is defined as the pres-
to detect and transduce the stimulus to the central sure–volume relationship, represented by a sig-
nervous system. The response bias (or perceptual moid shape, composed of an initial reflex
response) is the reporting behavior (intensity, pain- relaxation followed by a linear section and a final
fulness), a cognitive process influenced by past plateau phase. Compliance is calculated accord-
experience and psychological state. The tools cur- ing to a nonlinear model fitting the pressure–volume
rently used (distending protocols, methods for curves. Pressure–volume curves are constructed
reporting subjects’ response) are not able to accu- with average computed volumes during each
rately measure separately the two components. consecutive pressure step (when equilibration of
Adult studies have shown that the threshold mea- the volume is reached, typically after 30–45 s).
146 C. Faure

Compliance is calculated as the maximum slope hypersensitivity when compared to control chil-
of the pressure–volume curves [3, 9, 12, 14–18]. dren [6, 8–10, 13]. In adults affected by IBS, the
Normal pediatric values have been published for prevalence of visceral hypersensitivity varies from
rectal compliance by two different groups 20% [20] to 94% [21] across studies suggesting
(16 mL/mmHg, range 12–20 mL/mmHg in 22 that rectal hypersensitivity is a more reliable diag-
healthy volunteers aged 12 ± 2.6 years [16]; nostic marker of IBS in children than in adults.
8.7 mL/mmHg, range 6.0–14 mL/mmHg in ten This has been confirmed in a prospective study that
control children aged 13.7 years [12]). Alteration included children with abdominal pain for whom
of gastric compliance has been reported in eight rectal sensory threshold was measured prior to any
children after Nissen fundoplication [17]. other diagnostic procedures [9]. In the 51 children
included, rectal sensory threshold was lower in the
Tone and Accommodation functional gastrointestinal disorders (FGID) group
The volume of air entering or withdrawn from than in the organic disease group (25.4 mmHg vs.
the balloon is an indirect measurement of tone of 37.1 mmHg; P = 0.0002) and 77% of the children
the organ. Changes in volume in response to a with FGID displayed rectal hypersensitivity. At the
meal (accommodation) can thus be easily mea- cutoff of 30 mmHg, the rectal sensory threshold of
sured by subtracting preprandial from postpran- pain measurement for the diagnosis of FGID had a
dial balloon volumes. Rectal volume response to sensitivity of 94% and a specificity of 77%. Rectal
feeding (decrease of 25 ± 3% from 88 ± 8 mL compliance has not been found different between
before the meal to 66 ± 7 mL after the meal) has IBS and control subjects [6, 8, 9, 11, 13]. Children
been reported in healthy children [6]. In the stom- with functional dyspepsia (FD) have normal rectal
ach, no data have been reported in children but sensitivity suggesting that visceral hypersensitivity
they been described in young adults [18]. is organ specific [10].
Data regarding visceral sensitivity in children
Qualitative and Quantitative Assessment with functional abdominal pain (FAP) according
of the Sensations to Rome criteria are less clear with discrepancies
Sensations elicited during the barostat test, painful (sensory threshold similar to controls [6] or simi-
or not, must be rated (intensity) and qualitatively lar to IBS [10]) among authors.
reported. Visual analog scales can be used by chil-
dren aged 6–7 years or older to rate sensations Gastric Sensitivity Measurement
such as urgency or pain [9, 11, 12] and are easier Because of the invasiveness of gastric barostat, the
to use than verbal descriptors in this population. pathophysiology of functional dyspepsia has been
Rating separately pain from unpleasantness is studied scarcely in children. A subset of children
difficult in children. Qualitative evaluation of the with recurrent abdominal pain studied by gastric
pain has been conducted by using validated human barostat using a latex balloon was reported to have
body diagrams [10, 19] and questionnaires inquir- hypersensitivity at the gastric level [13]. More
ing about the similarity of the induced pain and the recently, 16 dyspeptic children were extensively
typical pain felt in the real life [9, 13]. studied using gastric barostat [18]. Compliance was
similar between patients and controls (69.5 ± 8.9 mL/
mmHg). Pressures at the discomfort threshold were
Clinical Relevance of Barostat significantly lower in dyspeptic children compared
Measurements with young healthy controls. Accommodation to a
meal was also significantly lower in dyspeptic chil-
Functional Gastrointestinal Disorders dren. Hypersensitivity to gastric distension was
Rectal Sensitivity Measurement present in 56% (9/16) of patients and impaired
Using the rectal barostat, several independent accommodation in 11 (69%). When studied by gas-
groups have reported that 75–100% of children tric barostat, children with IBS seem to have normal
with irritable bowel syndrome (IBS) have rectal gastric sensitivity [13].
13 Barostat and Other Sensitivity Tests 147

Somatic Projections and Reproducibility been developed. A satiety drinking test using a
of the Visceral Pain liquid meal has been validated in adults and
Somatic referral induced by rectal distension dif- has been correlated to gastric barostat mea-
fers in IBS, FAP and FD children. surements [22]. Subjects are studied after an
In normal children without any gastrointes- overnight fast. A peristaltic pump fills one of
tinal complaints and in dyspeptic patients rec- two beakers at a rate of 15 mL/min with a liq-
tal distension-induced sensations refer to the uid meal (Nutridrink [23], Ensure [24]). The
S3 dermatome (perineal area). In IBS and FAP, children are instructed to drink the meal at the
children refer their sensation to aberrant sites filling rate, thereby alternating the beakers by
compared to the controls, i.e., with abdominal filling and emptying. Every 5 min, they score
projections to dermatomes T8 to L1 [10]. their satiety using a graphic rating scale, graded
However, similar results have been obtained in 0–5 (1 = no sensation, 5 = maximum sensation).
barostat study of children with organic diseases Satiety is defined and explained to the children
suggesting that subjects with protracted com- as the opposite of desire to eat. Children are
plaints of abdominal pain not related to FGID asked to cease the meal intake when a score of
may have in contrast to “true” controls an 5 is reached. The maximal tolerated volume
abnormal perceptual response to distension has been thought to reflect gastric accommoda-
(i.e., abnormal interpretation and sensation in tion. This method has been used in a large
response to rectal distension) [9]. The repro- group of 59 children aged 5–15 years for which
duction of pain during rectal distension is fre- normal values have been published [23].
quent in IBS and FAP children but is not Adolescents with FD have been shown to
predictive of a diagnosis of FGID as compared develop increased symptoms 30 min after
to organic diseases [9]. reaching maximum satiation [24].

Constipation
In constipated children a high rectal compli- Role of Visceral Sensitivity
ance (>20 mL/mmHg) is present in a majority Measurement in Clinical Practice
(58%) of patients suggesting that in order to
reach the intrarectal pressure threshold that By providing an objective criterion in addi-
triggers the sensation of the need to defecate, a tion to the clinical symptoms of FGID, the
larger stool volume is required. In contrast to determination of a low sensory threshold may
previous studies which had used different give a pathophysiological explanation to pedi-
methodologies, it has now been reported that atric patients and their parents, making it possible
only 10% of the patients have a true rectal for them to understand the nature and mecha-
hyposensitivity [15, 16]. Whether the abnormal nisms underlying the symptoms and providing
rectal compliance is primitive or secondary to effective reassurance. Children with IBS or
fecal impaction is uncertain although there is FAP symptoms with a normal rectal sensory
no difference in compliance between groups threshold of pain should be carefully reexam-
with and without impaction [16]. Moreover, ined to exclude other diagnoses. Rectal hyper-
rectal emptying by regularly using enemas sensitivity has been reported in children with
does not normalize compliance [15]. inactive Crohn’s disease suffering from pro-
tracted abdominal pain, suggesting that rectal
barostat may be useful to recognize FGID in
Satiety Drinking Tests such patients [12] . Whether measurement of
visceral sensitivity impacts the outcome of
Because gastric barostat studies are more inva- patients with FGID (number of procedures
sive than rectal barostat tests, less invasive ordered by the physician, long-term progno-
methods of measuring gastric sensitivity have sis, and response to drugs) is unknown.
148 C. Faure

13. Di Lorenzo C, Youssef NN, Sigurdsson L, Scharff L,

References Griffiths J, Wald A. Visceral hyperalgesia in children
with functional abdominal pain. J Pediatr.
1. Camilleri M. Testing the sensitivity hypothesis in 2001;139:838–43.
practice: tools and methods, assumptions and pitfalls. 14. Fox M, Thumshirn M, Fried M, Schwizer W. Barostat
Gut. 2002;51:34i–40. 10.1136/gut.51.suppl_1.i34. measurement of rectal compliance and capacity. Dis
2. Distrutti E, Azpiroz F, Soldevilla A, Malagelada JR. Colon Rectum. 2006;49:360–70.
Gastric wall tension determines perception of gastric 15. van den Berg, Bongers MEJ, Voskuijl WP, Benninga
distention. Gastroenterology. 1999;116:1035–42. MA. No role for increased rectal compliance in pedi-
3. Whitehead WE, Delvaux M. Standardization of atric functional constipation. Gastroenterology. 2009;
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and sensory thresholds in the gastrointestinal tract. 16. Voskuijl WP, van Ginkel R, Benninga MA, Hart
The Working Team of Glaxo-Wellcome Research, GA, Taminiau JA, Boeckxstaens GE. New insight
UK. Dig Dis Sci. 1997;42:223–41. into rectal function in pediatric defecation disor-
4. Ford MJ, Camilleri M, Zinsmeister AR, Hanson RB. ders: disturbed rectal compliance is an essential
Psychosensory modulation of colonic sensation in the mechanism in pediatric constipation. J Pediatr.
human transverse and sigmoid colon. Gastroenterology. 2006;148:62–7.
1995;109:1772–80. 17. Mousa H, Caniano DA, Alhajj M, Gibson L, Di
5. Vlieger AM, van den Berg MM, Menko-Frankenhuis C, Lorenzo C, Binkowitz L. Effect of Nissen fundoplica-
Bongers ME, Tromp E, Benninga MA. No change in tion on gastric motor and sensory functions. J Pediatr
rectal sensitivity after gut-directed hypnotherapy in chil- Gastroenterol Nutr. 2006;43:185–9.
dren with functional abdominal pain or irritable bowel 18. Hoffman I, Vos R, Tack J. Assessment of gastric sen-
syndrome. Am J Gastroenterol. 2010;105:213–8. sorimotor function in paediatric patients with unex-
6. Van Ginkel R, Voskuijl WP, Benninga MA, Taminiau plained dyspeptic symptoms and poor weight gain.
JA, Boeckxstaens GE. Alterations in rectal sensitivity Neurogastroenterol Motil. 2007;19:173–9.
and motility in childhood irritable bowel syndrome. 19. Savedra MC, Tesler MD, Holzemer WL, Wilkie DJ,
Gastroenterology. 2001;120:31–8. Ward JA. Pain location: validity and reliability of
7. van den Berg MM, Voskuijl WP, Boeckxstaens GE, body outline markings by hospitalized children and
Benninga MA. Rectal compliance and rectal sensa- adolescents. Res Nurs Health. 1989;12:307–14.
tion in constipated adolescents, recovered adolescents 20. Camilleri M, McKinzie S, Busciglio I, Low PA,
and healthy volunteers. Gut. 2008;57:599–603. Sweetser S, Burton D, Baxter K, Ryks M, Zinsmeister
8. Iovino P, Tremolaterra F, Boccia G, Miele E, Ruju AR. Prospective study of motor, sensory, psychologic,
FM, Staiano A. Irritable bowel syndrome in child- and autonomic functions in patients with irritable bowel
hood: visceral hypersensitivity and psychosocial syndrome. Clin Gastroenterol Hepatol. 2008;6:772–81.
aspects. Neurogastroenterol Motil. 2009;21:940–e74. 21. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer E.
9. Halac U, Noble A, Faure C. Rectal sensory threshold Altered rectal perception is a biological marker of
for pain is a diagnostic marker of irritable bowel syn- patients with irritable bowel syndrome.
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Pediatr. 2010;156:60–5.e1. 22. Tack J, Caenepeel P, Piessevaux H, Cuomo R, Janssens
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sensations and rectal sensory threshold for pain in tion by a satiety drinking test in health and in severe
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Pediatr. 2007;150:66–71. 23. Hoffman I, Vos R, Tack J. Normal values for the
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Gastroenterol Nutr. 2008;46:272–8. 24. Chitkara DK, Camilleri M, Zinsmeister AR, Burton
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 Radionuclide Transit Tests
14
Lorenzo Biassoni, Keith J. Lindley,
and Osvaldo Borrelli

Scintigraphic techniques are well established tolerated and not operator-dependent [3]. The
methods in the assessment of motility throughout radiation burden is smaller than conventional
the gastrointestinal tract [1, 2]. However, although radiology, and, as g-cameras are linked to digital
research has expanded our understanding of the computers, quantification is relatively easy.
gastrointestinal physiology and our available However, the main pitfalls of most scintigraphic
clinical tools, in the last decade the routine clini- tests are still the lack of standardization of the
cal application of scintigraphy for assessing gas- technique and the poor image processing.
trointestinal motility has been relative static as As in adults, scintigraphic tests in infants and
the technical advantages achieved have not gained children usually require a modest amount of
widespread clinical acceptance. For instance, cooperation; however, some aspects of pediatric
scintigraphy is the gold standard for measuring nuclear medicine are unique due to differences in
gastric motility, but its application is usually lim- organ size, cooperation and neurological and
ited to measuring total gastric emptying time developmental maturation. Performing scintig-
although several data support the clinical value of raphy in children require great patience and skills
evaluating both antral and fundal motor function from the radiographers who interact with the
in patients with dyspeptic symptoms. Moreover, child and family at the time of the examination
small bowel and colonic transit scintigraphic [4]. A fully explanation of the procedure to both
studies are still performed only in selected spe- child and parents is mandatory, including the
cialized centers. length of time they will need to be in the hospital.
Scintigraphic tests are attractive as a means of The parents should be present during the test in
providing exquisite gastrointestinal function order to support the child during the examination.
under physiological conditions with a set of low- The cooperation of the child can also be improved
cost procedures that are easy to perform, well by the use of age-appropriate relaxation and dis-
traction techniques. For example, infants relax
with swaddling and use of a pacifier. Having a
L. Biassoni, M.Sc., F.R.C.P.
Nuclear Medicine, Department of Radiology, Great favorite toy can comfort toddlers. School age and
Ormond Street Hospital for Children, older children may find it helpful to listen to a
London, UK full explanation of the function of the different
K.J. Lindley, M.D., Ph.D. • O. Borrelli, M.D., Ph.D. (*) pieces of equipment before starting the proce-
Division of Neurogastroenterology & Motility, dure. Furthermore, immobilization of the child
Department of Paediatric Gastroenterology,
during the test is an essential part to obtain high-
ICH University College of London, Great Ormond Street
Hospital for Children, London, UK quality images; this is often challenging, and in some
e-mail: [email protected] instances sedation may have to be considered.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 149

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_14, © Springer Science+Business Media New York 2013
150 L. Biassoni et al.

Finally, the administered activity of the radiop- been used without standardization, thus limiting
harmaceutical depends on the child’s body weight its widespread use [7]. Some protocols used in
or body surface. adults are applicable to older children able to of
swallow a bolus on command. Some variations
have been introduced for assessing esophageal
Radiopharmaceuticals motility in young children and infants [8, 9].
This test provides imaging and quantitative data
Tracers used in gastrointestinal motility studies on the transit of a radiolabeled bolus through the
have to be nonabsorbable and stable in the gastric esophagus. It can be used for the diagnosis of
acidity. For esophageal transit, gastroesophageal organic and functional esophageal disorders and
reflux (GER) and gastric emptying studies the is especially valuable when performed serially to
main tracers utilized are 99mTc sulfur colloid or evaluate the effect of medical or surgical treat-
99m
Tc nanocolloid. For instance, for a gastric ments [10].
emptying study these tracers are used for both the The procedure is performed after a fast of at
liquid phase, as they bind well to milk, and for least 3 h in infants and 6 h in children. Any med-
the solid phase, as they have a good affinity for ication with a known effect on esophageal motil-
the protein matrix of the egg white. The maximal ity should be discontinued at least 72 h before
limit of the activity that can be administered var- the testing. 99mTc sulfur colloid is routinely used
ies according to the different countries, ranging for esophageal transit scintigraphy. In adults, the
between 18 and 74 MBq [5, 6]. In the UK, the majority of the studies have been performed
maximal limit is 40 MBq for studies evaluating using a liquid bolus, whereas only few studies
oesophageal motility and GER: this activity gives have used a semisolid bolus [11, 12]. A semi-
a maximal radiation burden of 0.9 mSv. For gas- solid bolus requires more intense peristalsis to
tric emptying studies the maximal activity is complete the transport over the distal half of the
12 MBq, which gives a radiation burden of esophagus and this can increase the sensitivity of
approximately 0.3 mSv. the test [13]. Because of the difficulty in reach-
99m
Tc diethyl-triamine-pentacetic acid (DTPA) ing a consensus on the viscosity and the type of
is used as a tracer for the liquid phase of the gas- the semisolid bolus, as well as the difficulty of
tric emptying, for small bowel transit and colonic keeping the bolus viscosity constant to avoid its
studies. The maximal administered activity var- fragmentation, the liquid bolus is still routinely
ies between 18 and 37 MBq. 99mTc macroaggre- used for assessing esophageal motility abnor-
gates of albumin (MAA) can be used in the liquid malities. In infants and children a dose of at least
phase of the gastric emptying study. 150 m(mu)Ci (5.55 MBq) is added to 10 mL
With regard to the small bowel and colon tran- bolus of milk or water. In the case of milk allergy
sit studies, 111In-DTPA is frequently used as a a substitute may be used.
tracer for the liquid phase. The administered Infants can lie on a slightly inclined collima-
activity varies between 5.55 and 18.5 MBq. The tor. Older children can sit up with their back to
maximal administered activity in the UK is the collimator. It is essential to turn the head of
10 MBq, which gives a radiation burden of the bottle fed infants to the side, to avoid super-
approximately 3 mSv. imposition of the radioactivity in the bottle over
the upper esophagus. Older children can be fed
with a cup or with a straw. Before the administra-
Esophageal Transit tion of the radiolabeled bolus an external small
radioactive marker is placed over the cricoid car-
Esophageal transit scintigraphy is a non invasive tilage as anatomical landmark. After a practice
method to qualitatively and quantitatively assess swallow with unlabeled liquid, the radioactive
esophageal motility. It is fast, easy to perform bolus is placed in the mouth and swallowed on
with minimal radiation exposure. However, since command followed by a dry bolus at least 30 s
its introduction by Kazam several protocols have later. Since some swallows are not completely
14 Radionuclide Transit Tests 151

propagated even in healthy subjects, 4–6 swal- into upper, middle and lower zones. Equal regions
lows should be obtained. The patient’s position of interest (ROI) are placed on each zone and a
during the study can affect the results due to the fourth ROI is placed over the stomach. Time–
effect of gravity. Performing the study with the activity curves for the proximal, mid and distal
patient in an upright position may be more physi- parts of the esophagus are generated. The curves
ologic. Eliminating the force of gravity by per- allow quantitative and qualitative assessment of
forming the study with the patient in the supine the bolus transit. Condensed dynamic images that
position is more practical in infants and young summarize the whole deglutition event into one
children and more efficient in exposing motility single image may also be used. A condensed
disorders. dynamic image displays the profile of the swal-
A large-field-of-view g(gamma)-camera fitted lowing event side by side on the y-axis, along
with a low-energy high-sensitivity collimator is with the time on the x-axis. The total transit time
usually used due to high temporal resolution is usually calculated as the period between the
required for quantitative studies. Dynamic images first appearance of the marker in the proximal
in 128 × 128 matrix must be acquired in a rapid esophagus and the time needed to obtain 90%
sequence. Because many of the events occur in a radioactivity clearance from the distal esophagus.
short time, images should be acquired at 4–10 The residual 10% of the marker is ignored in
frames per second for 60 s. The field of view of order to avoid any potential overlap with the
the g(gamma)-camera must include the entire marker contained in the fundus. Besides total and
esophageal tract including the mouth and the gas- segmental transit times, a clearance rate at time t
tric fundus. An additional 10 min static acquisi- is usually obtained with the following formula:
tion is obtained when the patient is asked to dry C = (Emax − Et)/Emax × 100%, where Emax is the
swallow, in order to measure the clearance from maximal esophageal radioactivity and Et is the
the esophagus. If a large residual remains in the radioactivity at time 0 [9, 11, 12]. In healthy
esophagus delayed static images are obtained at adults and in children, the pharyngeal transit is
30 and 60 min. A Co-57 transmission image may quite rapid requiring less than 1 s. The normal
be taken immediately or at 10 min following transit time through the esophagus is typically
completion of the dynamic acquisition when the less than 10 s, ranging from 3.4 ± 1 s for infants,
anatomical location of the tracer is uncertain 4.6 ± 1.9 for children aged 8–16 years, 5.5 ± 1.1
(gastric fundus versus esophagus). for adults [17].
Once the study has been completed, the images The sensitivity and specificity of the esopha-
are reviewed in a one-to-one single-frame analy- geal scintigraphy to detect esophageal disorders
sis and then played back in a cine display mode. vary widely depending on the technique used and
This procedure depicts the dynamics of the swal- the esophageal disorder investigated. No diag-
lowing and swallowing-related esophageal motor nostic benefit of esophageal scintigraphy has
pattern, and helps to identify aberrant patterns. been shown in patients with normal peristalsis
For instance the adynamic pattern is character- even in the presence of severe motor abnormali-
ized by slow progression or even stopping of the ties as nutcracker esophagus or isolated hyper-
bolus along the esophagus, such as in achalasia tensive lower esophageal sphincter (LES)
and scleroderma, whereas the uncoordinated pat- [18–20]. On the other hand, several studies have
tern is characterized by random disorganized ret- shown its ability in detecting abnormalities of
rograde/antegrade contractions throughout the esophageal peristalsis, such as achalasia, sclero-
esophagus as occur in patients with diffuse derma, esophageal atresia, and diffuse esopha-
esophageal spasm [14–16]. This visual pattern geal spasm [14, 21–23]. However, it still
corresponds to multiple peaks of the time–activity represents an ancillary test when compared to
curves as determined by the quantitative assess- esophageal manometry.
ment of the esophageal transit. Esophageal transit The main indications for esophageal transit
can be measured quantitatively with time and scintigraphy are the evaluation of esophageal
retention parameters. The esophagus is divided motility in patients who cannot tolerate manometry,
152 L. Biassoni et al.

the lack of availability of esophageal manometry, bags and Velcro straps) may be used to secure
equivocal manometric results, and follow-up of young children to the imaging bed and prevent
patients with esophageal motor disorders such as motion. Dynamic images are acquired from the
achalasia and scleroderma (for instance, to assess posterior view with the stomach and chest in the
the efficacy of surgical or medical therapy). field of view at a frame rate variable between 10
and 30 s/frame for 60 min [31]. Any event dur-
ing the acquisition (motion, coughing, vomiting,
Gastroesophageal Reflux and reflux), is recorded, with the time when it hap-
Aspiration pens. The dynamic images are followed by ante-
rior and posterior static views of the chest with
GER scintigraphy has been widely used for the the stomach out of the field of view. These
evaluation of GER in children [8, 24–28]. It is images are recorded on a 256 × 256 matrix over
easy to perform, is well tolerated and requires 3–5 min. It is important to perform the dynamic
minimum patient’s cooperation. It also entails a study over 60–120 min because a significant
low radiation burden. Advantages of GER scin- number of GER episodes can be missed by lim-
tigraphy include the ability to detect pulmonary iting the study to 60 min. The supine position is
aspiration and to evaluate gastric emptying in the more sensitive than the prone position to detect
same study [29, 30]. GER [32].
In young infants the radioactive milk or formula New appearance of tracer in the esophagus
should replace the normally scheduled feeding, indicates a reflux episode. Placing markers over
while older children should fast at least 4 h prior to the shoulders, suprasternal notch, and xiphoid is
the test. The tracer used is 99mTc sulfur colloid or helpful in determining the level of reflux in the
nanocolloid (or 99mTc DTPA) mixed with an appro- esophagus or oropharynx and in localizing pos-
priate volume (between 30 and 240 ml) of milk, or sible activity within the lungs. The interpretation
milk formula. The amount of activity administered can be enhanced by generating time–activity
is 0.55 MBq/kg, with a minimum activity of curves from ROIs placed over the esophagus.
7.4 MBq and a maximum of 40 MBq. The tracer is GER episodes are seen as sharp spikes in the
added to a portion of the patient’s feeding (one third curves. Patient motion during the study can intro-
to one half of the normal milk or formula feeding duce significant artifacts in the curves. Images
volume). This volume is introduced into the stom- should always be inspected for motion prior to
ach by oral feeding or alternatively by nasogastric interpretation and motion correction should be
tube (which should be removed after feeding) or by applied when necessary. Visual inspection of the
gastrostomy tube when used for routine feedings. images in conjunction with curve interpretation
A second tracer free volume is then given to com- and viewing of the study in cine mode is the most
plete the meal. The tracer free volume has an impor- accurate way to read the study.
tant role of clearing residual tracer from the The presence of GER can be quantified using
oropharynx and esophagus prior to imaging. The the formula: R = E(t) − E(b) × 100/Go, where R is
volume of the feeding varies according to the the percentage of reflux material into the esopha-
patient’s age and weight. In most cases the desired gus, E(t) the esophageal count at time t, E(b) the
volume is similar to the volume the patient is given para-esophageal background counts, Go the gas-
for regular meals. The times of beginning and com- tric counts at the beginning of the study. R and
pleting feeding should be recorded. E(t) may refer to the entire organ and the indi-
There is no single universally accepted pro- vidual regions [33]. According to this formula,
tocol for this study. Most protocols however the presence of a reflux >5% is considered abnor-
share the same basic principles. After feeding, mal [27].
the child is positioned supine on the g(gamma)- Sensitivity and specificity of a 1-h scintigraphy
camera couch. Young infants should be burped for the diagnosis of GERD are 15–59% and
when possible prior to imaging. Restraints (sand 83–100%, respectively, when compared with 24-h
14 Radionuclide Transit Tests 153

esophageal pH monitoring [26, 28, 34, 35]. test meal is considered more reliable than a liquid
Interestingly, scintigraphy has been shown to be meal for measuring gastric emptying. Solid meals
more sensitive in the detection of reflux beyond the are used in older children and adolescents. In
first postprandial hour as compared to pH monitor- infants milk or milk formula is the natural and
ing, which usually fails to detect some types of only practical choice for a test meal. Medications
reflux, especially when little or no acid is present in that affect gastric motility should be discontinued
the refluxate [28]. Evidence of pulmonary aspira- for an appropriate period prior to the test depend-
tion is usually assessed through images obtained up ing on the pharmacokinetics of the drugs, unless
to 24 h after administration of the radionuclide [29, the purpose of the study is to evaluate the effect
30]. However, a negative test does not exclude the of specific drugs on gastric motility. Furthermore,
possibility of infrequently occurring aspiration. fasting blood glucose should be within normal
Following the introduction of multichannel intralu- range, due to the well-known effect of hypergly-
minal impedance and pH (MII-pH) monitoring that cemia on the gastric motor activity [43].
can characterize the reflux episodes as acid or non- The child has to be kept nil by mouth for approx-
acid, as well as the level reached by the refluxate, imately 4 h. Young infants should miss a normal
nuclear scintigraphy is not recommended in the feeding just prior to the test. The meal (either liquid
routine diagnosis and management of GER disease or solid or both) has to be introduced within
(GERD) in infants and children [36]. 10–15 min. The tracer of choice is either 99mTc
nanocolloid or sulfur colloid or 99mTc-DTPA, mixed
with an appropriate volume of liquid (between 30
Gastric Emptying Study and 240 ml, according to age) [24]. The liquid used
can be milk or formula, orange or apple juice. The
Children with gastric motor disorders may present radioisotope is added to the meal and a second trac-
with a wide array of foregut symptoms from nau- er-free volume is added to complete the desired
sea and vomiting to early satiety and abdominal feeding volume. Oral feeding is preferred but feed-
distension of varying severity. Although there is a ing through a nasogastric tube or gastrostomy tube
poor correlation between severity of symptoms is occasionally required. The gastric emptying study
and the degree of gastric emptying, assessment of with a liquid feed is performed preferentially in
gastric emptying in some circumstances helps to children up to 2 years of age. In older children the
guide treatment decisions [37]. Measurement of liquid phase is used in addition to the solid phase.
gastric emptying is generally indicated when mor- After completion of the feeding, the patient is
phologic investigations fail to reveal the cause of placed in the supine position and continuous
dyspeptic symptoms, in diabetics with poor con- dynamic images of the stomach and chest are
trol of the disease and in severe GERD unrespon- recorded on a 128 × 128 matrix, 30 s/frame, for
sive to medical treatment [38–41]. Meaningful 60–120 min. Images are obtained in the anterior
quantification of gastric emptying requires stan- and posterior projections using a dual head cam-
dardization of study techniques and standardiza- era. Static images of the chest and abdomen using
tion of the test meal. Standardization is essential a 256 × 256 matrix at 60 min are acquired. If gas-
for inter- and intra-subject comparisons. Gastric tric emptying is delayed, additional images
emptying scintigraphy is the most widely accepted should be obtained at hourly intervals up to 4 h
technique in clinical practice and is regarded as the [44, 45]. A ROI is placed around the stomach,
gold standard [42]. It is a physiologic, noninvasive, as seen in the immediate post-feeding image.
low cost technique to evaluate gastric emptying A time–activity curve, corrected for decay, is
based on imaging and quantification of a radiola- generated from the stomach ROI. Motion correc-
beled test meal. tion should be applied when required. Care
Several protocols for gastric emptying are should be taken not to include bowel activity in
used in clinical practice. These vary in the meal the gastric ROI. Gastric emptying can be
content, volume, and imaging technique. A solid expressed as a percentage of the initial activity
154 L. Biassoni et al.

remaining at a specific time point (residual) or as imaging projection, normal control values can be
the activity emptied by the stomach at these used as a guide. These values expressed as a per-
times. It can also be expressed as the half-empty- centage of gastric residuals are 60–82% at 1 h
ing time (t½). The pattern of the emptying curve and 25–55% at 2 h. An example of delayed gas-
is important, including the presence and the dura- tric emptying with GOR is shown in Fig. 14.1.
tion of the lag phase (seen in solid gastric empty- At the end of the dynamic acquisition further
ing), which can provide evidence on abnormalities imaging is performed at 2 h to assess for further
in gastric motility. Milk usually empties in an gastric emptying. It is expected that no significant
exponential or bi-exponential manner [24]. activity persist in the stomach by 2 h with a liquid
Some features of the protocol are subject to feed. This delayed imaging acquisition is per-
variability and warrant further discussion. The formed in the same way as the remainder of the
duration of the study is not well standardized, study, to allow comparison with the previous
although several studies in adults support the imaging and extrapolation of the time activity
superiority of a longer, 4 h study rather than 2-h curve to the delayed images.
study [44, 45]. Geometrical mean of the anterior Gastric emptying with a solid test meal is the
and posterior counts, acquired simultaneously preferred method to assess gastric emptying in
with a dual detector camera, is recommended to older children and adolescents. It is important
correct for the artifacts produced by the non-uniform that the radioactive label remains firmly attached
attenuation of the radiotracer within the stomach, to the solid phase. A stable label can be achieved
with the fundus situated more posteriorly and the by mixing and cooking 99mTc sulfur colloid with
antrum more anteriorly. Continuous data record- a whole egg (82% bound at 3 h) or with the egg
ing is preferable over recording data only at dis- white (95% bound at 3 h). A stable label can also
crete time intervals, as it gives information on the be obtained with fat free egg substitutes. The
lag phase and may be helpful in identifying pat- consensus guidelines for the gastric emptying
terns of rapid gastric emptying. study using a solid meal recommend a meal based
A major problem with gastric emptying scin- on egg whites, two slices of toasted white bread,
tigraphy in children is the lack of age related jam or jelly and water. The guidelines specify the
normal values derived from large groups of nor- details of how to cook the meal, with the amount
mal controls. Normal children cannot be studied of the different ingredients. The tracer of choice
as control subjects due to ethical considerations. is 99mTc sulfur or nanocolloid, as it sticks well to
Pooling data from different institutions to estab- the egg white. If the child is intolerant to eggs, a
lish a normal range is problematic due to lack of different meal should be used. It is important that
standardization of the study technique and the every effort is made to follow the standardized
test meal. Given these limitations, it is best for meal as this allows comparison with an estab-
individual laboratories to establish their own lished normal range and between results from
normal range. For milk, a residual of 36–68% at different centers. A detailed record of the time it
1 h was reported in infants, and 42–56% in a takes to ingest the meal (or if any portion of it has
small number of older children [46]. The normal not be eaten) should be kept.
range for liquid gastric emptying residuals with At the time of reporting, it is very important to
99m
Tc sulfur colloid labeled dextrose at 1 h in have a detailed clinical history including possible
children less than 2 years of age can range previous surgical procedures, current medica-
between 27 and 81%, and in children 2 years of tions, and current symptoms. The clinical ques-
age or over 11–47% [47]. The range of normal tion that motivates the examination should be
values for solid gastric emptying in children has clear. Symptoms occurring during the examina-
not been established. In a small series of 11 tion (cough, vomit) should be documented, with
normal control children, 5–11 years old, solid the time when they occurred. The type of meal
gastric emptying values corresponded well to given, the amount, the imaging protocol, the
those described in adults [48]. Using the anterior technique of acquisition, should be described in
Fig. 14.1 Twenty-two-months-old girl complaining of the oesopagus during the first 40 min of the dynamic
difficulties in feeding. A gastric emptying study with liq- study. At the end of the 60 min acquisition only 10% of
uid feed was performed. Images were acquired at a frame the administered tracer leaves the stomach. By 2 h,
rate of 20 s/frame over 60 min. A delayed acquisition for approximately 60% of tracer has left the stomach, with
1 min at the same rate was performed. 15 MBq Tc-99m- 40% of the initial gastric content still seen. The appear-
nanocolloid mixed with 150 ml of milk was given through ances are compatible with a severely delayed gastric emp-
the gastrostomy tube. There are multiple episodes of gas- tying for liquids and several episodes of GER
troesophageal reflux (GER) reaching the upper third of
156 L. Biassoni et al.

the report. The percentage of tracer retained in clinical management, although its analysis needs
the stomach at specific times in comparison to the to be interpreted with caution, keeping in mind
normal reference values should be mentioned. A that both delayed colonic transit and gastric emp-
description of the different patterns of gastric tying can affect small bowel transit. No data are
emptying (i.e., tracer remaining within the antrum available in children.
or fundus, possible dysmotility) may be helpful.
Possible sources of error include a nonstan-
dard meal, poor labeling of the meal, nausea Colonic Transit Scintigraphy
caused by the meal, vomit after the ingestion of
the meal, ingestion of food just before the study, Two techniques are used to evaluate motility
overlap of small bowel activity over the stomach, through the GI tract, both of which involve
prolonged time to ingest the meal, and GER. irradiation of the subjects: transit of radiopaque
Furthermore, although a delayed gastric empty- (plastic) markers viewed by x-ray and transit
ing can be found in up to 70% of patients with of radioisotope viewed by g(gamma)-camera
functional dyspepsia, it does not prove that symp- (scintigraphy). Together, with the assessment
toms are due to gastroparesis, as well as both of rectal evacuation dynamics and rectal sensa-
rapid and delayed gastric emptying cause similar tion, the radioisotope studies of colonic transit
symptoms [49]. represent the cornerstone investigations in
patients with chronic constipation. These
investigations have led to constipation being
Small Intestine Transit Scintigraphy conceptualized in three broad and overlapping
categories: normal transit constipation, slow
Assessment of small bowel transit time is largely transit constipation, and evacuation disorders.
dependent on gastric emptying time and complex Transit studies per se address the question of
movements of the chyme into the small intestine whether the patient has a normal or delayed
[50]. In adults, small bowel scintigraphy is not colonic transit.
commonly used outside research settings, and it Colonic transit scintigraphy is a safe and non-
is usually performed as part of whole gut transit invasive method for the quantitative evaluation of
study. To our knowledge in children there are overall and regional colonic transit [57]. It has
only few published data regarding this issue. The been shown to correlate with radiopaque markers
study involves the ingestion of either a solid [58–62]. The radioisotope can be given orally
(meals or capsule) or liquid (water) materials either in a nonabsorbable form together with a
labeled with 99mTc or 111In (see colonic transit test meal (radiolabeled mixed meal), or in a non-
study) [51–53]. The commonest scintigraphic digestible capsules. As the images are captured
method for assessing small bowel transit is to on a g-camera there is no increase of radiation
measure orocecal transit time, defined as the time exposure with multiple scans, as the radiation
taken for 10% of small bowel radioactivity to burden is the same irrespective of the number of
accumulate into the cecum [54–56]. Thus, it is a times the patient is imaged. It has been shown
very laborious method since it requires multiple that the total amount of radiation exposure is sim-
image taken every 10 min until 10% of the activ- ilar to two abdominal x-rays [63]. This test offers
ity reaches the colon. A valid surrogate for the reproducible and accurate performance across a
10% activity is the percentage of the adminis- spectrum of disorders, linking colonic transit
tered activity in the terminal ileum at 6 h after measurement to symptoms and disease processes,
meal ingestion. Normative data in adults are lim- and demonstrating response to treatment [57].
ited, thus the test seems to be diagnostic only if The patient should use their usual method of
extreme value are present. Identification of abnor- bowel emptying 2 days before the study and
mal small bowel transit through scintigraphy has should not use any further stool softeners, laxa-
been shown to modify both initial diagnosis and tive, enemas, and suppositories until the end of
14 Radionuclide Transit Tests 157

the study. The procedure is performed after a fast acceptable specificity and high sensitivity for
of at least 6 h in children. The isotope (99mTc or detecting motility disorders, although in selected
111
In) can be given orally in a nonabsorbable form circumstances images can be taken at 72 h and
with a test meal, or in a capsule coated with pH possibly up to 96 h [66]. Anterior and posterior
sensitive material that dissolves in the colon or images are obtained for an acquisition time up to
terminal ileum [64, 65]. 111In labeled tracers are 400 s on a 256 × 256 matrix. The pulse height ana-
the most widely used in this clinical setting. lyzer of the g(gamma)-camera is centered on
Because the test is relatively new in clinical prac- 140 keV with a window of ±20% to detect counts
tice, there are many different protocols. A stan- from Tc-99 m and on two peaks (173 and 247 keV)
dardized protocol of acquisition has not been ±20% to detect counts from In-111. An example
agreed yet. In the single-isotope test meal, 99mTc of colonic scintigraphy in a patient with slow tran-
phytate colloid is suspended in 20 ml of milk. sit constipation is shown in Fig. 14.2.
The dose is determined according to body’s The analysis of colonic transit is performed
weight based on an adult dose of 250 MBq. The drawing different colonic ROIs on both the ante-
dual isotope test meal consists of a sandwich of rior and the posterior images in order to quantify
two 99mTc sulfur colloid labeled scrambled eggs the geometric center (GC) which represents the
and 300 ml of water labeled with 111In-DTPA. weighted average of radioactivity over specific
The meal is consumed by the patient at the start regions of the bowel and determines the median
of the study. The rationale for utilizing radiola- point of radioactivity for each time point. The
beled liquids for the small intestine and colonic number of ROIs varies from 5 to 7, including the
transit studies is the reduction of variability in segment referring to the expelled stools (Fig. 14.3).
small intestine and colonic transit that might be For instance, Southwell and coworkers defined six
caused by delayed gastric emptying for solids. In colonic ROIs each with a numerical values: (1)
general, the liquid component of a test meal Small Intestine, (2) Cecum-Ascending Colon, (3)
leaves the stomach much more rapidly than the Transverse Colon, (4) Descending Colon, (5)
solid component. In a different single and dual Rectosigmoid Colon, and (6) Excreted Stools [66].
method 111In-Cl3 (0.1 mCi) mixed with a slurry of The geometric center is calculated as the sum of
5 mg of activated charcoal is delivered within a the products of the proportion of 111In counts in
coated capsule. The slurry is evaporated to dry- each region and its weighting factor from the fol-
ness on a hotplate at 90 °C, and the dried charcoal lowing equation: GC: S(Sigma)n fraction of activ-
is placed into a size 1 gelatine capsule and coated ity in ROIn × n, where n is the number of each
with pH-sensitive methacrylate. Luminal pH region (1–5, 1–7, or 1–8, based on the method
increases in the distal ileum and the capsule opens applied). A low GC indicates that the center of the
to release its contents into the cecum. Markers activity is in the proximal colon, and a higher GC
placed on the patient’s anterior superior iliac indicates that it has progresses on the left side of
spine facilitated identification of the small bowel, the colon has been eliminated in the stool. In
in order to ascertain that the capsule had emptied adults, based on the method, the normal mean (±1
from the stomach before feeding the 99mTc sulfur SD) GC values range between 2.67 ± 1.09 to
colloid-labeled test meal. 4.6 ± 1.5 at 24 h, 3.89 ± 0.15 to 6.1 ± 1.0 at 48 h,
Imaging is performed with the patient in upright and 6.6 ± 0.19 at 72 h [59, 67]. In children, the nor-
position using a large g-camera equipped with a mal mean ± SD GC values are 3.9 ± 1.1 at 24 h, and
medium energy collimator. During dual isotope 5.2 ± 0.9 at 48 h [68]. Of note, as a summary of the
test images are acquired immediately after inges- colonic transit some researchers also utilize the
tion of the meal every 30 min for 2 h to measure emptying of ascending colon expressed as t½ (time
gastric emptying of solid and liquids. Afterwards, for 50% emptying), which is significantly corre-
the images are usually taken at 4, 6, 24, and 48 h. lated with stools consistency.
There is a consensus that images at 24 and 48 h Three categories of colonic transit could be
give a good summary of colonic transit with readily distinguished also by visual assessment of
158 L. Biassoni et al.

Fig. 14.2 Colonic transit study of a patient with severe after tracer ingestions and subsequently on days 2, 3, and
slow transit chronic constipation. The study was per- 4. The images show slow progression of the tracer
formed following the administration of 3 MBq In-111 throughout the whole of the colon, not just in a specific
chloride as a liquid. Imaging was obtained on day 1 6 h portion of it

Fig. 14.3 To quantitate colon transit, the geometric cen- number of Regions of Interest (ROIs) used in different
ter (GC) has been defined to measure the progression of studies varies from 5 to 7, including the segment referring
colonic activity. To calculate the GC, the colon is divided to the expelled stools
into anatomic regions each with a numerical value. The

the acquired images. In normal studies, the tracer verse colon at 24, 36 and 48 h. In children with
reaches the cecum in 6 h, and is largely excreted outlet obstruction or functional fecal retention, the
by 48 h. Slow colonic transit is identified when the tracer reaches the rectosigmoid by 24 to 36 h but is
tracer reaches the cecum at 6 h, but most radioac- not passed at 48 h. In children and adolescent with
tivity is retained in the proximal colon and trans- refractory functional constipation, slow transit in
14 Radionuclide Transit Tests 159

the proximal colon occurs in 20–50% and outlet 11. Tatsch K, Voderholzer WA, Weiss MJ, Schrottle W,
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pylori-negative non-ulcer dyspepsia. J Pediatr Scintigraphic evaluation of small bowel transit in
Gastroenterol Nutr. 2004;39:246–52. healthy subjects: inter- and intrasubject variability.
39. Spiroglou K, Xinias I, Karatzas N, et al. Gastric emp- Am J Gastroenterol. 1995;90:938–42.
tying in children with cerebral palsy and gastroesoph- 55. Miller MA, Parkman HP, Urbain JL, et al. Comparison
ageal reflux. Pediatr Neurol. 2004;31:177–82. of scintigraphy and lactulose breath hydrogen test for
40. Argon M, Duygun U, Daglioz G, et al. Relationship assessment of orocecal transit: lactulose accelerates
between gastric emptying and gastroesophageal reflux in small bowel transit. Dig Dis Sci. 1997;42:10–8.
infants and children. Clin Nucl Med. 2006;31:262–5. 56. Charles F, Camilleri M, Phillips SF, et al. Scintigraphy
41. Caldaro T, Garganese MC, Torroni F, et al. Delayed of the whole gut: clinical evaluation of transit disor-
gastric emptying and typical scintigraphic gastric ders. Mayo Clin Proc. 1995;70:113–8.
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57. Camilleri M. Scintigraphic biomarkers for colonic 64. Bonapace ES, Maurer AH, Davidoff S, Krevsky B,
dysmotility. Clin Parmacol Ther. 2010;87:748–53. Fisher RS, Parkman HP. Whole gut transit scintigra-
58. van der Sijp JR, Kamm MA, Nightingale JM, et al. phy in the clinical evaluation of patients with upper
Radioisotope determination of regional colonic transit and lower gastrointestinal symptoms. Am J
in severe constipation: comparison with radio opaque Gastroenterol. 2000;95:2838–47.
markers. Gut. 1993;34:402–8. 65. Burton DD, Camilleri M, Mullan BP, Forstrom LA,
59. Cremonini F, Mullan BP, Camilleri M, Burton DD, Hung JC. Colonic transit scintigraphy labeled acti-
Rank MR. Performance characteristics of scinti- vated charcoal compared with ion exchange pellets. J
graphic transit measurements for studies of experi- Nucl Med. 1997;38:1807–10.
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2002;16:1781–90. Colonic transit studies: normal values for adults and
60. Lundin E, Graf W, Garske U, et al. Segmental colonic children with comparison of radiological and scinti-
transit studies: comparison of a radiological and a graphic methods. Pediatr Surg Int. 2009;25:559–72.
scintigraphic method. Colorectal Dis. 67. Krevsky B, Maurer AH, Niewiarowski T, Cohen S.
2007;9:344–51. Effect of verapamil on human intestinal transit. Dig
61. Stivland T, Camilleri M, Vassallo M, et al. Scintigraphic Dis Sci. 1992;37:919–24.
measurement of regional gut transit in idiopathic con- 68. Cook BJ, Lim E, Cook D, et al. Radionuclear transit
stipation. Gastroenterology. 1991;101:107–15. to assess sites of delay in large bowel transit in chil-
62. Degen LP, Phillips SF. Variability of gastrointestinal dren with chronic idiopathic constipation. J Pediatr
transit in healthy women and men. Gut. Surg. 2005;40:478–83.
1996;39:299–305. 69. Chitkara DK, Bredenoord AJ, Cremonini F, et al. The
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 Electrogastrography, Breath Tests,
Ultrasonography, Transit Tests, 15
and SmartPill

Leonel Rodriguez

computed based on spectral analysis. This allows

Electrogastrography an objective interpretation of the results. Since
the first recording of an electrogastrogram in
Electrogastrography (EGG) is a noninvasive test 1921 by Alvarez [4] multiple improvements to
that records the gastric myoelectrical activity the technique have been applied with the
through cutaneous leads. The basis of the test is advances of technology. In the early stages, most
to identify the normal rhythmicity of the stom- of the investigations on EGG were focused on
ach of 3 cycles per minute (range 2–4) which its role on diagnosing peptic ulcer disease and
reliably corresponds to the slow wave generated gastric cancer and the physiological changes
by the gastric pacemaker, confirmed by simulta- caused by gastric surgery. Over the last two
neous electrode recordings from gastric mucosa decades the focus has expanded to evaluate
and serosa and skin in animals and humans [1–3]. symptoms more than conditions. The first report
Values above and below this range are called of the use of EGG in children occurred in 1976,
tachygastria and bradygastria, respectively when Disembaeva et al. reported the normal
(Fig. 15.1). The variables evaluated include the patterns of EGG in healthy children [5], followed
dominant frequency, the dominant power (ampli- by a report from Mirutko et al. describing its
tude in decibels), the percentage of normal fre- potential applicability on the evaluation and
quency and the percentage of coupling. The management of peptic ulcer disease [6]. The
rhythmicity from other organs (like heartbeat field of pediatric EGG exploded in the 1990s,
and respiration) is filtered out during the record- when the technique was evaluated in multiple
ing and motion artifact can be either analyzed disorders and symptoms.
visually or via a motion sensor and then manu-
ally excluded. The signal from all recordings is
then selected and then the EGG parameters are Developmental Aspects

The gastric rhythm of three contractions per

minute seems to be irregular or absent at birth
and matures over time [7, 8]. Although some
L. Rodriguez, M.D., M.S. (*) have reported no difference between term and
Gastroenterology Division, Department of Medicine, preterm infants [9], there seems to be agreement
Harvard Medical School, Children’s Hospital,
that the rhythmicity reaches adult characteristics
300 Longowood Avenue, Boston, MA 02493, USA
e-mail: [email protected] in late childhood [7, 10].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 163

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_15, © Springer Science+Business Media New York 2013
164 L. Rodriguez

Fig. 15.1 Electrogastrogram parts of two electrogastrogram studies. (a) Shows normogastria or normal gastric rhythm
of 3 cpm and (b) shows tachygastria with a rhythm of 5 cpm

Normal Values used in children and adolescents when same meth-

odology is applied [14]. Among the factors that may
Multiple studies have attempted to develop norms affect the values of the test are the meal content and
for children, unfortunately with different method- position. For infants, breast feeding compared to
ologies. The largest study evaluating normal values formula feeding [15] and for adults solid meals
was done by Riezzo et al. in 114 healthy children compared to liquid meals [16] are associated with
aged 6–12 years, reporting a gastric rhythm in the higher dominant frequency and power.
2.0–4.0 cpm range with a significant increase in
postprandial dominant frequency and power [11].
Another study with 55 healthy volunteers age Clinical Applications
6–18 years showed a mean dominant frequency
2.9 ± 0.40 cycles per minute preprandially and EGG has been regarded as substitute to other more
3.1 ± 0.35 postprandially, 80% ± 13% preprandial invasive tests, like the gastric emptying by scintig-
normogastria and 85% ± 11% postprandial nor- raphy and the antroduodenal manometry, and also
mogastria [12]. These normative values were inde- for others noninvasive but associated to operator
pendent from age, gender, BMI [11, 12], and dependent concerns, like ultrasonography.
position [13]. A recent study demonstrated that However, most studies have not used the same
the adult norms reported by the American methodology in terms of number and position of
Neurogastroenterology and Motility Society can be electrodes, recording time, test meals and analytical
15 Electrogastrography, Breath Tests, Ultrasonography, Transit Tests, and SmartPill 165

software, limiting the validity of the test. Multiple and EGG is normal in the early stages of anorexia
studies in healthy adults as well as adults with nervosa [30].
specific disorders have shown no significant
correlation between the findings on the EGG and Effect of Medications on Gastric
the gastric emptying by scintigraphy, and small Myoelectrical Activity
series in children have replicated those findings Prokinetic agents domperidone [31] and cisap-
[17]. EGG is not useful to discriminate between ride [32] unlike erythromycin [33] were effective
the three phases of the myoelectric migrating in normalizing gastric myoelectrical activity in
complex in adults [18] but is helpful differentiating children. General anesthesia has been associated
children with normal or abnormal antroduodenal with significant gastric dysrhythmias that return
manometry although there is significant overlap in to baseline about an hour after anesthesia is
EGG results with significant artifact from move- stopped [34]. EGG has been helpful to elucidate
ment leading to inability to interpret data in up to the potential mechanism of chemotherapy
12% of patients [19]. Also, EGG findings do not induced emesis. EGG overall findings do not dif-
correlate with ultrasonographic findings of gastric fer before and after chemotherapy, but tachygas-
emptying and motility [20]. Rather than a substi- tria was noticed only during emesis episodes
tute for these studies, EGG should be seen more as preceded by normal myoelectrical activity [35].
an adjunct in the evaluation of patients with func-
tional and motility gastrointestinal disorders. Surgery
Nissen fundoplication may increase gastric myo-
Functional Gastrointestinal Disorders electrical abnormalities in neurologically
Although some have reported that EGG may not be impaired children; this could explain in part the
helpful to differentiate functional abdominal pain postoperative retching in some [36].
from gastritis [21], others have reported significant
EGG abnormalities in children with functional dys- Strengths: Noninvasive, easy to perform, can be
pepsia and functional abdominal pain [22–24] par- performed at bedside, no radiation required, not
ticularly in children with more severe pain [22]. operator dependent.
Also, EGG does not seem to be a helpful tool to dif- Limitations: Methodology nonstandardized, motion
ferentiate functional abdominal pain from peptic artifact significant limitation.
disease since chronic gastritis does not seem to be
associated with gastric dysrhythmias [21, 25].
Breath Tests
Gastroesophageal Reflux
EGG has been extensively used to assess the The most common indications for breath testing
potential role of gastric myoelectrical abnormali- (BT) include assessment for lactose intolerance
ties in GER. In children, myoelectrical abnormal- and evaluation of small bowel bacterial over-
ities associated with delayed gastric emptying growth. The first is assessed by the elevated levels
seem to be associated with severe GER [26]. of expired hydrogen in response to lactose inges-
tion and the second by the early rise of expired
Chronic Intestinal Pseudo-Obstruction hydrogen after an oral challenge with glucose or
In children EGG has been reported to be abnormal lactulose.
[27] showing significant difference in the values Recently, BT has been used as a noninvasive and
of either preprandial dominant frequency with nonradioactive alternative to the gold standard test
tachygastria or the postprandial value of 3 cpm for gastric emptying with scintigraphy and also to
compared to normal subjects [28]. assess whole gut transit (WGT). For this purpose,
13C is used to label the substrate used for the oral
Eating Disorders challenge. The test is based on measuring the ratios
Gastric myoelectrical abnormalities seem more of Carbon 12 (12C) and Carbon 13 (13C). Both iso-
common in bulimia than anorexia nervosa [29] topes naturally exist in normal breath, 99% as 12C
166 L. Rodriguez

and about 1% as 13C. This ratio is changed by the substrate. A correction factor of approximately
test meal enriched with 13C resulting in enriched 60 min has been classically added and validated in
expired 13CO2. The exhalation of 13CO2 in patients’ infants [57] while others have suggested the use of
breath over time reflects the emptying of the sub- the Wagner-Nelson method [58]. BT with
strate from the stomach. The substrates used for the 13C-sodium acetate for liquids and semisolids [59]
evaluation of gastric emptying are 13C-octanoic and 13C-octanoic acid for solid meals [60] have
acid for solids and 13C-sodium acetate for liquids. been validated for gastric emptying compared to
Recently the 13C-Spirulina platensis breath test has scintigraphy. In adults, both the 13C-sodium acetate
been validated compared to scintigraphy for gastric [61] and 13C-octanoic acid [62] do not seem to be
emptying in healthy volunteers [37–39]. Lactulose affected by age, gender or BMI.
has been classically used in the evaluation of WGT,
but due to concerns of inherent acceleration of WGT
by increasing the osmolality of the gut contents, Clinical Applications
other substrates have been used, including lactose
13C-ureide breath test and more recently inulin that Gastric Emptying
has been found to be the most reliable substrate Functional Gastrointestinal Disorders
since does not seem to affect gastric emptying [40, BT does not correlate with scintigraphy in func-
41]. The 13C is typically measured in breath by tional dyspepsia [63] and could not discriminate
continuous flow isotope ratio mass spectrometry, between healthy volunteers and subjects with
although some have also suggested the non-disper- dyspeptic symptoms [64].
sive infrared spectrometry (IRMS) as a feasible
method [42, 43]. The test relies on normal small Gastroparesis
intestine absorption, liver metabolism and pulmo- In children, the ½ emptying of 13C-sodium
nary excretion to validate the results. An important acetate correlates with the time to empty half
concern is the reported high inter [44] and intrasu- of radioisotope in children with gastroparesis
bject [44, 45] variability and significant variability symptoms [65, 66] and also discriminates
associated with the meal caloric content [46] in between healthy volunteers and children with
adult healthy volunteers, although some have gastroparesis symptoms [65]. BT has also been
reported very little intrasubject variability in criti- reported also as feasible in neurologically
cally ill subjects [47], making the test particularly impaired children with GER [67]. BT can be
attractive for that population. 13C-Octanoic acid done at the bedside, which makes it useful for
has been reported as feasible [48], reliable and special situations like in mechanically venti-
reproducible in preterm [49, 50] and term infants lated patients in the intensive care unit [68]. In
[51] and relatively independent from milk amount the evaluation of diabetic gastroparesis in
in preterm newborns in the first hours of life [50]. In adults, 13C-octanoic acid BT was useful to dis-
children, BT was poorly reproducible in healthy criminate between subjects with normal or
children for gastric emptying of both liquids [52] delayed gastric emptying using scintigraphy as
and solids [53] and a high day-to-day variability has the gold standard [69].
been reported in the evaluation of WGT [54]. The
13C-octanoic acid BT in children does not seem to Whole Gastrointestinal Transit
be affected by osmolality, volume or density but BT has demonstrated a constant WGT after the
reducing osmolality and increasing volume increases first month of age when a weight adapted dose of
gastric emptying in preterm infants [55]. It is impor- lactulose is given [70]. The lactose-[13C] ureide
tant to take into account the meal utilized for the breath test has been reported useful to evaluate
study in children, as human milk [51] and hydro- WGT in children older than 8 months [71].
lyzed formulas [56] empty faster than partially and Lactulose BT has been reported reproducible in
non-hydrolyzed formula. Another significant con- healthy volunteers [72] and useful in the evalua-
cern is the potential overestimation of the GE by the tion of small bowel transit in patients with
13C-octanoic BT due to gastric processing of the anorexia nervosa [73].
15 Electrogastrography, Breath Tests, Ultrasonography, Transit Tests, and SmartPill 167

Strengths: Noninvasive, low cost, safe, office [85]. The frequency of these emptying cycles
based, not operator dependent, no radiation reaches up to a periodicity of 35–55 min by about
required, useful in particular situations 35 weeks [86] and demonstrates a clear normal-
(pregnancy, intensive care setting and infants). ization along pregnancy with cycles of longer
Limitations: Requires normal intestinal, liver and duration and stronger power along the third tri-
pulmonary functions, poorly reproducible in chil- mester [87]. Gastric accommodation also seems
dren and adults, certain equipment may be expen- to develop over time with preterm infants show-
sive (IRMS). ing delayed gastric distention with feeds at
26 weeks, followed by a subsequent improve-
ment by the time full feeds are tolerated and
Ultrasonography almost immediate gastric distention with feeds
by 32 weeks [88].
Ultrasonography (US) is a noninvasive technique
that can be used to evaluate gastric emptying and
receptive accommodation, antral contractility, Clinical Applications
transpyloric flow, and gastric anatomical changes
(volume and wall width) during meal and therapy Gastric Emptying
challenges. US has been useful to demonstrate Most common technique requires measurements
trituration of solids to small size particles and by the same observer after fasting and at regular
retention of larger particles with linear emptying 30-min intervals postprandially. The emptying
of liquids [74] and antral motility coordination time is the time at which the antral area or vol-
with pylorus flow [75] during normal conditions. ume returns to a basal value [89], although others
Antral waves noticed in US correlate with peri- have also reported the half emptying time. US
staltic waves seen in antroduodenal manometry, has shown a strong correlation with scintigraphy
with 99% propagating aborally and 68% becom- in assessing gastric emptying of liquids in healthy
ing lumen occlusive at the site of the ultrasound adult volunteers at rest [90, 91] and after exercise
marker [76]. It has been also useful to evaluate [92] as well as in subjects with diabetic gastropa-
duodenogastric reflux in healthy volunteers [77] resis [93]. In children, US has shown good cor-
as well as in subjects with gastric ulcers [78]. The relation with scintigraphy with discordances
reproducibility in the assessment of gastric emp- associated to overlapping of duodenum and stom-
tying is controversial with some reporting ach during scintigraphy and shadowing of the
significant intra and interobserver variability [79, gastric antrum by air [94]. Establishing a safe
80] while others report differing findings [81, preoperative fasting time has been another use of
82], but there is a common agreement on the US in children after ingesting liquids [95] and in
significant day-to-day variability [81]. More adults before undergoing anesthesia [96] and
recently, 3D US has been used to assess gastric endoscopy [97]. US is reliable in assessing gas-
emptying with good correlation with scintigra- tric emptying in preterm infants with a good cor-
phy in healthy subjects [83], but more studies are relation with intragastric volume [98] and
needed to validate the test. particularly in very low birth weight infants with
nasal continuous positive airway pressure [99].
US is also useful during pregnancy when radia-
Developmental Aspects tion should be avoided. Another advantage is that
allows for simultaneous assessment of gallblad-
US is invaluable for the evaluation of fetal gastro- der emptying [100]. US reliably assess changes
intestinal physiology demonstrating evidence of in gastric emptying in response to use of proki-
gastric emptying by 12–13 weeks [84] with gas- netic agents like domperidone [101–103], meto-
tric filling and emptying by 20 weeks with an clopramide [104], cisapride [105], mosapride
important change in gastric volume by 25 weeks [106], and erythromycin [107].
168 L. Rodriguez

Gastric Receptive Accommodation used in multiple research studies as an indirect

US has emerged as an attractive alternative to the and noninvasive test to assess gastric emptying of
more invasive barostat to assess gastric accom- liquids. The test has low interindividual variabil-
modation. The test demonstrates no significant ity [115] with good correlation with scintigraphy
intra and interobserver variability but moderate [116, 117] although recent studies have ques-
day-to-day variability in healthy adult volunteers tioned this correlation [118]. It is not widely used
[108]. It has been reported as a reliable tool to in clinical practice due to the technical require-
assess gastric accommodation in subjects with ments of frequent blood draws, the cost of the
functional dyspepsia [109], children with recur- assays as well as lack of sensitivity to assess gas-
rent abdominal pain [110] and after therapy with tric emptying in clinical situations [119, 120]. Its
prokinetic agents like mosapride [111]. use has been relegated mostly to pharmacokinetic
studies [121] and in special situations where radi-
Antral Motility ation, mobilization, or meal intake is a limitation,
A novel use of the US is to characterize the like patients in the intensive care units [120] and
antroduodenal motility associated with transpylo- during pregnancy [122].
ric fluid movement in healthy volunteers [112] and
in subjects with GER symptoms [113]. Some have Epigastric Impedance
suggested an advantage of US by allowing a simul- It is a noninvasive method for the assessment of
taneous observation of antral contractions and gas- gastric emptying/transit by measuring electrical
tric emptying, and have reported a good correlation impedance through skin electrodes. It is compa-
between antral hypomotility and delayed gastric rable to scintigraphy [123]. The method has been
emptying in patients with dyspepsia [114]. revised and improved by adding applied potential
tomography to generate images of the electrical
Strengths: Noninvasive, no radiation required, impedance of tissues and estimate gastric empty-
readily available, non-expensive. ing and/or transit [124, 125]. Despite being an
Limitations: Reliable for assessment of liquids attractive noninvasive alternative its use has not
only, different and nonstandardized methodolo- spread and recommended due to low reproduc-
gies, requires certain expertise, operator depen- ibility from significant motion artifact [126, 127]
dent, obesity and presence of air impair study and inconsistency of the impedance changes
(gaseous distention is common in gastrointestinal compared to phasic contractions obtained from
motility disorders). applied potential tomography [128].

Radiopaque Markers
Transit Studies Extensively used in the evaluation of transit in
the gastrointestinal tract due to their low cost,
Several tests have been developed to assess gas- minimal radiation exposure and uncomplicated
trointestinal transit as an alternative to other more performance and interpretation. Despite the good
invasive and expensive tests associated with radi- agreement between gastric transit of radiopaque
ation, like scintigraphy transit studies. Here we markers (ROM) to emptying measured by US
describe tests to assess transit in different seg- [129] the test is not widely used due to the lack of
ments of the gastrointestinal tract. standard methodologies and availability of other
more reliable tests.

Gastric Emptying
Intestinal Transit
Paracetamol Absorption Test
The rate of paracetamol absorption measured by Carmine dye, pellets and radiopaque markers
serial serum levels after oral ingestion has been have been used in the evaluation of intestinal
15 Electrogastrography, Breath Tests, Ultrasonography, Transit Tests, and SmartPill 169

assess for normal vs. abnormal colonic transit.

The Metcalf protocol is used for the same purpose
with the added information on segmental transit,
providing a broader extent of information. In this
method, three sets of distinctive ROM are ingested
on 3 consecutive days followed by an abdominal
film on the fourth day. This method has shown
good correlation with the transit values obtained
with other methods with multiple films. The nor-
mal values for the test are: total colonic transit
35.0 ± 2.1 h, right colon 11.3 ± 1.1 h, left colon
11.4 ± 1.4 h and rectosigmoid colon 12.4 ± 1.1 h
with overall shorter transit in men and no effect by
age [130]. Norms by the Metcalf protocol in chil-
dren have been established: total colonic transit
time 37.8 ± 6.2 h, 10.8 ± 3.5 h for the right colon,
12.2 ± 2.7 h for the left and 14.7 ± 2.1 h for the rec-
tosigmoid [131]. The Metcalf protocol has been
used to discriminate between constipated and
non-constipated adolescents showing a statisti-
cally significant difference for the total colonic
transit time and in both the right and left colon
Fig. 15.2 Radiopaque marker study. This abdominal film transit times [132]. Transit measured by ROM
was obtained on day 4 after ingesting three daily capsules
seems to be faster than colonic transit measured
with 24 markers each. Note the retention of all markers
by scintigraphy [133]. ROM transit studies show
similar transit times in young adults and children
transit with poor correlation with the gold stan- [133] but segmental transit seems to be different,
dard scintigraphy. Small intestine transit is best with faster transit time in the right and left colon
assessed by scintigraphy and wireless motility and most of the transit in the colon spent in the
capsule or breath testing when the former are not rectosigmoid in children compared to adults
available. [134]. In regard to clinical applications in chil-
dren, ROM transit studies have been helpful to
define pediatric slow transit constipation [135]
Colon Transit and to demonstrate correlation between colonic
transit and severity of symptoms [136], slower
Multiple protocols have been developed using colonic transit in constipated children without
ROM to evaluate colonic transit, ranging from soiling compared to those with soiling [137], rec-
laborious protocols with multiple abdominal films tosigmoid transit delay in low variety and global
to a simplified protocol with a single capsule and delay in high variety anorectal malformations
single abdominal film and the segmental transit [138], constipation in neurologically impaired
Metcalf protocol (Fig. 15.2). The main drawback children associated with slow colonic transit
for the ROM studies is the lack of standardization rather than fecal retention [139] and response to
between the multiple methods and the centers per- therapy for constipation [140].
forming the studies. The simplified protocol
requires a single capsule with ROM ingested on Strengths: Readily available, minimal radiation,
the first day followed by an abdominal film on the noninvasive, easy to interpret, inexpensive.
fifth day. Retention of >5 rings is considered Limitations: Multiple methodologies not
abnormal, and this protocol is used mostly to simply standardized
170 L. Rodriguez

Clinical Applications
SmartPill
Gastric Emptying
This novel device offers the ability to simultane- Gastric residence time of the WMC correlates
ously measure contractility and transit. The with the gastric emptying by scintigraphy with
SmartPill or wireless motility capsule (WMC) higher sensitivity at 4 h than at 2 h [143]. The
measures 26.8 × 11.7 mm and has three sensors: WMC also has been useful to discriminate
pressure (to measure contractility), pH (to measure between healthy subjects and patients with diabetic
transit from stomach to small bowel and from small gastroparesis by the GRT [143] and to measure
bowel to colon) [141] and temperature (to assess contractility assessed by number of contractions
exit from the body). After ingesting the capsule and motility index in antrum and small bowel
orally with a standard meal, the patient is dis- [147]. WMC has proven to be important in classi-
charged and wears the recording device for fying motility disorders by region and diagnosing
3–5 days. The most important uses of this device generalized motility disorders with good agree-
are to record pressures and measure transit simulta- ment with conventional motility studies [148].
neously in different segments of the gastrointesti-
nal tract. In this regard, it has been used to evaluate Constipation
gastric residence time (GRT), small bowel transit WMC is useful to measure contractility pressures
(SBT), and colonic transit (CT) as well as whole in different segments of the gastrointestinal tract,
gut transit (WGT) (Fig. 15.3). Perhaps the most including colon. Colonic contractility is poorly
significant contributions of the WMC in gastroin- characterized in adult patients with constipation
testinal physiology are the reaffirmation of the con- and constipation-IBS. WMC has been instrumen-
cept that non-digestible solids empty from the tal in the evaluation of colonic contractility and
stomach primarily with the return of the phase III transit simultaneously in adults, demonstrating
of the migrating motor complex (MMC) when the greater pressures in distal compared to proximal
fed state is over and the pylorus is completely open. colon in healthy individuals and increased motor
No less important is the novel finding of the empty- activity in constipated patients with normal or
ing of non-digestible solids in some subjects moderately delayed transit, emphasizing the
associated with high amplitude antral contractions importance of segmental evaluations of the colon
and not associated with the phase III of the MMC [149]. In regard to CTT, the WMC has been vali-
[142]. Since the WMC is an equivalent to a non- dated for CTT and WGT by the simplified as well
digestible solid, in healthy volunteers the gastric as by the Metcalf protocol. For the Metcalf proto-
residence time correlates moderately with the gas- col, a recent large multicenter study evidenced that
tric emptying of digestible solids by scintigraphy although the transit was significantly different by
and it is not surprising that there is a stronger cor- WMC and ROM the agreement for delayed transit
relation with emptying at 4 h than at 2 h [142, 143]. was 80% and for normal transit was 91% with an
The WMC has been also useful to demonstrate the overall device agreement of 87% [150]. The WMC
lack of effect of proton pump inhibitors on antral with the simplified method showed slower GRT,
and small bowel motility and transit [144]. A great SBT, CT and WGT in subjects with constipation
concern with transit studies with scintigraphy is the compared to controls. Interestingly CTT was
significant daily variability, which also potentially slower in women than men and, more importantly,
applies to the WMC. This has not been addressed showed upper gastrointestinal transit delay in sub-
in humans, but animal studies have shown a jects with constipation [151]. Also WMC demon-
significant variability of GRT by WMC and gastric strated that stool form predicts delayed vs. normal
emptying by scintigraphy with important intraindi- transit in adults in contrast to stool frequency [152]
vidual variability [145] and an inverse relationship and reiterated the concept of a more generalized
between GRT and body weight [146]. At present, gastrointestinal dysmotility in patients with gas-
there are no reports yet of the utility of the WMC in troparesis by evidencing also delayed CTT [153].
children. WMC has been also validated with scintigraphy
15 Electrogastrography, Breath Tests, Ultrasonography, Transit Tests, and SmartPill 171

Fig. 15.3 SmartPill tracing Notice the prolonged gastric residency time as well as significantly prolonged colonic
transit. Courtesy of Dr. Braden Kuo and Dr. Margarita Brun

for the evaluation of gastric emptying, colonic and 5. Disenbaeva LG, Khorunzhii GB. Motor function of the
stomach in healthy children, 3–15 years of age, accord-
whole gut transit (WGT) in healthy subjects as ing to electrogastrography. Pediatriia. 1976;3:21–4.
well as patients with constipation [154]. In regard 6. Mirutko DD. Electrogastrography in chronic gas-
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colonic transit: prospective comparison with 154. Maqbool S, Parkman HP, Friedenberg FK. Wireless
radiopaque markers in chronic constipation. capsule motility: comparison of the SmartPill GI
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e233. whole gut transit. Dig Dis Sci. 2009;54(10):2167–74.
151. Rao SS, et al. Investigation of colonic and whole-gut 155. Timm D, et al. The use of a wireless motility device
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2009;7(5):537–44. Br J Nutr. 2010;105(9):1337–42.
 Autonomic Nervous System Testing
16
Gisela Chelimsky and Thomas C. Chelimsky

2. Discuss the utility of these tests in clinical

Autonomic Nervous System Testing practice
Autonomic testing in children is becoming
The role of autonomic testing in pediatric func- increasingly available, though at this time still
tional gastrointestinal disorders is slowly taking only a few centers perform more than just a tilt
shape. At the simplest level, the autonomic ner- table test. Although cardiologists may perform
vous system constitutes the link between the cen- tilt table tests, this is seldom performed in patients
tral control of gastrointestinal function and the with primarily gastrointestinal complaints. This
enteric nervous system. So far, no clinical tests chapter describes the tests done most commonly
directly assess the portion of the autonomic ner- in autonomic function referral centers (summa-
vous system that innervates the gastrointestinal rized in Table 16.1 below).
tract. Current routine clinical testing is limited to
examination of cardiac, vasomotor and sudomo-
tor function, and based on the results of these Tests Currently Available
tests in the appropriate clinical setting, the gas-
troenterologists or autonomic specialists must The most common tests can be divided in two
infer the potential role of the autonomic nervous categories:
system in the pathogenesis of gastrointestinal 1. Tests of cardiovascular autonomic function:
symptoms. The goal of this chapter is as (a) Deep breathing
follows: (b) Valsalva maneuver
1. To describe the current available autonomic (c) Head up tilt table test
testing and discuss the portion of the auto- (d) Handgrip
nomic nervous system assessed by each test (e) Cold pressor test
2. Tests of sudomotor autonomic function
(sweating)
(a) Quantitative sudomotor reflex test (QSART)
G. Chelimsky, M.D. (*) (b) Thermoregulatory sweat test (TST)
Division of Pediatric Gastroenterology, Medical College The tests of cardiovascular autonomic func-
of Wisconsin, 8701 Watertown Plank Rd, Milwaukee,
tion are particularly helpful in evaluating the
WI 53226, USA
e-mail: [email protected] branch of the autonomic nervous system involved
(afferent baroreflex, or efferent sympathetic vs.
T.C. Chelimsky, M.D.
Neurology Department, Medical College of Wisconsin, parasympathetic), whereas the sweat tests pro-
Milwaukee, WI, USA vide information on lesion localization (central vs.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 177

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_16, © Springer Science+Business Media New York 2013
 178

Table 16.1 Tests of autonomic function

Autonomic test Receptor Afferent Integrating center Efferent signal
Deep breathing Pulmonary stretch J-receptors Vagus nerve Nucleus tractus solitarius Dorsal motor nucleus of the vagus
(DMNX) to vagus nerve
Valsalva maneuver Low-pressure atrial baroreceptors Vagus nerve Nucleus tractus solitarius Phase II:
1. Inhibition of DMNX HR
2. Excitation VLM to descending
sympathetics exiting at
T1 vasoconstriction
Phase IV:
Reverse of 1 and 2
Tilt-table test Low-pressure atrial baroreceptors Vagus nerve Nucleus tractus solitarius 1. Inhibition of DMNX to HR
2. Excitation of VML to descending
sympathetics exiting at
T1 vasoconstriction
Sudomotor axon reflex test Nicotinic cholinergic Sudomotor nerve None Sudomotor nerve (axon reflex)
Thermoregulatory Sweat test Temperature sensors in the Temperature C-fibers Anterior hypothalamus Descending projections from anterior
anterior hypothalamus and and lateral hypothalamus to intermedio-
peripheral veins lateral cell horn preganglionic spinal
neurons postganglionic sudomotor
axons
DMNX dorsal motor nucleus of the vagus, VLM ventrolateral medulla
G. Chelimsky and T.C. Chelimsky
16 Autonomic Nervous System Testing 179

peripheral nervous system). At this time, the blowing against a fixed resistance and then sud-
pediatric norms are not well defined [1], and denly releases the pressure. This sudden high pres-
therefore, norms are inferred from adult values. sure in the chest cavity impedes venous return to the
Other tests of autonomic function such as pupil- heart, and reduces ventricular filling and stroke vol-
lometry and pharmacologic evaluation of the ume. Phase I and III are mechanical phases unre-
baroreflex also exist; these are even less com- lated to autonomic physiology. During Phase I,
monly utilized, have even less clearly defined blood pressure rises for a few seconds as the held
norms, and therefore are not described in this pressure is transmitted directly as a pressure wave
chapter. through the vascular system. Phase II is mediated a
sympathetic nervous system response to the decline
in cardiac output, resulting in vasoconstriction and
Deep Breathing tachycardia to restore blood pressure. The lost car-
diac output is reflected in a drop in systolic pressure,
This test assesses heart rate variability, a para- while vasoconstriction causes a rise in diastolic
sympathetic nervous system function. The test is pressure, resulting in a marked reduction in pulse
performed by instructing the patient to breathe pressure. When the subject releases pressure, blood
deeply and regularly at a rate of 6 breaths per pressure drops transiently during the mechanical
minute for 1 min. This is repeated after a minute phase III. The dominant effect occurs when blood
of rest. Values for this parameter are age-depen- fills the heart again, reaching higher levels than
dent and a reduction in heart rate variability is baseline, due to thoracic pressure normalization in
considered abnormal. The authors utilize the data the face of continued vasoconstriction. The
published by Ingall et al. [1] as age-based norms baroreflex triggers a relative bradycardia through
in their laboratory. The presumed purpose of the sympathetic withdrawal and parasympathetic exci-
reflex is to provide adequate blood volume to tation. Since vasodilation is slow, the blood pressure
absorb incoming oxygen during deep inspiration. overshoots temporarily before returning to baseline.
When an individual inhales deeply, both air and The result is usually read as a ratio of the fastest
vascular spaces expand and requiring increased heart rate during phase II and the slowest heart rate
lung blood volume. This need is met through an during phase IV. If the ratio is below the age-based
increase in heart rate during inspiration, triggered normal value, one must determine if this is due to an
by vagal parasympathetic inhibition. When the inadequate bradycardia during phase IV or inade-
individual exhales, the heart rate decreases, due quate tachycardia during phase II. In most centers,
to parasympathetic excitation [2]. In teenage results of this study are repeated three times, with
years, this heart variability may become very the two largest responses included in the dataset [2].
large, probably due to high vagal tone. The The values vary with age and we currently utilize
Nucleus Tractus Solitarius orchestrates this the pediatric values published by Ingall et al. [1].
response to pulmonary stretch receptor afferents
(J-receptors) [3] also accounting for baroreflex
responses to blood pressure changes, and intrin- Head Up Tilt
sic central respiratory rhythms.
This test evaluates sympathetic vasomotor responses.
The patient must remain supine for a minimum of
Valsalva Maneuver 10 min to obtain reliable baseline values, and then
passively tilted to 70°. The length of time of the tilt
The Valsalva maneuver (VM) (Fig. 16.1) evaluates is varies greatly across centers, being 10 min in
cardiac parasympathetic, cardiac sympathetic, and many neurologic autonomic centers, and up to
vasomotor sympathetic functions in response to low 45 min when performed by cardiologists. No data
pressure baroreceptor afferents from the right atrium are available to guide tilt duration in children.
and the great veins. The patient generates a continu- Currently, in our institution, we tilt children without
ous expiratory pressure of 40 mmHg for 15 s by history of syncope for 30 min and if there is a
180 G. Chelimsky and T.C. Chelimsky

Fig. 16.1 Valsalva maneuver, showing the four phases and the blood pressure and heart rate changes of each phase

history of recurrent fainting the tilt is extended to clinical experience, children seldom demonstrate
40 min. In our clinical experience, many subjects true orthostatic hypotension, while POTS and
would be diagnosed as normal had the tilt table test POTS associated with reflex syncope is the more
been stopped at 10 min. The clinical significance is common finding.
still unknown. A study performed by Carew et al.
[4] in adolescents to adult age group (14–60 years) The Normal Response to a Tilt Table Test
showed that 75% of the subjects develop a sustained A normal tilt response includes a mild increase in
increase in heart rate to fulfill the heart rate criteria diastolic pressure by 5–10 mmHg, a mild decrease
for postural tachycardia syndrome (POTS) within in systolic blood pressure of 5–10 mmHg and an
the first 3 min of head-up tilt and by 7 min had increase in heart rate of about 10–20 bpm. A tran-
developed the diagnostic criteria for POTS. None of sient drop in blood pressure with reflex tachycar-
the subjects in the control group had sustained dia within the first few minutes of tilt is common
tachycardia. Thirty six percent of the subjects with in healthy adolescents during tilt test [7].
POTS developed reflex syncope between 7.4 and
32 min into the head-up tilt [4]. This frequency of Postural Tachycardia Syndrome
syncope in POTS is remarkably similar to that found POTS is defined in adults as an increase in heart
by Ojha et al. of 38% [5]. Based on these various rate greater than 30 bpm within 10 min of becom-
data sources, children should be tilted for a mini- ing upright or to greater than 120 bpm, without a
mum of 30 minutes, or less if they experience a pre- gradual drop in BP, and associated with orthos-
syncopal or syncopal event. During the test, all tatic symptoms [8]. There are no pediatric norms.
symptoms should be documented (and rated on a The mechanism involved in the pathogenesis of
numeric rating scale) so they can later be correlated POTS symptoms is still unknown. However, the
with vital sign changes. It is of particular impor- common final pathway is probably an excessive
tance if children replicate their gastrointestinal com- cardiovascular sympathetic activation perhaps
plaints during the upright portion of the tilt test, as secondary to abnormal blood volume distribution
they will often benefit from treatment aimed at with venous pooling resulting in central hypov-
orthostatic intolerance [6]. olemia and inadequate cardiac return [9].
The tilt table test may demonstrate four pat-
terns (Fig. 16.2): (a) normal response, (b) pos- Reflex Syncope
tural tachycardia syndrome (POTS), (c) orthostatic Other terms for this include neurally mediated
hypotension (OH), and (d) reflex syncope. In our syncope, vasovagal syncope, cardiogenic syncope,
16 Autonomic Nervous System Testing 181

Fig. 16.2 This figure summarizes the different blood pressure (black line) and heart rate (red line) changes in the three
orthostatic syndromes as well as the physiologic mechanism and a graphic description of the vital signs. (nl normal)

and vasodepressor syncope. It is defined as a tem- ent sympathetic signal to the arterioles with con-
porary loss of consciousness caused by inadequate sequent vasoconstrictive insufficiency [10].
brain perfusion. It is produced by a sudden dis- Figure 16.2 graphically summarizes the three
charge from the medullary vasomotor center orthostatic syndromes and their etiopathology.
decreasing sympathetic tone and increasing vagal
tone and leading to peripheral vasodilation,
hypotension, and bradycardia. Subjects usually Sustained (Static) Handgrip
experience a brief episode of loss of consciousness
followed by a relatively clear sensorium. It is This test evaluates sympathetic vasomotor func-
important to note that syncope is a normal reflex tion, sympathetic cardiac and parasympathetic
that may occur in all subjects if enough strain is function. After baseline recording, the patient is
placed on orthostatic pressure maintenance (for instructed to sustain a grip at 30% of their maxi-
example through the application of lower body mal grip strength for 3 min by squeezing a hand
negative pressure). Its probable function is the dynamometer. Heart rate and blood pressure are
continued perfusion of the brain through gravita- monitored continuously from the contralateral
tional mechanisms when the individual experi- upper extremity. The maneuver results in both
ences severe loss of blood volume. Thus, the cardio-acceleration and an increase in blood pres-
occurrence of syncope per se is not abnormal, but sure. In contrast to the tilt table test and the Valsalva
its occurrence at an inappropriate time is. POTS maneuver, the afferent signal here originates from
and syncope can coexist, being present in 30% of muscle and is related to lactate accumulation, in
the children evaluated in our center. contrast to the former two tests where the initial
afferent signal originates from the low-pressure
Orthostatic Hypotension baroreceptor in the right atrium. An early heart
Orthostatic hypotension is defined as sustained rate increase is due to vagal withdrawal and a later
drop in blood pressure of greater than 20 mmHg heart rate response is due to sympathetic activa-
systolic or 10 mmHg diastolic within 3 min of tion. The blood pressure increase is due to both
being upright, associated with symptoms. The increased cardiac output and to sympathetically
underlying pathophysiology is an impaired effer- mediated arterial vasoconstriction [11].
182 G. Chelimsky and T.C. Chelimsky

Quantitative Sudomotor Reflex Test Critical Steps in Preparation for All

Autonomic Function Testing
This study evaluates for an autonomic neurop-
athy through the presence and function of post- Prior to testing, the patients should be asked to
ganglionic sudomotor axons. Though have a normal meal at the usual mealtime with
innervated by the sympathetic nervous system, plenty of fluid. They must also taper or stop all
acetylcholine is the post-gangliononic neu- medications and dietary or nutritional supple-
rotransmitter to the sweat gland. The test is ments that may influence test results. This
performed by applying a capsule with dual includes caffeine and passive or active exposure
concentric chambers to the patient’s skin. to nicotine. When the patient is unable to hold
Acetylcholine from the outer chamber is ionto- medications results need to be interpreted accord-
phoresed into the skin, and via an axon reflex ingly. Each center has protocols for when and
stimulates axons that innervate the local sweat which medications should be stopped. As a gen-
glands. The axon reflex stimulates more distant eral guideline, a(alpha)- and b(beta)-receptor
sweat glands whose output is then measured in agonists and antagonists, pro- and anticholin-
the area of the central chamber of the capsule. ergics (particularly phenothiazines and tricyclic
The capsules are usually placed from distal to agents) and mineralocorticoids (including
proximal on two sites on the upper and lower fludrocortisone) must be discontinued at least 5
extremities respectively, though other groups half lives prior to testing. Selective serotonin
use three capsules in the lower extremity and reuptake inhibitors (SSRI) and serotonin nonse-
one in the upper [11]. A reduced response indi- lective reuptake inhibitors (SNRI) agents should
cates postganglionic sympathetic sudomotor be discontinued 5–7 days prior to the testing.
impairment. The sudomotor reflex is preserved
in central nervous system processes.
Utility of Autonomic Testing
in the Evaluation of Children with
Thermoregulatory Sweat Test Functional Gastrointestinal Disorders
and Motility Disorders
This study helps differentiate a central disorder
from a neuropathy or radiculopathy. It evaluates To date, autonomic testing in children has been
both preganglionic and postganglionic pathways. deployed in limited ways, being primarily uti-
The patient dressed in a disposable swim-suit like lized in the evaluation of rare disorders such as
garment is covered with a powder that changes Familial Dysautonomia. The utility of autonomic
color on contact with moisture. The subject is testing in functional gastrointestinal disorders
placed supine in a sauna-like enclosure, kept at (FGID) is just emerging. About 10 years ago the
an air temperature of 50 °C, with a relative humid- first case series was reported of children with
ity of 50%. The skin temperature is maintained FGID demonstrating a postural tachycardia in
between 38.5 and 39.5 °C. The skin may also be most subjects, and an autonomic neuropathy in
heated with infrared heaters. The test is inter- many. The cardiac parasympathetic function was
preted based on the detection of areas of lack of preserved in all the subjects [13]. A few case
sweat (anhidrosis) [12]. Usually a subject with reports further supported this association and
central disorder will have lack of sweating all reported improvement of the gastrointestinal
over the body, although sweating on hands and symptoms when treatment was aimed at the
feet may be preserved. Reduced sweating in the orthostatic intolerance [14, 15]. A few years later,
toes, fingers with a distal to proximal gradient is Sullivan and collaborators reported tilt table
suggestive of a peripheral process. If there is lack results in 24 children with FGID [16]. These chil-
of sweating following a nerve root pattern, the dren had symptoms of abdominal pain (71%),
study may suggest a radiculopathy. nausea (56%) and vomiting (50%). The tilt table
16 Autonomic Nervous System Testing 183

showed POTS in 4, POTS and neurally mediated and sham venous pooling by inflating the trousers
hypotension (termed reflex syncope in this chap- to −5 mmHg and vacuum pump activation with-
ter) in 8 and neurally mediated hypotension alone out lower body negative pressure in subjects with
in 12. In about half of the cases, the tilt table test POTS and in controls [18]. They also performed
reproduced the gastrointestinal complaints. mental stress to determine if there were differ-
Follow-up was available in 18/24. Twelve chil- ences in the heart rate increase in the two groups.
dren were treated with fludrocortisone (4 had also They demonstrated that only significant venous
sertraline) with either improvement or resolution pooling caused a rise in heart rate in the POTS
of symptoms [16]. A retrospective study sup- group, whereas the heart rate increase in response
ported the concept that children that replicate the to “sham” venous pooling and mental stress was
gastrointestinal symptoms during the tilt table not significantly different between the two
test usually had POTS and often show improve- groups. These results suggest that the heart rate
ment of gastrointestinal symptoms when treated increase in patients with POTS is not related to
with fludrocortisone [6]. anxiety, but rather to reduced venous return to the
This association was further explored by per- heart [18].
forming electrogastrography in subjects with and Although many of these studies are either ret-
without POTS in the supine position and during rospective or small series, evidence is slowly
the upright portion of the tilt test. The study found mounting for the role of autonomic dysfunction
that in the upright position, children with POTS in children with FGID and hence a benefit of
developed more gastric electrical abnormalities autonomic testing in the evaluation of children
in the locations corresponding to the fundus and with FGID. Prospective studies are needed com-
the antrum, while the opposite happened in the paring different treatment modalities and deter-
non-POTS group [17]. These findings suggested mining if fludrocortisone, salt supplementation,
a possible mechanism for the association between beta blockers may be beneficial in these
orthostatic intolerance and the gastrointestinal children.
symptoms. Further prospective, blinded studies
will determine if treatment aimed at the orthos-
tatic intolerance is superior to “conventional”
treatment of FGID or to placebo. Against the
References
concept of placebo response, most children have 1. Ingall TJ, McLeod JG, O’Brien PC. The effects of
failed all “conventional” gastrointestinal treat- ageing on the autonomic nervous system function.
ments prior to referral to our center. Sullivan and Aust N Z J Med. 1990;20:570–7.
collaborators reported that tilt table was per- 2. Freeman R. Noninvasive evaluation of heart rate: time
and frequency domains. In: Low PA, Benarroch EE,
formed after having symptoms for more than a editors. Clinical autonomic disorders. 3rd ed.
year, sometime even 3 years (48%) and had failed Philadelphia: Lipincott Williams &Wilkins; 2008. p.
gastric acid secretory blockers, antispasmodics, 185–97.
and prokinetics. Many of them (50%) had been 3. Bonham AC, Coles SK, McCrimmon DR. Pulmonary
stretch receptor afferents activate excitatory amino
referred to a psychiatrist or psychologist for their acid receptors in the nucleus tractus solitarii in rats.
symptoms, having then resolution with J Physiol. 1993;464:725–45.
fludrocortisone or sertraline [16]. One would not 4. Carew S, Cooke J, O’Connor M, et al. What is the
expect a placebo effect to be restricted to orthos- optimal duration of tilt testing for the assessment of
patients with suspected postural tachycardia syn-
tatic agents. drome? Europace. 2009;11:635–7.
Practitioners often wonder if anxiety may be 5. Ojha A, McNeeley K, Heller E, Alshekhlee A,
the primary cause of the increase in heart rate Chelimsky G, Chelimsky TC. Orthostatic syndromes
during tilt table test. Masuki et al. attempted to differ in syncope frequency. Am J Med.
2010;123:245–9.
answer that question by performing graded 6. Safder S, Chelimsky TC, O’Riordan MA, Chelimsky
venous pooling with lower body negative pres- G. Autonomic testing in functional gastrointestinal
sure by wearing antishock trousers to −40 mmHg disorders: implications of reproducible gastrointestinal
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complaints during tilt table testing. Gastroenterol Res 13. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC.
Pract. 2009;2009:868496. Autonomic abnormalities in children with functional
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tachycardia syndrome. In: Low PA, Benarroch EE, dysfunction resolving gastrointestinal symptoms in a
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Philadelphia: Lippincott Williams &Walkins; 2008. p. 15. Chelimsky G, Chelimsky T. Familial association of
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syndrome. Cardiol Rev. 2007;15:67–75. 16. Sullivan S, Hanauer J, Rowe P, Barron D, Darbari A,
10. Low PA, Fealey RD. Management of neurogenic ortho- Oliva-Hemker M. Gastrointestinal symptoms associ-
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Clinical autonomic disorders. 3rd ed. Philadelphia: Gastroenterol Nutr. 2005;40:425–8.
Lippicott Williams & Walkins; 2008. p. 547–59. 17. Safder S, Chelimsky TC, O’Riordan MA, Chelimsky
11. Low PA, Sletten DM. Laboratory evaluation of auto- G. Gastric electrical activity becomes abnormal in the
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 Part III
Disorders of Digestive Motility:
Developmental and Acquired
Anomalies of the Enteric
Neuromuscular System
 Pathology of Enteric
Neuromusculature 17
Virpi Vanamo Smith

The pathology can diffusely affect the entire

Introduction gastrointestinal tract or only a segment of the
bowel. The histological changes are often subtle
Over many decades, pathology of enteric neuro- and can be either congenital (genetic) or acquired
muscular diseases has been elusive and continues and are classified as enteric neuropathies (abnor-
to be a challenge to the histopathologist. Although malities in enteric nervous system) or myopathies
the causes of intestinal pseudo-obstruction such (abnormalities in intestinal smooth muscle).
as “an insufficient degree of intestinal muscular Unlike in adults, in children the changes are
power and action as a physical cause for costive- rarely secondary to a systemic disease but may be
ness” were already recognised by Jacobi in 1869 seen in muscular dystrophies, cystic fibrosis or
[1], the pathology was not understood. Even after mitochondrial cytopathies. In order to identify
Harald Hirschsprung in 1886 first presented his the subtle changes, a number of different histo-
detailed necropsy findings on two infants (aged pathological techniques are required, thus neces-
11 and 8 months) for the Gesellschaft for sitating the preservation of tissue in several
Kinderheilkunde in Berlin and in 1888 published different ways.
a paper [2] on the subject in the Jahrbuch fur The optimal diagnostic specimen is a com-
Kinderheilkunde, it took another 60 years for the plete circumference of a full-thickness intestinal
pathology of aganglionosis to be universally sample about 4 cm in length taken at a time of a
accepted as the cause of this distinct clinical surgical intervention (an exploratory laparotomy
entity bearing Hirschsprung’s name. or when raising a stoma). The specimen is cut
It soon became apparent that other pseudo- open and a longitudinal block of full-thickness
obstructive diseases without aganglionosis but bowel is fixed in formalin and embedded in
clinically mimicking Hirschsprung’s disease paraffin-wax for routine histology using haema-
(pseudo-Hirschsprung’s disease) also existed [3] but toxylin and eosin and tinctorial special stains
only in the past two to three decades the patho- (Masson trichrome, picrosirius, periodic acid
logical changes (abnormalities in the enteric nerves Schiff) and immunostains (smooth muscle actin,
and muscle) have reliably been identified [4–9]. desmin, CD56, CD117 or c-kit, PGP9.5, S100
and inflammatory markers including HLA-DR).
A full-thickness block is snap-frozen for enzyme
V.V. Smith, Ph.D., FRCPath (*) histochemistry (acetyl cholinesterase and acid
Paediatric Surgery Unit, Institute of Child Head,
phosphatase activities and possible genetic stud-
University College London,
30 West Avenue, London N31AX, UK ies) and a thin full-thickness block is fixed in glu-
e-mail: [email protected] taraldehyde for electron microscopy. It is

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 187

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_17, © Springer Science+Business Media New York 2013
188 V.V. Smith

important that the latter sample is kept whole to malities in the proportions of neurons expressing
facilitate identification of all the layers of the a particular neurotransmitter cannot be diagnosed
bowel wall. on routine sections due to insufficient number of
Care must be taken that the apparent changes neurons and would require tangential orientation
seen on routine histology or on electron micros- of the plexus in sections or whole mounts and
copy are not over-interpreted as pathology, as immunohistochemistry but this is expensive of
they may be due to ischaemia and hypoxia during tissue and control data is scarce. Silver staining,
surgery. Equally, the fixation especially for elec- which identifies two populations of neurons
tron microscopy may be suboptimal if too large (argyrophilic and argyrophobic), had been used
(thick) pieces of tissue are processed. in the past on tangential sections to identify neu-
In this chapter the histopathology of currently ral abnormalities [10–12] including an absence
recognised enteric neuropathies and myopathies of argyrophilic neurons [13]. We now know,
in children are discussed. The pathology of mes- however, that argyrophilic neurons in the very
enchymopathies (changes in the population of young may normally be absent; thus, silver stain-
interstitial cells of Cajal; ICC) and channelopa- ing is less informative in the young paediatric
thies are principally considered in Chap. 18. population [14]. Moreover, the technique of sil-
ver staining is capricious and prone to artefacts.

Enteric Neuropathies (Table 17.1) Aganglionosis

Aganglionosis (Hirschsprung’s disease) is by far
Genetic/Congenital Neuropathies the commonest enteric neuropathy; thus, before
embarking on the search for the diagnosis of rarer
The diagnosis of subtle enteric neuropathies is enteric neuromuscular diseases, Hirschsprung’s
based on the availability of a sufficient number of disease must be excluded on cryostat sections of
myenteric neurons in routine sections of the an adequate suction rectal biopsy containing
biopsy/resection analysed. The most obvious sufficient submucosa [15]. In aganglionosis no
abnormality is the absence of enteric neurons submucosal neurons are found on a haematoxylin
(aganglionosis) but disorders with reduced or and eosin stain and instead there are hypertro-
increased numbers of myenteric neurons are also phied nerve trunks. An acetylcholinesterase
diagnosed. Rare conditions with intestinal gan- preparation on frozen tissue shows an increase
glioneuromatosis, neuronal degeneration, neu- in thick nerve fibres in the muscularis mucosae.
ronal immaturity and abnormalities in the amount In the older baby, thick fibres running trans-
of the glial cell component of the myenteric versely as well as vertically in the lamina propria
plexus have also been reported. Quantitative of the mucosa are often found (Fig. 17.1). As a
analysis is hindered by a lack of normative con- note of caution acetyl cholinesterase enzyme
trol data especially in childhood. Subtle abnor- histochemistry is not reliable in samples taken

Table 17.1 Genetic/congenital nerve diseases

Diseases Genetic defect
Aganglionosis Multigenic including Ret and/or endothelin signalling and
Sox10
Ganglioneuromatosis RET M918T and/or A883F
Hypoganglionosis Not known
Hyperganglionosis ? Enx (Hox11L1)
Glial cells hyperplasia Not known
Neuronal degeneration 2-bp D exon 2 of FLNA (filamin a) on chromosome Xq28
Neuronal immaturity Not known
17 Pathology of Enteric Neuromusculature 189

Fig. 17.1 (a) Acetyl cholinesterase preparation showing cholinesterase activity in normal rectum. A ganglion
positive thick fibres in the mucularis mucosae and fibres indicated by arrow
in the lamina propria in Hirschsprung’s disease. (b) Acetyl

proximal to the splenic flexure and the presence Ganglioneuromatosis

of prominent acetyl cholinesterase-positive Intestinal transmural ganglioneuromatosis is a
mucosal nerve fibres in the normal small bowel diagnosis not to be missed or taken lightly
must not be confused with aganglionosis. In total because it carries serious implications. The dis-
colonic aganglionosis, an entity first described by tinct appearances can be seen in the submucosa
Bodian et al. [16] in 1951, the acetyl cholinest- even in a suction rectal biopsy where there is a
erase pattern in the rectal biopsy may be normal profound “tumour-like” proliferation of neural
and no hypertrophied nerves are seen in the sub- tissue (neurons, supporting cells, and nerves) that
mucosa. The combination of haematoxylin and appear as thickened nerve-like bundles embed-
eosin stain with acetyl cholinesterase enzyme ded with mature nerve cells (Fig. 17.2). If gangli-
histochemistry is the most reliable way to exclude oneuromatosis is suspected, there is justification
or confirm the diagnosis [17]. Acetyl cholinest- to embark in further investigations to exclude
erase activity is best demonstrated by using a multiple endocrine neoplasia type IIB (MEN IIB)
method that enhances the colour of the final reac- requiring germline M918T and/or A883F muta-
tion product as described by Lake et al. 1978 tion analysis of the RET proto-oncogene [19].
[17]. Some laboratories appear to be reluctant to Children with intestinal ganglioneuromatosis
use frozen tissue and acetyl cholinesterase and the above-mentioned molecular diagnosis
enzyme histochemistry and have developed of MEN IIB inexorably develop medullary thy-
methods including immunohistochemistry for roid carcinoma [6]. Monitoring the calcitonin
calretinin on paraffin sections [18]. The advan- concentrations and scanning for adrenal and
tage of acetyl cholinesterase histochemistry is thyroid masses do not suffice because micro-
that there is an increase in enzyme-reactive nerves scopic medullary thyroid carcinoma can be
in aganglionic bowel whereas with calretinin present without obvious masses on imaging or
immunostaining there is an absence or decrease without raised calcitonin concentrations, even
of immunoreactivity. For confirmation of agan- with pentagastrin stimulation. A prophylactic
glionosis it is far easier to rely on a positive thyroidectomy is recommended, as well as con-
increase in enzyme-reactive nerves rather than tinued surveillance of the adrenal glands for evi-
the absence of immunoreactive ones. dence of pheochromocytoma.
190 V.V. Smith

Fig. 17.2 H&E stained section showing ganglioneuromata in the submucosa

Hypoganglionosis teric, granular cytoplasm and open vesicular nuclei

Hypoganglionosis is a disorder in which there is a with prominent nucleoli but the cytoplasmic
reduction in myenteric neuronal numbers, hence appearance alone suffices for a cell to be counted as
the specimens suitable for the assessment of hypo- a neuron. Counts below 2 standard deviations from
ganglionosis must be full-thickness intestine. the control mean are considered abnormal.
Routine haematoxylin and eosin-stained paraffin
sections are suitable for the analysis. In this condi- Hyperganglionosis
tion the myenteric ganglia are sparse and small Hyperganglionosis is a disorder in which the
containing grossly reduced numbers of neurons. It myenteric neuronal density is increased. Routine
can also been seen in the transitional zone of vary- paraffin sections can be used for formal assess-
ing length in Hirschsprung’s disease proximal to ment of the neuronal density (see above). Counts
the aganglionic segment, however the transitional above 2 standard deviations from the mean of the
zone in addition to hypoganglionosis has thickened control values are considered to be abnormal.
nerves trunks. Often the diagnosis can be made Additional features in myenteric hyperganglion-
semi-quantitatively but for formal assessment of osis are seen on acetyl cholinesterase enzyme
myenteric neuronal density there are normal con- histochemistry in frozen sections of the bowel.
trol data for distal descending colon, terminal ileum These include ectopic ganglia (Fig. 17.3) in the
and proximal jejunum [20]. Normal density in the lamina propria of mucosa and muscularis propria
colon is 7 ± 2.12 neurons per mm of bowel length as well as an increase in fine vertical acetyl cho-
examined. In the small bowel the ganglia are more linesterase-positive fibres in the lamina propria
widely spaced and neurons are fewer (4.6 ± 1.51 of the mucosa. An increase in the number of
per mm in ileum, 4 ± 1.07 per mm in jejunum). nerve varicosities may also be seen in the muscu-
Counts in a single section are valid provided a laris propria but unlike in aganglionosis in the
sufficient bowel length is analysed. Longitudinally muscularis mucosae the acetyl cholinesterase
orientated sections are preferred but the counts do pattern is within normal limits.
not significantly differ even if the orientation is
transverse. Bowel lengths less than 10 mm are con- Glial Cell Hyperplasia
sidered insufficient especially in the small bowel. Glial cell hyperplasia was first described in 1990
The normative data are based on haematoxylin and [21]. In this entity there is a prominent increase
eosin stained paraffin sections of 3 m(mu)m thick- in neural elements in the myenteric plexus but it
ness and the neurons are identified by their ampho- is not accompanied by hyperganglionosis and
17 Pathology of Enteric Neuromusculature 191

Neuronal Degeneration
This condition was first described [22] in 1996 in
a large kindred in which abnormal myenteric
neurons were noted. These were shrunken on
routine histology and on ultrastructural examina-
tion showed degenerative changes. The inheri-
tance appeared to be X-linked and the linkage
was mapped to chromosome Xq28. Later it was
shown that there was a two base-pair deletion in
exon 2 of the FILAMIN A [23].

Neuronal Immaturity
The majority of neonatal neurons are small with
a small amount of perikarya (8–15 m(mu)m in
diameter) surrounding the nucleus. With growing
age of the child the amount of perikarya increases.
In children most neurons measure (20–23 m(mu)
m) and only reach the adult dimensions by the
age of 2–5 years when neurons measuring
30–40 m(mu)m are common. The diagnosis of
neuronal immaturity should be considered if
inappropriately small neurons are seen in the
bowel from an older child [20].

Fig 17.3 Acetyl cholinesterase preparation showing an Genetic/Congenital Myopathies

ectopic ganglion in the lamina propria of the mucosa
(Table 17.2)

may have reduced nerve cell density. The Enteric myopathies can result from an abnormal
appearances are of an almost continuous myen- layering of the enteric musculature where there
teric plexus but this is not to be confused with may be a fusion of all the muscle coats resulting in
ganglioneuromatosis, which is a distinct histo- one muscle layer only or there may be additional
pathological entity (pseudo-tumourous nodular muscle layers. The former generally affects a seg-
proliferation of glial and neural tissue in which ment of the bowel whereas the latter may be seg-
mature nerve cells are embedded—see above). mental or diffuse typically with an additional
Glial cell hyperplasia can be seen in a distal seg- circular muscle coat [5]. Recently we have also
ment of the colon (personal observation, Smith seen two patients with an additional muscle layer
VV) and distal colonic manometry in these on the outside of the longitudinal muscle coat adja-
patients is also abnormal (personal observation, cent to the serosa (Personal observation, Smith VV
Lindley KJ). In one patient with abnormal distal 2009; Fig. 17.5). The diffuse form of an addition
colonic manometry, on histology the abnormal circular muscle coat appears to have an X-linked
neural tissue was not confined to the myenteric mode of inheritance. Apart from the abnormalities
plexus but hyperplastic neural tissue was seen in muscle layering, enteric myopathies may show
located in the longitudinal muscle coat forming fibrosis of the muscularis propria with atrophy,
a parallel plexus (Fig. 17.4) to the myenteric drop-out and vacuolation of myocytes (Fig. 17.6).
plexus as well as traversing from the serosa These include a degenerative leiomyopathy with or
through the longitudinal muscle coat into the without evidence of inflammation [24], and thus,
plexus (personal observation, Smith VV). some of these may be considered acquired [25].
192 V.V. Smith

Fig. 17.4 PGP9.5 immunostained section of full-thickness bowel showing “wandering” myenteric plexus (arrows)

Table 17.2 Genetic/congenital muscle diseases

Diseases Observation
Abnormal muscle layering
Segmental absence of muscle coat Intrauterine varicella in 2nd trimester
Segmental extra circular muscle coat Sporadic
Diffuse extra circular muscle coat X-linked mode of inheritance
Myocyte vacuolation, atrophy and fibrosis
Myopathy with pink blush and nuclear crowding ? myocyte phenotype changed from contractile to secretory
Myopathy with autophagic activity ? lysosomal activation/defect

Often the changes not only affect the intestine but cosal plexus [5]. The mothers of all the patients
may also involve the urinary tract in the so-called with this disorder seen by in our institution have
hollow visceral myopathies within which specific had varicella infection in the second trimester of
histological phenotypes are seen. In children with the pregnancy.
vertically acquired human immunodeficiency virus
there may be extensive leiomyolysis due to cyto- Segmental Extra Muscle Coat
megalovirus enterocolitis [26]. On the inside (lumenal) of the circular muscle
coat in this entity there is an extra muscle layer
composed of bundles of leiomyocytes with the
Abnormal Muscle Layering same orientation as the circular muscle [5]. There
also appears to be an additional neural plexus
Segmental Absence of Muscle Layer between the additional muscle coat and the mus-
This abnormality affects a segment of the bowel cularis propria. This abnormality affects only the
showing a fusion of the three enteric muscle distal bowel and we have not noted it to involve
coats (muscularis mucosae, circular and longi- the small intestine. Resection of the abnormal
tudinal muscle) to form one single muscle layer segment restores normal bowel motility.
with no myenteric plexus or obvious submu-
17 Pathology of Enteric Neuromusculature 193

Fig. 17.5 Smooth muscle actin immunostained section showing an additional longitudinal muscle layer (arrow)

Fig. 17.6 Masson trichrome showing fibrosis, atrophy and drop-out of myocytes in the muscularis propria

Diffuse Extra Muscle Coat ing the circular muscle coat (Fig. 17.7) [5].
An additional muscle layer found throughout Clinically it is associated with short bowel,
the small and large intestine appears to be the malrotation and megacystis and appears to
result of a misplaced myenteric plexus bisect- have an X-linked mode of inheritance.
194 V.V. Smith

eosin stain and using connective tissue stains

(Masson trichrome and picrosirius) and peri-
odic acid Schiff for glycogen. Lesser degrees of
fibrosis, myocyte vacuolation and glycogen
accumulation require ultrastructural examina-
tion. The use of immunohistochemistry for
myocyte contractile proteins and their isoforms
is also helpful in explaining the dysmotility
[31]. In the paediatric population, the following
two specific histological phenotypes are
recognised.

Pink Blush and Nuclear Crowding

Haematoxylin and eosin staining throughout

the gastrointestinal tract the circular muscle
coat shows patchy crowding of myocyte nuclei
with areas in which there is a paucity of nuclei
[5]. There is a “pink blush” on picrosirius stain
corresponding to the areas devoid of nuclei.
Electron microscopy reveals that the areas
with nuclear paucity are filled with amorphous
granular proteinacious material with a few
collagen fibre remnants expanding the distance
Fig. 17.7 H&E stained section of full-thickness small between the leiomyocytes, thus disrupting
bowel showing bisected circular muscle by a misplaced their electric connectivity (Fig. 17.8). We pos-
myenteric plexus (arrow). LM longitudinal muscle
tulate that the myocytes have changed their
phenotype from contractile to secretory pro-
Fibrosis, Myocyte Vacuolation and ducing this granular material. Cases include
Atrophy both sexes and appear sporadic. The urinary
tract is also involved showing megacystis/
In contrast to enteric neuropathies, which usu- megaureters.
ally affect a segment of the distal bowel, most
intestinal myopathies commonly involve the
entire gastrointestinal tract and may affect other Myopathy with Autophagic Activity
organs such as the gall bladder and the urinary
tract [27] and are often termed hollow visceral Light microscopy in this phenotype shows pro-
myopathies [28]. The most frequently described found fibrosis of the muscularis propria with
changes are fibrosis of the muscularis propria, atrophy and loss of leiomyocytes [5]. Enzyme
and vacuolation of leiomyocytes together with histochemistry for acid phosphatase activity
myocyte atrophy and drop-out. Accumulation shows reactive lysosomes in the enteric myo-
of sarcoplasmic glycogen [29] and intramyo- cytes, which in a normal child should have no
cyte inclusions [30] has also been described. acid phosphatase activity. Ultrastructural exami-
The latter, although seen in the adults, does not nation confirms the profound fibrosis with sheets
appear to be a feature in paediatric enteric myo- of collagen fibres separating the grossly abnor-
pathies. These gross changes are easily recogn- mal and vacuolated myocytes. The vacuoles are
ised by light microscopy on a haematoxylin and dilated lysosomes containing electron dense deg-
17 Pathology of Enteric Neuromusculature 195

Fig. 17.8 Pink blush and nuclear crowding. Electron micrograph showing separation of myocytes by granular pro-
teinacious material with remnants of collagen fibrils

Abnormalities in Contractile Proteins

Deficiency of alpha smooth muscle actin

(Fig. 17.9) confined to the bulk of the circular
muscle, sparing the innermost circular muscle
coat (nearest to the lumen), longitudinal muscle
and muscularis mucosae was first described in
1992 in an adult patient with life-long intestinal
pseudo-obstruction [31]. It was postulated that
this deficiency was congenital since the type of
myocyte contractility depends on the cocktail of
contractile protein isoforms. For instance, actin
exists in at least six different isoforms, each of
which encoded by a separate gene and expressed
in a tissue-specific pattern. There are three alpha
isoforms (smooth muscle, skeletal muscle and
cardiac muscle) and two gamma isoforms (smooth
muscle and cytoplasmic). The beta isoforms are
cytoplasmic and are not involved in muscle con-
traction. The major isoactins in mature intestinal
Fig. 17.9 Section of full-thickness bowel showing absent
smooth muscle actin activity in bulk of the circular muscle
smooth muscle are alpha and gamma smooth
and normal immunoreactivity in other muscle layers muscle actins, the gamma isoform being the larg-
including the inner circular muscle est constituent, although less abundant, the alpha
isoform is nevertheless an important component.
radation products. The abnormality diffusely The proportions of contractile protein isoforms
affects the entire bowel and is associated with vary in smooth muscle from different tissues [32]
megacystis/megaureters. Most patients appear to and in different stages during development [33]
be sporadic but in one family two siblings (brother with non-muscle cytoplasmic isoforms predomi-
and sister) were affected. nating in undifferentiated smooth muscle in the
196 V.V. Smith

Table 17.3 Diffuse or segmental acquired diseases in these children. The inflammation, unless
Autoimmune ganglionitis promptly treated, results in denervation and per-
Autoimmune myositis manent dysfunction of the entire gastrointestinal
Eosinophilic ganglionitis tract.
Immune modulation of smooth muscle phenotype by
inflammation (eosinophils, mast cells)
Immune modulation of nerves by mucosal eosinophils/
Autoimmune Myositis
mast cells

In autoimmune myositis the biopsy shows promi-

early embryo whereas in mature fully differenti- nent T-lymphocytic infiltration in the muscularis
ated myocytes the muscle specific isoforms propria, particularly dense around blood vessels
(gamma and alpha smooth muscle actin) predom- and obscuring the myocytes beneath it [7]. If left
inate. These isoforms modulate the type of con- untreated, the myocytes initially change their
traction required; alpha smooth muscle actin for contractile protein profile and subsequently
tonic contractions and gamma smooth muscle degenerate, atrophy and drop-out. In the end-
actin for phasic contractions. stage disease there is a paucity of enteric myo-
It is also possible that isoprotein proportions cytes in the muscularis propria, only smooth
may vary in response to various stimuli [34, 35]. muscle cells in the capillary walls seem to sur-
Recently it has become evident that insults such vive. Anti smooth muscle auto-antibodies are
as inflammation modulate leiomyocyte contrac- detected on serology.
tile protein profile in enteric smooth muscle [7].
Regardless of the mechanism responsible for
absent smooth muscle alpha actin immunostain- Eosinophilic Ganglionitis
ing (congenital vs. acquired) this appearance can
contribute to bowel dysmotility. Enteric ganglia may be affected by an
inflammatory infiltrate predominantly composed
of eosinophils rather than lymphocytes [8]. The
Diffuse and Segmental Acquired neurons in the ganglia express IL-5 attracting
Diseases (Table 17.3) eosinophils into the area and altering neuronal
plasticity, function and survival [36] and result-
Autoimmune Ganglionitis ing in a rare, steroid-responsive, acquired form of
pseudo-obstruction.
Autoimmune ganglionitis should be suspected if
a school-age patient, who had passed meconium
within 24 h of birth and had normal bowel habits Immune Modulation of Smooth Muscle
previously, presents later in life with severe con- by Eosinophils and Mast Cells
stipation. Although a full-thickness bowel sample
is ideal, a biopsy containing sufficient submucosa Predominantly eosinophilic leiomyositis of the
may give a clue to this entity. muscularis propria is occasionally seen in full-
The biopsy shows predominantly T-lymphocytic thickness intestinal samples from patients with
ganglionitis, initially with intense infiltration gut dysmotility. Eosinophil trafficking and acti-
involving the ganglia but in time the inflammatory vation is said to lead to tissue damage in target
infiltrate is reduced resulting in degeneration and organs by releasing eosinophil specific granule
loss of enteric ganglia (Fig. 17.10) [9]. The proteins (eosinophil derived neurotoxin, eosinophil
patient’s serum contains IgG-class circulating peroxidase, eosinophil-associated ribonucleases).
autoantibodies against enteric nerve cells often In addition, eosinophils are regulators of local
indistinguishable from those seen in patients with immune responses. Together with mast cells they
paraneoplastic disease but no neoplasia is found are involved in immune modulation and tissues
17 Pathology of Enteric Neuromusculature 197

Fig. 17.10 H&E stained section showing lymphocytic myenteric ganglionitis

remodelling and have direct effect on smooth glycans and others). The expression of many of
muscle activities [36]. the proteins is shared between skeletal and
smooth muscle; thus, the myopathy may not only
be confined to skeletal muscle but also affects
Immune Modulation of Nerves by enteric muscle resulting in bowel dysmotility.
Mucosal Eosinophils and Mast Cells Cystic fibrosis is a multisystem disorder
caused as a consequence of defects in the cystic
Mucosal nerve fibres are in close contact with fibrosis membrane regulator (CFTR) protein
immunocytes in the lamina propria of the mucosa. encoded by ABBC7 and these mutations are
In particular eosinophils and mast cells interact inherently proinflammatory. Meconium ileus and
with nerves in the mucosa and these interactions distal ileal obstruction syndrome (DIOS) are seen
are critical for the initiation or disturbance of in patients with cystic fibrosis. In DIOS there is a
muscle electrical activity [37]. Activated eosino- marked lymphocytic leiomyositis and myenteric
phils and mast cells release their granules (eosino- ganglionitis, which results in bowel obstruction
phil derived neurotoxin, eosinophil peroxidase, [38]. The diagnosis of cystic fibrosis should be
eosinophil-associated ribonucleases; and mast borne in mind if the intestinal sample shows
cell tryptase and histamine respectively) close to transmural lymphocytic inflammatory process
the mucosal nerve fibres activating PAR-2 recep- particularly affecting the muscularis propria and
tors co-localised with the mucosal nerve fibres the myenteric plexus. As a consequence there
and with the loss of myoelectric activity. may be myofibroblastic transformation in the
bowel wall culminating in disarranged muscle
layers (Fig. 17.11).
Secondary to a Systemic Disease Mitochondrial cytopathies are regulated by two
genomes, mitochondrial DNA and nuclear DNA.
Unlike in adults, in children enteric neuromuscu- In patients with mitochondrial cytopathies such as
lar diseases secondary to systemic diseases are Kearns-Sayre, MERRF (myoclonic epilepsy and
rare. The pathology of many muscular dystro- ragged red fibres) and MELAS (myoclonic epi-
phies affecting skeletal muscle is well understood lepsy lactic acidosis and stroke-like episodes) with
and involves dystrophin and dystrophin associ- mutations in the mitochondrial DNA and a mater-
ated membrane proteins (sarcoglycans, dystro- nal pattern of inheritance often show abnormal
198 V.V. Smith

Fig. 17.11 Smooth muscle actin immunostained section of full-thickness bowel showing myofibroblastic transforma-
tion (arrows)

mitochondria in skeletal myocytes but in enteric reported case, a thinning of the bowel wall and
smooth muscle cells they are not found even after atrophy and fibrosis of the longitudinal muscle
an intensive search (personal observation, Smith coat has been described [40]. The deltoid muscle
VV). Some mitochondrial cytopathies are clini- had numerous cytochrome oxidase-negative mus-
cally associated with gut dysmotility and bear the cle fibres and fibres with increased succinate dehy-
following acronyms POLIP (polyneuropathy, drogenase activity. Electron microscopy showed
opthalmoplegia, leukoencephaly and intestinal abundant mitochondria and cytoplasmic lipid
pseudo-obstruction), OGIMD (oculogastrointesti- droplets corresponding to vacuolation on light
nal muscular dystrophy), MEPOP (mitochondrial microscopy but these findings are not universal
encephalomyopathy with sensorymotor polyneu- (personal observation, Dr VV Smith). If there is a
ropahy, opthalmoplegia and pseudo-obstruction) suspicion of MNGIE, skeletal muscle biopsy may
and MNGIE (neurogastrointestinal encephalomy- be diagnostic and intestinal tissue is unlikely to be
opathy) [39]. MNGIE is an autosomal recessive helpful. In addition, thymidine phosphatase activ-
mitochondrial disease with mutations in the ity should be measured in blood white cell prepa-
nuclear genome and is associated with severe gas- rations, plasma thymidine concentration measured
trointestinal dysmotility [40]. There are loss-of- and mutation analysis of the thymidine phosphory-
function mutations in the nuclear encoded lase to be undertaken.
thymidine phosphorylase resulting in pathological
accumulation of thymidine (deoxythymidine) and
uridine (deoxyuridine). The abnormal accumula- The Future
tion of the metabolites creates an imbalance in the
mitochondrial nucleotide pool and defects in mito- Although in the past couple of decades advances
chondrial DNA (depletion, point-mutations and have been made to diagnose enteric neuromuscu-
deletions), thus impairing mitochondrial replica- lar diseases, at the present time the methods
tion and maintenance. Histologically, in one available to identify the subtle histological
17 Pathology of Enteric Neuromusculature 199

changes encountered are basic and require Interstitial Cells of Cajal

refining [41]. Moreover, difficulties continue to
be encountered in securing normal baseline data ICC are important cells in the control of intestinal
from children’s bowels due to understandable motor function by modulating neurotransmission
stringent ethical constraints [42]. of noncholinergic nonadrenergic (NANC) inhibi-
Following are some of the areas to pursue. tory activity [44] but until the mid-1990s they
could only be studied by electron microscopy. In
1995 Huizinga et al. demonstrated in the mouse
Contractile Protein Isoforms that ICC express c-kit (cd117) and that mice with
mutations in c-kit lack ICC as well as intestinal
It is known that the contractile protein cocktail pacemaker activity [45]. This observation led to
crucially determines the type of smooth muscle the study of these critically important cells by
contraction. Defects in this process may con- using immunohistochemistry in intestinal sam-
stitute the basis of some forms of intestinal ples from patients with intestinal motility disor-
myopathies in which conventional histology ders. Many studies have been published with
and ultrastructural examination currently fail often conflicting results due to the plasticity
to demonstrate morphological abnormalities. shown by ICC [46]. There seems to be tremen-
There is a need to obtain further isoform- dous potential for meaningful studies on this
specific antibodies to assess the isoform profile topic but only after reliable normative data in
of a variety of contractile proteins involved in children have been secured.
smooth muscle contraction. Such antibodies
could be used to study the ontogeny of iso-
forms and irregularities in the isoform profile CD56 (N-CAM) Immunostaining
and might identify further patients in whom
abnormalities of this type underlie intestinal CD56-immunostaining is confined to the periph-
muscle dysfunction. This could also open the ery of the perikarya of enteric neurons, neuronal
way to more fundamental studies at the genetic processes, glial cells and to varicosities in the
and molecular levels. muscularis propria in post-natal gut. However, in
foetal gut (12–23 weeks gestation) enteric muscle
in the developing muscularis propria shows posi-
Muscle Membrane Proteins tive punctate immunostaining for CD56 (personal
observation, VV Smith 1993). We have noted
Muscle membrane proteins (dystrophin, dystro- that leiomyocytes in the innermost circular mus-
glycans, sarcoglycans and others) are not only cle layer may retain CD56-positivity in intestinal
expressed by skeletal muscle but also cardiac and samples from some younger patients with intesti-
smooth muscle including enteric leiomyocytes. nal motility disorders (Fig. 17.12). This immuno-
In X-linked dilated cardiomyopathy, which exclu- reactivity was transient in a couple patients
sively affects the heart muscle without skeletal disappearing on follow-up sampling. The assump-
muscle involvement, mutations in the dystrophin tion is that there is a delay in muscle maturation
gene are found [43] but the protein levels between but this is an area that requires a systematic
different types of muscles vary. Dystrophin lev- study.
els as low as 30 % suffice to avoid skeletal mus- Other areas of potential interest are channelop-
cular dystrophy but not cardiac muscle athies and neurotransmitter receptors, which have
dysfunction. Parallel situations may exist in received little attention so far [47]. Histopathology
enteric smooth muscle. A particular level of pro- alone, even with electron microscopy as well as
tein expression may be sufficient to cause leio- enzyme- and immunohistochemisty, does not
myopathy without affecting cardiac or skeletal suffice to identify the subtler changes and there is
muscle function, thus warranting further study. a need for techniques such as proteomics and
200 V.V. Smith

Fig. 17.12 CD56 immunostained section showing abnormal immunoreactivity in the innermost layer of the circular
muscle coat (arrow)

maybe due to autoimmune enteric leiomyositis.

genomics to identify more abnormalities. The
Gastroenterology. 2002;122:1133–9.
validity of all the aforementioned investigations is 8. Schäppi MG, Smith VV, Milla PJ, Lindley KJ.
underpinned by availability of normative data in Eosinophilic myenteric ganglionitis is associated with
childhood, which continues to be a problem in functional intestinal obstruction. Gut.
2003;52:752–5.
paediatrics.
9. Smith VV, Gregson N, Foggensteiner L, Neale G,
Milla PJ. Acquired intestinal aganglionosis and circu-
lating auto-antibodies without neoplasia or other neu-
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 Genetics of Motility Disorder:
Gastroesophageal Reflux, Triple A 18
Syndrome, Hirschsprung Disease,
and Chronic Intestinal Pseudo-
Obstruction

Jonathan M. Gisser and Cheryl E. Gariepy

Introduction Gastroesophageal Reflux Disease

The identification of gene mutations associated The lower esophageal sphincter is an anatomic
with a disease often provides important initial and physiologic barrier that limits the backflow
insight into its molecular basis and can hold the of gastric contents into the esophagus while
key to developing an effective therapeutic strat- allowing the passage of food into the stomach. In
egy. After several decades of identifying single theory, any developmental process affecting the
gene mutations causing usually rare GI motility position and function of the lower esophageal
disorders, we are beginning to understand the eti- sphincter may result in GERD and be genetically
ology of complex, multigenic motility disorders. influenced. Moreover, a predisposition to com-
In this chapter we review the current genetic plications of lower esophageal sphincter dys-
understanding of four motility disorders; gastroe- function may also be genetically influenced. It is
sophageal reflux disease (GERD), Triple A syn- therefore likely that the genetic contribution to
dromic achalasia, Hirschsprung disease, and the symptoms and complications arising from
chronic intestinal pseudo obstruction. The molec- lower esophageal sphincter dysfunction, com-
ular and developmental consequences of some of monly referred to as GERD, is multifactorial [1].
these mutations are described in detail in other Pathophysiologic determinants of GERD that
chapters. may be genetically modulated have been enu-
merated previously and are listed in Table 18.1
[2]. Since various definitions of GERD are
employed in genetic studies and the disease may
be genotypically and phenotypically heteroge-
neous, no clear genetic determinants have yet
J.M. Gisser, M.D., M.Sc.
emerged [1]. To date, evidence for a genetic pre-
Division of Pediatric Gastroenterology, Hepatology and
Nutrition, Pediatrics Department, Center for Molecular disposition to GERD has been inferred from epi-
and Human Genetics, The Research Institute at demiologic, twin concordance, and genetic
Nationwide Children’s Hospital, The Ohio State linkage studies, with little attention paid to
University College of Medicine, Columbus, OH, USA
specific host genetic factors. Evidence supporting
C.E. Gariepy, M.D. (*) genetic risk factors in the development of syn-
Center for Molecular and Human Genetics, Nationwide
dromic GERD and complications from GERD
Children’s Research Institute,
700 Children’s Drive, WA2015, Columbus, OH 43205, USA also exists, but is beyond the scope of the present
e-mail: [email protected] discussion.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 203

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_18, © Springer Science+Business Media New York 2013
204 J.M. Gisser and C.E. Gariepy

Table 18.1 Pathophysiologic determinants of gastroe- metaplasia, and esophageal adenocarcinoma

sophageal reflux disease that could be genetically were more prevalent than in spouse controls.
modulated
A similar increased prevalence among relatives
Refluxate toxicity of patients with uncomplicated esophagitis, was
Gastric acid secretion
not observed in this study, suggesting that only
Duodenogastric reflux
severe GERD is heritable [5]. However, another
Intrinsic gastric volume and pressure
investigation of patients with abnormal pH stud-
Gastric compliance
Gastric emptying
ies revealed that relatives of patients with
Gastric acid volume secretion increased esophageal acid exposure were more
Extrinsic pressure on gastric contents likely to experience frequent reflux symptoms,
Weight (obesity) even in the absence of GERD complications [6].
Somatic motor tone (spasticity) Familial clustering of GERD can also arise
Somatic and crural episodic contractions (cough, from shared environmental risk factors rather
wheeze,…) than genetic factors. In twin studies, conditions
Gastroesophageal barrier that bear a large genetic predisposition are more
Lower esophageal sphincter tone likely concordant in monozygotic twins than
Gastric fundic sensory thresholds (for transient lower dizygotic twins. Two large-scale studies have
esophageal sphincter relaxations)
investigated the concordance of GERD in mono-
Crural diaphragm location (relative to sphincter
location) and function and dizygotic twins. In one of these studies,
Esophageal defenses twins belonging to the national Swedish Twin
Salivary secretion Registry were queried for GERD using a ques-
Peristaltic motor function tionnaire. In almost 3,100 twin pairs with
Esophageal cytoprotection GERD, aged 55 years or greater, the concor-
a
Adapted from Orenstein SR, Shalaby TM, Barmada MM, dance was significantly higher among monozy-
Whitcomb DC. J Pediatr Gastroenterol Nutr. gotic twins compared to dizygotic twins,
2002;34(5):506–10. Lippincott Williams & Wilkins, Inc., suggesting that heritability accounts for approx-
Philadelphia, publishers
imately one third of the susceptibility to GERD
[7]. A similar study from a twin registry in the
The first studies to infer a genetic component United Kingdom corroborated the Swedish
to GERD were case reports describing familial study, finding concordance rates of 42% for
clusters of radiologically confirmed hiatal hernia monozygotic twins versus 26% for dizygotic
(reviewed in [3]). In the largest and most detailed twins, and concluding that 43% of the predilec-
of these studies, Carre and colleagues described a tion to GERD is genetically influenced [8].
kindred of 38 family members across five genera- In an attempt to detect specific genetic loci
tions, all of whom were interviewed and sub- associated with GERD, Hu and colleagues per-
jected to a barium meal. Among this pedigree formed a genetic linkage analysis of five families
were 20 individuals with both symptoms of gas- in which multiple family members were afflicted
troesophageal reflux, and radiologic evidence of with severe pediatric GERD. They found a 9-cen-
hiatal hernia. An autosomal dominant mode of tiMorgan locus on the long arm of chromosome
inheritance was suggested [4]. 13 (13q14; termed GERD1) that segregated with
Although familial clusters of hiatal hernia are the severe pediatric GERD phenotype in their
established, most cases of hiatal hernia are spo- cohort [9]. A candidate gene in this region is the
radic and most pediatric GERD is not associated 5-hydroxytryptamine receptor 2A. However, no
with hiatal hernia. Therefore hiatal hernia proba- coding sequence mutations were identified [9,
bly accounts for a small minority of cases of 10]. The authors proposed that mutations in regu-
hereditary GERD. Other studies support a famil- latory or other non-coding regions, null alleles,
ial predisposition to GERD even in the absence segmental deletions and duplications, and epige-
of a hiatal hernia. In case control studies, GERD netic effects in the 13q14 region could still
symptoms in relatives of patients with Barrett’s account for the pediatric GERD phenotype in
18 Genetics of Motility Disorder: Gastroesophageal Reflux, Triple A Syndrome, Hirschsprung... 205

these families [10]. In support of this, a recent q33, confirming this association in a separate
case report describes a dysmorphic infant with cohort. Biopsies from those subjects with abnor-
severe GERD who possesses a 12.8 megabase mal endoscopic or pHmetric findings, or those
deletion spanning the GERD1 locus, implicating who had undergone fundoplication, were then
GERD1 haploinsufficiency in the patient’s subjected to gene expression analysis and the
symptoms [11]. However, independent linkage COL3A1 gene (collagen type III alpha I), resid-
analyses in different cohorts failed to confirm ing within this locus, was found to be differen-
the association of the 13q14 locus with GERD tially expressed in subjects with GERD compared
[12, 13], underscoring the genetic heterogeneity to controls. As collagen type III contributes to tis-
of GERD. sue strength, flexibility, and wound response, the
The subjective sensation of GER has been authors proposed a mechanism whereby altered
attributed to the exposure of esophageal mucosa collagen type III expression in the esophagus
to the acidic gastric refluxate causing a mucosal results in a predisposition to esophageal damage
inflammatory response which, in turn, activates in patients with gastroesophageal reflux. Although
afferent sensory nerve pathways. As such, varia- they immunohistochemically demonstrated
tions in genes that participate in inflammation, increased expression of the collagen III protein in
wound healing, and sensory neuromodulation esophageal tissue biopsies, they did not investi-
could theoretically contribute to the experience of gate whether this was a cause or a consequence
gastroesophageal reflux. With this in mind, three of gastroesophageal reflux. Also, sequencing of
recent studies have focused on genes in these the COL3A1 gene in 48 subjects did not identify
pathways. A study by Chourasia et al. evaluated any causative mutations. The authors propose
the relationship of polymorphisms in genes encod- that disease causing mutations reside in regula-
ing the Interleukin 1B (IL-1B) and the interleukin tory regions [12].
1 receptor antagonist (IL-1RN) to GERD in G-proteins are second messengers involved in
patients referred to a tertiary center [14]. A single the neurotransmission of gastroesophageal sen-
nucleotide polymorphism in the promoter region sation. The C825T substitution polymorphism
of the IL-1B gene predisposes to increased con- within the gene encoding the G-protein b3 sub-
centrations of IL-1beta, a potent pro-inflammatory unit results in enhanced G-protein activation and
cytokine. In contrast, a polymorphism consisting signal transduction [15], and is associated with
of two intronic tandem repeats (as opposed to 3–5 functional dyspepsia [16]. On this basis, De Vries
repeats) within the IL-1RN gene tends to decrease and coworkers explored the relationship of the
IL-1beta levels and has an anti-inflammatory C825T allele with GERD in 363 subjects with
effect. Hypothesizing that increased gastric either pathologic esophageal acid exposure or a
inflammation destroys proton-excreting parietal positive symptoms association score for heart-
cells, thus lowering esophageal acid exposure, burn or regurgitation. Compared to healthy con-
investigators characterized the IL-1 genotypes of trols, individuals with GERD were more likely to
144 patients with confirmed GERD and 368 be heterozygous for the C825T. The likelihood of
healthy controls. They found that subjects with being heterozygous for C825T was highest
genotypes and haplotypes combining to decrease (adjusted odds ratio 1.5; 95% CI 1.06–2.13)
IL-1beta levels had predictably lower gastric among patients with a positive symptom associa-
mucosal IL-1beta expression, and generally had a tion score, but no correlation was observed among
higher risk of GERD. These genotypes and haplo- those with pathologic acid exposure. This sug-
types were also more prevalent in the GERD pop- gests that enhanced perception of physiologic
ulation [14]. acid exposure, and not pathologic acid exposure,
In another genome wide association study, underlies the association of C825T heterozygos-
Asling and colleagues collected 36 GERD- ity and GERD [17].
affected families and mapped familial GERD to a Each of the above studies propose different
35 megabase pair region on chromosome 2q24- heritable host factors in the pathophysiology of
206 J.M. Gisser and C.E. Gariepy

GERD, increasing the likelihood that still other cytoplasm and the nucleus [28, 29]. ALADIN is
host factors exist. Furthermore, replication and the first nuclear pore protein linked to a human
validation of existing studies is required, high- heritable disease. In most cases of AAAS,
lighting the great need for further investigation in ALADIN is truncated, resulting in its exclusion
this area. from nuclear pore complex and in ectopic cyto-
plasmic accumulation [30]. This may be due to
an inability of the mutant ALADIN protein to
Triple A Syndrome anchor to proteins required for nuclear pore com-
plex assembly [31] or to the deletion of a critical
Triple A syndrome, AAAS is a condition charac- nuclear localization signals in the AAAS tran-
terized by alacrima, adrenocorticotrophic hor- script [32]. Although the nucleus and the nuclear
mone-resistant adrenal insufficiency, and pore complex remain morphologically and struc-
achalasia [18]. Although its name connotes a turally intact without ALADIN, the nuclear
triad, the syndrome is phenotypically heteroge- import of selected proteins is interrupted. Proteins
neous: fewer than three features may be present involved in DNA repair and the attenuation of
and additional features not originally identified in oxidative stress fail to localize to the nucleus
the initial report by Allgrove, including progres- when ALADIN is absent from the nuclear pore
sive autonomic, central, and peripheral nervous complex [33, 34]. On this basis, it is proposed
system deficits, are associated with the syndrome that defective ALADIN renders cells susceptible
[19]. The etiology of achalasia in AAAS appears to oxidative DNA damage and cell death in a
to be distinct from other forms of achalasia [20]. tissue-specific manner [33]. In support of this,
Although it is a rare condition and epidemiologic fibroblast cultures derived from patients with
data are scant, symptoms of swallowing difficulty AAAS possess a higher basal level of reactive
and achalasia in AAAS usually manifests by the oxygen species, a heightened response to oxida-
end of the first decade of life and can begin in tive stress and a predilection for premature stress-
infancy [21, 22]—in contrast to idiopathic acha- induced senescence [35]. Given the variety and
lasia, where very small minority of patients man- abundance of macromolecules that depend on a
ifest symptoms before 10 years of age [23]. The competent nuclear pore complex, it is probable
diagnosis of achalasia in AAAS relies on the that additional genes and proteins will one day be
same manometric, radiographic, and endoscopic identified that will further elucidate how the
criteria as for idiopathic achalasia, and the treat- ALADIN defect translates into the observed phe-
ment is similar. notypes of AAAS.
Frameshift, point, or missense mutations in
the gene AAAS, located at 12q13, account for the
majority of cases of AAAS [19, 24, 25]. Hirschsprung Disease
Consanguinity is often present in kindreds of
AAAS and the condition segregates in an auto- Hirschsprung disease (HSCR) is the develop-
somal recessive pattern. The penetrance of AAAS mental absence of enteric ganglion cells from a
with bi-allelic mutations in AAAS approaches continuous segment of distal intestine. The
100%, though expressivity is variable, possibly enteric ganglia are neural crest-derived and con-
due to allelic variation or the existence of as yet genital distal aganglionosis is generally attrib-
unidentified modifier genes. uted to a failure of vagal neural crest cells to
AAAS encodes the ALADIN protein (an acro- complete colonization of the developing intes-
nym for alacrima, achalasia, adrenal insufficiency tine between the 5th and 12th week of gestation
and neurological disorder) [26, 27]. ALADIN is [36]. A minority of HSCR (30%) is syndromic
part of the nuclear pore complex, a large, multi- (associated with other congenital anomalies)
protein complex spanning the nuclear envelope with several monogenic syndromes recognized
and forming a selective channel between the and chromosomal abnormalities found in 12% of
18 Genetics of Motility Disorder: Gastroesophageal Reflux, Triple A Syndrome, Hirschsprung... 207

cases. Isolated and syndromic HSCR are dis- There are two major isoforms of RET pro-
cussed separately, however, the distinction is not duced by alternative splicing of the transcript,
always clear-cut with syndromic phenotypes RET9 (1,072 amino acids) and RET51 (1,114
sometimes not apparent at birth and the implica- amino acids). The evidence is conflicting as to
tion of several genes in both isolated and syndro- whether both isoforms are equally supportive of
mic forms of the disease. Approximately 20% of enteric nervous system development [42, 43].
HSCR is familial with a recurrence risk in rela- The expression of a particular mutation may have
tives up to 200 times increased over the general significantly different developmental effects
population. HSCR is classified as short-segment depending upon the isoform in which it is
disease (S-HSCR) when aganglionosis is distal expressed. For example, in genetically manipu-
to the splenic flexure, long-segment (L-HSCR) lated mice, a specific mutation in RET51 pro-
when aganglionosis begins proximal to the duces only distal colon aganglionosis, while the
splenic flexure (20% of cases) and total colonic same mutation in RET9 leads to aganglionosis
(TC-HSCR) when the entire colon is aganglionic with parasympathetic, sympathetic, and renal
(~5% of cases) [37]. anomalies [43].
Mutations in the coding sequence of RET are
found in ~50% of familial and 15% of sporadic
Isolated HSCR HSCR. However, most individuals with isolated
HSCR carry a non-coding sequence mutation in
Isolated HSCR is a complex, multigenic disorder RET. An allele including a single nucleotide
with low, sex-dependent penetrance, and variable change in an enhancer sequence within intron 1
expression. The incidence of HSCR varies among (the “T allele”, also known as rs2435357) is very
ethnicities with a range from 1 to 2.8 per 10,000 common in the USA, European (~24%), and
live births in Hispanics and Asians, respectively Asian (47% in China) populations and likely
[38]. The two major genes implicated in isolated plays a pivotal role in HSCR susceptibility despite
HSCR are the gene encoding the RET (REarranged conferring low penetrance of the phenotype.
after Transfection) receptor tyrosine kinase, RET, Coding sequence mutations are more likely to be
and the gene encoding the endothelin B-receptor, found in less common forms of the disease
EDNRB. (females with familial L-HSCR). The T allele
RET is a proto-oncogene that is disease interferes with SOX10 binding to the RET
causing in Multiple Endocrine Neoplasia syn- enhancer and is a genetic susceptibility factor in
drome 2 (MEN2), congenital abnormalities of all forms of HSCR (discussed further below)
the kidney and urinary tract [39] and HSCR. A [44]. Interestingly ~5% of the Caucasian popula-
large number of RET coding sequence muta- tion carries a different non-coding sequence
tions spanning the length of the gene are polymorphism in RET that appears to reduce the
identified in HSCR. In contrast, MEN2A muta- risk of HSCR [45].
tions occur in a cluster of cysteines on exon 10 Glial-Derived Neurotrophic Factor (GDNF)
or exon 11 and the MEN2B mutation is a is a ligand that requires the co-receptor
unique codon substitution, M918T, in the GFRa(alpha)1 to activate RET. While targeted
tyrosine kinase domain. HSCR mutations gen- disruption of GDNF and GFRa(alpha)1 produces
erally reduce biological activity of the receptor a HSCR-like phenotype in mice, GDNF muta-
whereas MEN2 mutations are activating muta- tions are a rare cause of HSCR and a GFRa(alpha)1
tions leading to constitutive dimerization of mutation has only been described in one family
the receptor in the absence of ligand. However, with HSCR [46].
HSCR and MEN2A occur together in some EDNRB is a G-protein coupled, heptahelical
patients and families, requiring a more com- transmembrane receptor that is activated by the
plex explanation for the signaling consequences endothelins (EDN1, 2, and 3). While EDNRB
of these mutations [40, 41]. accepts all three ligand with equal affinity, devel-
208 J.M. Gisser and C.E. Gariepy

opmentally EDN3 is the relevant ligand as tar- ling in question. The lowest recurrence risk is for
geted disruption in mice of EDN3 alone (but not the female sibling of a male with S-HSCR (1%)
EDN1 or EDN2) produces a very similar pheno- and the highest risk is for a male sibling of a
type as EDNRB disruption [47]. Pre-proendothelin female with L-HSCR (33%) [46].
is proteolytically activated by Endothelin
Converting Enzyme (ECE)1 [48].
Mutations in EDNRB and EDN3 are disease- Syndromic HSCR
causing in Waardenburg Syndrome type 4 (WS4,
hearing loss and pigment abnormalities with A wide range of isolated anomalies are reported
HSCR) and isolated HSCR [49]. While coding with HSCR. Cardiac defects (most commonly
sequence EDN3 mutations are a rare cause of iso- atrial- or ventricular-septal defects) and renal
lated HSCR [50], EDNRB coding sequence muta- anomalies are found in ~5% of HSCR patients
tions are found in ~5% of cases with incomplete and should be looked for systematically. For
penetrance of heterozygous mutations [46]. HSCR associated with other congenital anoma-
Sanchez-Mejias and colleagues recently reported lies, the prognosis is largely dependent on the
a single nucleotide polymorphism in an EDN3 severity of the other anomalies. Numerous syn-
intron significantly overrepresented in HSCR dromes are associated with HSCR and the recog-
patients and hypothesized that EDN3 may be a nition of these syndromes is important for disease
common low-penetrance susceptibility gene for prognosis and accurate genetic counseling.
sporadic HSCR, similar to the T allele in RET Careful evaluation by a clinician familiar with the
[51]. A heterozygous ECE1 mutation was varied associated syndromes is extremely valu-
identified in a single patient with skip-lesion able to the patients and their families. Below we
aganglionosis and other defects (including car- discuss syndromes most commonly associated
diac defects, craniofacial abnormalities, and with HSCR.
autonomic dysfunction, some of which may be HSCR occurs in syndromes with defects in
related to an absence of active EDN1) [52]. other neural crest-derived tissues, termed neuroc-
While RET and EDNRB signaling are thought ristopathies. The neural crest is a transient, multi-
to be independent, genetically there is clear inter- potent, migratory cell population in the embryo
action between the two pathways. Mice carrying that give rise to diverse tissues of the body, includ-
hypomorphic (causing a partial loss of gene func- ing melanocytes, craniofacial cartilage and bone,
tion) non-disease causing mutations of both RET cells in the thymus, the cardiac outflow tract, the
and EDNRB exhibit aganglionosis and a similar adrenal medulla, the autonomic nervous system,
phenomenon is reported in humans [53–55]. RET and the ENS. Multiple endocrine neoplasia
is the major disease causing gene in isolated (MEN) 2A, 2B, and familial medullary thyroid
HSCR, but in most cases alterations in other genes, carcinoma (FMTC) are autosomal dominant can-
particularly EDNRB and perhaps EDN3, modulate cer predisposition syndromes and neurocristopa-
clinical expression of the phenotype [44, 56]. thies. MEN2A includes medullary thyroid
Because of the poor genotype–phenotype cor- carcinoma (MTC, 70% by age 70), pheochromo-
relation in isolated HSCR, there is little benefit of cytoma (50%), and parathyroid hyperplasia
mutation screening except for the cancer predis- (~25%). MEN2B presents with oral neuroma,
posing MEN2A mutations in RET where it is marfanoid habitus, and hyperganglionosis (asso-
important to identify the syndrome before it ciated with dysmotility) of the gut. It also includes
becomes symptomatic (see below). Despite this, MTC and pheochromocytoma. FMTC and MEN2
relative risk figures for isolated HSCR recurrence are caused by mutations in RET and both FMTC
in siblings exist and depend upon the sex of the and MEN2A are associated with HSCR. The
known affected individual, the length of agangli- same mutations causing MEN2A and FMTC can
onosis in that individual, and the sex of the sib- cause HSCR suggesting that individuals with
18 Genetics of Motility Disorder: Gastroesophageal Reflux, Triple A Syndrome, Hirschsprung... 209

HSCR should be screened for these mutations to of HSCR. HSCR in patients with trisomy 21
allow for early cancer detection [57]. shows a more pronounced male predominance
Congenital central hypoventilation syndrome and is primarily S-HSCR [63]. Interestingly, the
(CCHS) is an autosomal dominant neurocristopa- T allele in RET intron 1 enhancer discussed
thy characterized by an abnormal ventilatory above appears to play a role in the expression of
response to hypoxia and hypercapnia due to HSCR in trisomy 21 as well as sporadic, non-
abnormal autonomic respiratory control. The syndromic HSCR. While incidence of the T
syndrome can be associated with broader dys- allele higher in individuals with trisomy 21
function of the autonomic nervous system and HSCR than in individuals with trisomy 21 alone,
with neural crest-derived tumors (5–10% of it is less than that observed in individuals with
CCHS patients develop neuroblastoma, ganglio- HSCR alone. This suggests interaction between
blastoma, or ganglioneuroma). CCHS is caused RET and chromosome 21 genes, perhaps through
by mutation in PHOX2B with a de novo heterozy- a reduced HSCR threshold conferred by the
gous in-frame duplication leading to polyalanine extra chromosome 21 [64].
expansion being the most common mutation Mowat-Wilson syndrome includes micro-
indentified. However, approximately 10% of the cephaly, epilepsy, facial dysmorphism, and
parents of CCHS patients will be mosaic for the severe mental retardation. Sixty percent of
mutation and may develop late onset central affected individuals have HSCR. The syndrome
hypoventilation. There is also a clear genotype– is caused by heterozygous de novo inactivating
phenotype correlation with the risk for tumor mutations of ZEB2 [65]. Goldberg-Shprintzen
development: individuals carrying the most com- syndrome includes microcephaly, polymicro-
mon polyalanine expansion mutation can be reas- gyria, facial dysmorphism, cleft palate, iris
sured, while those carrying a frameshift mutation coloboma, and moderate mental retardation. It
are at high risk and should be considered for reg- is caused by mutation in the gene encoding the
ular screening [58, 59]. Overall, 20% of individu- kif-1 binding protein (known as KBP or
als with CCHS have HSCR with L-HSCR or KIAA1279) [66]. Animal models suggest that
TCA being most common with a near equal male this protein is required for axonal outgrowth in
to female ratio [60]. However, the T allele of RET the central and peripheral nervous system and
affects the penetrance of HSCR with the inci- for axonal maintenance [67]. The details of how
dence of HSCR climbing to 60% in CCHS this leads to the HSCR phenotype are yet to be
patients homozygous for the T allele [61]. determined.
The combination of Waardenburg syndrome and Bardet-Biedl syndrome (BBS) includes pro-
HSCR is termed Waardenburg syndrome type 4 gressive pigmentary retinopathy, hypogonad-
(WS4) or the Shah-Waardenburg syndrome. ism, renal abnormalities, mild mental
It is called by homozygous mutations of the retardation, obesity, and postaxial polydactyly
endothelin-B signaling pathway (EDNRB or of the hands and feet. HSCR is reported in sev-
EDN3) or heterozygous SOX10 mutation. Patients eral cases. It is caused by at least 14 different
with SOX10 mutations are also at risk for other genes all of which are involved in the function
neurologic abnormalities including seizures, of primary cilia [68]. As with trisomy 21,
ataxia, and demyelinating neuropathies. HSCR is PHOX2B and EDNRB mutations, the presence
also associated with severe congenital deafness of the T allele of RET associated with expres-
in the absence of pigment abnormalities [62]. sion of the aganglionosis phenotype despite
HSCR also occurs in syndromes that are not independent biochemical signaling pathways
neurocristopathies. Trisomy 21 increases the [61]. McKusick-Kaufman syndrome is a rare
risk of HSCR by 40-fold (0.8% of individuals condition allelic to BBS that includes hydromet-
with trisomy 21 have HSCR) and is by far the rocolpos, postaxial polydactyly, and congenital
most frequent chromosomal abnormality heart defects. HSCR is reported in 10% of
identified in HSCR patients, involving 2–10% cases [69].
210 J.M. Gisser and C.E. Gariepy

Smith-Lemli-Opitz syndrome is characterized in a gene involved in cholesterol metabolism,

by growth retardation, microcephaly, severe metal 7-dehydro-cholesterol reductase [70, 71]. HSCR
retardation, dysmorphic facies, hypospadias, and occurs with limb anomalies in several other rare
syndactyly of the toes. A high percentage of patients syndromes. See Table 18.2 for more on the genet-
also have HSCR. The syndrome is due to mutation ics of isolated and syndromic forms of HSCR.

Table 18.2 Genetics of isolated and syndromic forms of Hirschsprung’s disease

Gene Mutation Phenotype
A. Isolated Hirschsprung
RET Heterozygous loss-of-func- Long-segment or total-colonic disease more
tion of tyrosine kinase common
receptor (many identified)
EDNRB Heterozygous loss-of-func- Generally produces short-segment disease
tion of G protein-coupled
receptor

B. Syndromic Hirschsprung
RET Heterozygous mutations of MEN2A: medullary thyroid carcinoma,
cysteines producing pheochromocytoma, parathyroid hyperplasia
constitutive dimerization and
activation of the receptor
Phox2B Heterozygous loss-of-func- Congenital Central Hypoventilation Syndrome:
tion mutation of transcrip- abnormal autonomic respiratory control,
tion factor Polyalanine frame-shift mutations increase risk of
expansion most common neuroblastoma
EDNRB Homozygous loss-of-func- Waardenburg Syndrome Type 4: pigment
tion mutation of G protein- abnormalities and deafness
coupled receptor
Waardenburg Syndrome Type 4: pigment
abnormalities, deafness. Sox10 mutations also
associated with ataxia, neuropathies and seizures
ZEB2 Heterozygous loss-of-func- Mowat-Wilson Syndrome: microcephaly,
tion mutation of transcrip- epilepsy, dysmorphic face, cognitive impairment
tion factor
KIAA1279 Homozygous loss-of-func- Goldberg-Shprintzen Syndrome: microcephaly,
tion in protein involved in polymicrogyria, dysmorphic face, cleft palate,
microtubule organization iris coloboma, mild cognitive impairment
BBS genes Homozygous loss-of-func- Bardet-Biedl Syndrome: obesity, renal abnor-
tion in proteins involved in malities, polydactyly, retinitis pigmentosa,
primary cilia hypogonadism, cognitive impairment
DHCR7 Homozgygous loss-of-func- Smith-Lemli-Opitz Syndrome: microcephaly,
tion of enzyme in cholesterol dysmorphic face, hypotonia, syndactyly,
production pathway polydactyly, ambiguous genitalia, poor growth

C. Modifying genes
RET T allele: single nucleotide This common allelic variant increases the
substitution in an enhancer penetrance of Hirschsprung disease in those with
sequence other genetic susceptibilities, like trisomy 21,
mutations in EDNRB, Phox2B and BBS genes
18 Genetics of Motility Disorder: Gastroesophageal Reflux, Triple A Syndrome, Hirschsprung... 211

Neurofibromatosis 1 (NF1) is a neurocristopa-

Chronic Intestinal Pseudo-Obstruction thy associated with disordered intestinal motility
related to neuroglial proliferation and often tumor
Chronic intestinal pseudo-obstruction (CIPO) is formation in the submucosal and myenteric
a heterogeneous group of rare primary and sec- plexus. It is also associated with HSCR. Fifty
ondary disorders in which ganglion cells are percent of cases result from de novo mutations
present throughout the GI tract in a patient with and 50% are inherited in an autosomal dominant
severe failure of intestinal propulsive motility. fashion with highly variable penetrance and phe-
The anatomic correlates of CIPO are most often notypic expression. The NF1 gene encodes
absent, subtle, subjective, or non-specific. Most neurofibromin which is an upstream regulator of
cases are sporadic and non-syndromic, but famil- the RAS/RAF/MAPkinase and RAS/RAL intrac-
ial and syndromic forms are reported. CIPO is ellular signaling pathways [78]. A GDNF muta-
generally divided into three groups: neuropathic, tion modifies the enteric phenotype of NF1.
mesenchymopathic, and myopathic, depending Individuals carrying both the neurofibromin and
upon whether predominant abnormalities are GDNF mutation develop NF1 with congenital
found in the enteric nervous system, Interstitial intestinal dysmotility associated with submucosal
Cells of Cajal (ICC), or intestinal smooth muscle, plexus hyperplasia [79].
respectively. While a genetic basis is suspected in MEN2B is a rare autosomal dominant syndrome
a large percentage of CIPO, it is established in characterized by medulary thyroid carcinoma,
only a small minority of cases. pheochromocytoma, marfanoid appearance, and
ganglioneuromas. The syndrome is most often
caused by activating mutation of codon 918 of
Neuropathic RET. Because 50% of mutations are de novo, a
family history is frequently absent. Constipation,
Intestinal Neuronal Dysplasia type B (IND B) is often severe, related to intestinal ganglioneuro-
characterized by hyperplasia of the submucosal matosis is present in 40% of patients and may be
and mucosal portions of the enteric nervous sys- present at birth [80, 81]. Recognition of this
tems, presents with chronic constipation in the potential cause of severe constipation is clinically
first 6 months of life, and is reported in the proxi- important because the intestinal symptoms usu-
mal gut of some individuals with HSCR [36, 72]. ally precede endocrine neoplasia. Individuals
Children with isolated IND B often improve in with MEN2B RET mutations develop early onset
GI function over time with conservative treat- MTC with metastatic disease reported in infants.
ment and do not progress to CIPO [73]. While the Total thyroidectomy during the first month of life
diagnosis of IND B remains somewhat contro- is recommended [82].
versial, several animal models and its association In addition to being associated with pigment
with HSCR suggest a genetic cause. IND-like abnormalities and HSCR (WS4), SOX10 mutations
hyperplasia of submucosal ganglia occurs in the are associated with additional nervous system
proximal gut of EDN3-deficient mice [74] and in symptoms, including nystagmus, hypotonia, cere-
the small intestine and colon of apparently healthy bellar ataxia, and peripheral demyelinating neu-
EDNRB heterozygous rats [75]. Attempts to ropathy [83]. Occasionally the enteric phenotype in
identify mutations in EDNRB in IND B patients individuals with SOX10 mutations is not HSCR but
have been unsuccessful [76]. CIPO with normal appearing ganglia [84].
IND A is a rare, fatal syndrome of aplasia An X-linked form of CIPO characterized by
or hypoplasia of the enteric sympathetic abnormal argyrophilic “shrunken, degenerating”
nerves which presents in the immediate neo- neurons in the myenteric and submucosal plexus
natal period with a tonically contracted intes- with “nerve fibers in the lamina propria of the
tine [ 77 ] . The genetics of the disorder are colon” associated with pyloric hypertrophy, a
unknown. short small bowel, and malrotation is reported
212 J.M. Gisser and C.E. Gariepy

[85]. Patients that survive the neonatal period Mesenchymopathic

develop severe CNS disease with spasticity and
seizures. The syndrome is cause by a deletion in The ICC are derived from mesenchymal precur-
the FLNA gene, which encodes a large cytoskel- sor cells and are located adjacent to the myenteric
etal protein [86]. plexus (ICC-MY), along the submucosal boarder
Our understanding of CIPO is hampered by a of the circular muscle (ICC-SM), within the cir-
paucity of animal models. Mutations clearly linked cular muscle layer in the deep muscular plexus
to CIPO in humans often cause no disease in mice. (ICC-DMP), and within muscle bundles of the
For example, mice carrying the MEN2B mutation tunica muscularis (ICC-IM). Various mutations
of RET do not develop intestinal ganglioneuromas in the gene encoding the receptor tyrosine kinase
[87]. Further, while HOX11L1 knockout mice are a KIT and its ligand, stem cell factor, produce
model of CIPO, descriptions of their ENS abnor- reductions in some classes of ICC. A reduction in
mality are inconsistent. HOX11L1 is expressed in ICC-MY results in mice without intestinal pace-
differentiating neurons primarily in the ileocecal maker activity, a reduction in ICC-IM results in
region, proximal colon, and gastric cardia where, in marked reduction in cholinergic excitatory and
a permissive genetic environment, it appears to nitrergic inhibitory input to intestinal smooth
influence neurotransmitter expression within the muscle. Animal models with genetic reduction in
ENS: 100% of HOX11L1 knockout mice on one ICC exhibit abnormal intestinal motility patterns
inbred genetic background show signs of intestinal without signs of intestinal obstruction, while ani-
pseudo-obstruction, with most dying in the first mals with antibody-mediated ICC reduction in
month of life and ~30% surviving with distended the neonatal period exhibit dysmotility with dis-
proximal colons. In contrast, only 15% on a differ- tension [92, 93]. This likely relates to the severity
ent inbred genetic background developed disease. and subtype of ICC reduction. The absence of
Strain-specific differences are also noted in the ICCs, their abnormal distribution or morphology
number of enteric neurons that express HOX11L1 is suggested to cause CIPO based on several case
[88]. Recently, however, a couple of animal models reports [94].
of myenteric ganglioneuromatosis have been
reported. Mice with ENS tissue specific disruption
of PTEN develop hypertrophy and hyperplasia of Myopathic
the myenteric and submucosal plexus throughout
the GI tract with lethal functional obstruction. PTEN Myopathic CIPO usually includes a variety of extraint-
deficiency alters intracellular MAPK/ERK signal- estinal manifestations and myopathies. The
ing and some patients with a ganglioneuromatosis Megacystis-Microcolon-Intestinal-Hypoperistalsis
form of CIPO not related to NF1 or MEN2B have Syndrome, MMIHS, is characterized clinically
decreased expression of PTEN [89]. Decreased by intestinal and urinary dysfunction and histo-
immunohistochemical detection of PTEN in the logically by a reduction in the expression of con-
hyperplastic ganglia of individuals with IND B has tractile and cytoskeletal proteins in the intestinal
been reported [90]. Mice that do not express SPRY2, and bladder smooth muscle. The genetic cause of
which encodes a fibroblast growth factor pathway the syndrome remains unknown, although an
antagonist, are another model of myenteric gangli- autosomal recessive pattern of inheritance is
oneuromatosis. These animals have a hyperplastic observed [95]. Mice with homozygous disruption
colonic myenteric plexus (as well as a non-relaxing of the alpha-3/beta-4 neuronal nicotinic acetyl-
lower esophageal sphincter), perhaps through choline receptor genes exhibit a similar pheno-
increased RET activation. Half of these mice die by type. Both of these genes map to human
6 weeks of age due to esophageal/intestinal chromosome 15q24 and a high frequency of
obstruction and the remaining animals are polymorphisms in these genes was reported in
significantly growth restricted [91]. human patients [96]. MMIHS is also reported in
18 Genetics of Motility Disorder: Gastroesophageal Reflux, Triple A Syndrome, Hirschsprung... 213

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 Feeding and Swallowing Disorders
19
Nathalie Rommel and Taher Omari

the term “feeding problem” is used to address

Introduction the multi-causal pathology of the child who is
not eating. When dealing with infants and chil-
The processes of deglutition and feeding differ dren, many clinicians use the term “dysphagia”
although both are complex and interrelated. to describe any type of difficulty with feeding
These terms are used interchangeably and no and swallowing or symptom of esophageal dys-
consensus exists on their definition. The term function. In this chapter, however, the term
“deglutition” or “swallowing” refers to the entire “dysphagia” is used for abnormal oropharyn-
act of deglutition from placement of food in the geal function.
mouth through the pharyngeal phases of the swal- Dysphagia is very common in the pediatric
low until the material enters the esophagus population within a wide range of disorders and
through the cricopharyngeal juncture while hinders the provision of adequate nutrition,
avoiding entry of substances into the airway. affecting growth and development and may lead
Swallowing is a motor event that in order to be to significant parental anxiety and family disrup-
successful requires intact and functioning central tion [3, 4]. Epidemiologic data on the prevalence
and peripheral nervous systems and the coordina- and incidence of feeding and swallowing disor-
tion of actions of multiple muscles of the oral ders in pediatric populations are limited.
cavity, pharynx and esophagus [1]. Lindsheid [5] and Burklow [6] summarized stud-
The term “feeding” is defined as the overall ies reporting the estimated prevalence of feeding
process whereby the infant or child ingests food. problems in the pediatric population as ranging
Feeding involves the act of deglutition, but is from 25 to 45% in typically developing children
also influenced by developmental, behavioral and 33 to 80% in children with developmental
and social factors [2]. Therefore, in this chapter delays. The estimated prevalence of oropharyn-
geal dysphagia among children with develop-
mental disabilities ranges from 12 to 71% [7, 8].
N. Rommel, M.Sc., Ph.D. (*) The incidence of dysphagia is unknown however
Department Neurosciences, Experimental there is a general agreement that the incidence of
Otorhinolaryngology, University of Leuven, swallowing dysfunction is increasing [8–11].
Herestraat 49, Leuven 3000, Belgium
As feeding is a highly integrated, multisystem
e-mail: [email protected]
skill, one or more contributing systems may be
T. Omari, Ph.D.
dysfunctional. Signs and symptoms frequently
Gastroenterology Unit, Child Youth & Women’s Health
Service, School of Paediatrics and Reproductive Health cross the traditional boundaries between tradi-
University of Adelaide, Adelaide, SA, Australia tional professional disciplines [12–14]. It is

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 217

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_19, © Springer Science+Business Media New York 2013
218 N. Rommel and T. Omari

nowadays accepted that feeding difficulties in adults as well as in children [16]. Disrupted effec-
infants and children need to be assessed from tiveness, duration and/or timing of any of these
multiple perspectives in order to determine the components can result in aspiration.
underlying causes. A multidisciplinary approach The UES is the specialized transition zone
has been described leading to better identifi- between the pharynx and the esophagus, which
cation and treatment of feeding and swallowing generates an intraluminal high-pressure zone to
disorders [4]. prevent reflux of material from the esophagus
This chapter discusses a variety of oropharyn- into the pharynx and airways and to prevent entry
geal swallowing disorders reported in newborns, of air into the digestive tract [17, 18].
infants and children, but does not intend to offer a Anatomically, the UES is compounded by the
comprehensive classification of feeding problems inferior pharyngeal constrictor muscle, the cri-
in young children. One of the reasons why the copharyngeal muscle and the cranial part of the
relationship between clinical presentation and cervical esophagus. The UES also plays a role in
underlying cause of feeding problems is often allowing passage of esophageal contents during
unclear relates to the fact that similar signs or vomiting or belching.
symptoms may reflect different etiologies. Because
of this lack of a one-to-one correspondence
between clinical presentations and underlying Assessment of Oropharyngeal
causes of dysphagia, careful identification of symp- Dysphagia
toms, documentation of their pathophysiology
and their relation to the mealtimes is crucial in pin- The assessment of oropharyngeal dysphagia
pointing the specific cause of feeding disorders. should consist of two major components: the first
one is direct observation of the child’s feeding
and swallowing skills through clinical oral assess-
Oropharyngeal Physiology ment. The second part is assessing the not-visu-
ally obvious motor function of pharynx and
Normal swallowing is usually subdivided in three esophagus through instrumental testing.
phases: oral, pharyngeal and esophageal. Some The main goal of the clinical oral assessment is
descriptions add an initial “oral preparatory to define the underlying cause and the severity of
phase” which is bolus preparation [15]. While the feeding and swallowing difficulties. In this
flawless in most individuals, safe and effective problem-solving process, the evaluation of the oral
swallowing is a very complex process initiated by cavity and its functions by observation plays a
voluntary actions (oral acceptance and prepara- major role. During the clinical assessment, the oral
tion of food and bolus delivery to the pharynx). anatomy, motor skills, reflex activity, responsivity,
This in turn initiates the pharyngeal swallow and swallowing are examined, and the nature of
reflex, during which the tongue base propels the the feeding problem and necessity for further eval-
bolus backwards, the soft palate seals the uation of pharyngeal swallowing function with
nasopharynx, the larynx is elevated, the vocal instrumental techniques is established. Normal
folds close, the upper esophageal sphincter (UES) and abnormal oral motor skills have been described
relaxes and opens to allow the bolus to pass. The extensively in many anatomy text books, as well as
pharyngeal constrictors then clear away any in the developmental and rehabilitation literature
remaining bolus from the pharynx into the esoph- [19]. In order to feed successfully, a child must
agus. With increasing age and central nervous adapt to the tactile characteristics of tools (breast,
system maturation, the oral phase becomes voli- bottle, spoon or cup) and food so that the correct
tional. The pharyngeal phase has both voluntary motor responses are performed [20]. Oral motor
and involuntary components whereas the esopha- and sensory based feeding disorders can be differ-
geal phase is fully involuntary. The entire dura- entiated [21] and a structured sensory examination
tion of a swallow sequence is about 1.0–1.5 s in in and around the oral cavity allows the examiner
19 Feeding and Swallowing Disorders 219

Table 19.1 Possible signs and symptoms of dysphagia ated or out of proportion to the strength of the
Signs stimulus. While similar to hyperresponses, aver-
Aspiration sive responses are even stronger and more nega-
Recurrent pneumonia or respiratory infections tive. Both hyperresponses and aversive responses
Weight loss or slow weight gain or growth
can be part of a general tactile processing problem
Altered and restricted diet in terms of consistency and
volume or be localized to the face and mouth or even more
Frequent low grade fever specifically to a certain part of the mouth, most
Vomiting frequently the tongue [23].
Lengthy feeding times (longer than 30 min)
During the examination the clinician will also
Dehydration
Food obstruction determine whether the parent’s reports and per-
Symptoms ceptions match the observations [24]. Referrals
Loss of appetite can then be made for further assessment or multi-
Coughing and choking during or after meals disciplinary management and a targeted treat-
Food or liquid spilling from the mouth ment plan can be developed. Instrumental
Breastfeeding problems
Difficulty breathing or coordinating breathing with assessment has the potential to assess oropharyn-
eating or drinking geal function objectively if selected and applied
Wet voice (gurgly sound) properly. The challenging decision is when to
Abnormal oral feeding skills refer for instrumental assessment and for what
Food refusal (total or during feeding)
Irritability during feeding with increased body tension type of testing. The signs and symptoms of dys-
Difficult transition from liquids to semisolid and solid phagia presented in Table 19.1 are common indi-
food cators for further instrumental evaluation of the
Lack of attention during feeding swallow function.
Selective eating
Crying during feeding When supplemental instrumental assessment
of the pharyngeal swallow is required, a variety
of pharyngeal and UES dysfunctions can be dis-
to uncover difficulties with the tactile components tinguished. The pharyngeal pathology varies
of feedings. However, it is only possible to observe from synchronous pharyngeal peristalsis, pha-
the reactions to sensations, not the sensations in ryngeal focal failure, pharyngeal hypocontractil-
themselves [17, 22], therefore the term responsiv- ity and pharyngeal paralysis. Upper esophageal
ity is more appropriate than sensitivity in the con- sphincter patterns range from a normally relaxing
text of dysphagia. The child’s ability to respond UES, to premature contraction to an incomplete
adequately to tactile input can be assessed during a or non-relaxing UOS in case of achalasia [25].
feeding observation or by a structured sensory How these deglutitive patterns are linked with
examination by grading the sensory input. A sen- aspiration risk remains unclear.
sory baseline on consistency, taste, temperature, Chronic pulmonary aspiration is the most seri-
tools, area of stimulation and amount needs to be ous complication of swallowing dysfunction
established, defined as the level of tactile input that causing recurrent pneumonia, progressive lung
the child can tolerate without any discomfort. disease, respiratory disability and even death
A wide range of tactile responses can be observed [26]. Pulmonary aspiration due to swallowing
and these responses form a continuum of function: dysfunction (deglutitive aspiration, when the
aversion, hyperresponsivity, normal tactile bolus has entered the larynx below the level of
responses, absent responses, hyporesponsivity, the true vocal folds) is a major reason for
and absent responses [20]. When tactile responses modification of feeding strategies (oral to tube
are severely diminished or absent, a significant feeding, avoidance of liquids, etc.) and therefore
sensory impairment should be suspected which has a significant impact on quality of life.
can hinder oral feeding. In hyporesponsivity, Deglutitive aspiration can be a cause of recurrent
strong stimulation is required and the responses pneumonia, recurrent wheezing, chronic cough,
are slow or partial. A hyperresponse is exagger- or stridor in infants and children [27].
220 N. Rommel and T. Omari

Many different functional tests are available cumstances when aspiration is likely. Intraluminal
to rule out aspiration risk and to assess oropha- impedance is a technique that can be used to
ryngeal function during swallowing [17]. detect failed bolus transport and is easily com-
Description of every available technique goes bined with manometry. The widespread applica-
beyond the scope of this chapter. Common tion of impedance measurement to assess the
assessment techniques available for use in the pharyngeal function has been slow to develop
pediatric population include fiberoptic endo- because attempts to establish criteria that reliably
scopic evaluation of swallowing (FEES), identify post-swallow residue have been largely
videofluoroscopy, and pharyngeal-oesophageal unsuccessful [33–35].
manometry. In practice, the use of a particular Manometric and impedance technologies
instrumental technique often depends on the have evolved in recent years such that catheters
institutional experience, available resources and with closely spaced pressure-impedance arrays
its commercial availability rather than being are now more widely available. In the most
based on the performance characteristics of the recent development, high resolution manome-
test. The main argument of using instrumental try-impedance (or HRMi) recordings have been
techniques in addition to clinical examination is uniquely combined in the novel technique
to provide a more precise understanding of the called Automated Impedance Manometry
biomechanics of the child’s swallow which then (AIM) analysis. AIM analysis provides a more
will lead to a more targeted therapeutic interven- objective, non-radiological assessment of pha-
tion [23]. Specific indicators for videomanomet- ryngeal function in patients with dysphagia.
ric evaluation are deglutitive aspiration and Unlike videofluoroscopy, this new technique is
penetration risk, suspicion of pharyngeal abnor- less resource intensive, easily performed at the
malities or dysfunction, upper esophageal bedside and delivers a non-subjective evalua-
sphincter abnormalities or dysfunction or no tion of swallow parameters (Fig. 19.1). AIM
therapeutic progress after 2 months after the ini- analysis detects swallowing dysfunction via
tial instrumental assessment. Unfortunately, cur- measurement of several swallow function vari-
rent abilities to diagnose aspiration are limited, ables and predicts aspiration risk through cal-
as there is evidence that fluoroscopy is poorly culation of a swallow risk index (SRI). The
predictive of progression to aspiration pneumo- higher the SRI, the more severe the pharyngeal
nia and a normal fluoroscopy cannot entirely rule dysfunction and the more likely aspiration will
out feed aspiration [28]. occur [36–38].

Non-radiological Instrumental
Methods: Manometry and Impedance Conditions Associated with Feeding
Problems
Manometry can be used to assess pharyngo-
esophageal motor function. Pharyngeal weakness Pediatric dysphagia is associated with multiple
or impaired UES relaxation can be relatively eas- etiologies, including anatomic or structural
ily determined and the technique can be com- defects and neurologic deficits, either congeni-
bined with videofluoroscopy. Manometry has tal or acquired. Many children have complex
been utilized to describe alterations in pressure medical issues that predispose them to dys-
patterns in relation to age-related changes, neuro- phagia and increase their vulnerability to respi-
degenerative disease, post-surgical dysfunctions, ratory and growth compromise resulting from
and UES obstruction [29–32]. However, while the dysphagia. It is important to realize that a
manometric recordings may identify functional previously confirmed diagnosis does not pre-
abnormalities that may predispose to aspiration clude other potential contributing etiologies, for
risk, manometry on its own cannot predict cir- example the diagnosis of esophageal dysmotility
19 Feeding and Swallowing Disorders 221

Fig. 19.1 An example of combined manometry and Upper Oesophageal Sphincter) pressure zone. The con-
impedance plot of a pharyngeal swallow. This shows the ductivity of the bolus swallowed is detected by impedance
changes in pressure (colors blue through red) that occur (purple shading). Plot created by M Szczesniak, Dept of
with the pharyngeal stripping wave as well as relaxation Gastroenterology St George Hospital & University of
and movement of the upper esophageal sphincter (UOS = NSW, Sydney Australia

does not exclude the coexistence of oropharyn- Gastroesophageal Reflux Disease

geal abnormalities. In the following section, we
discuss a few of the most common medical con- Gastroesophageal reflux disease (GERD) has
ditions associated with feeding and swallowing been identified as a common underlying condi-
disorders. tion associated with feeding problems [4, 39]. In
222 N. Rommel and T. Omari

infants, GER is recognized as a frequent and usu- included. Dysphagia has been mostly described
ally benign condition which occurs during or in broad CP populations and not specified accord-
after feeding. In the context of feeding problems, ing to the three main groups. Yet, the differences
GERD is associated with comorbidities such as in muscle tone among these groups cannot be
failure to thrive, feeding difficulties and irritabil- ignored and may cause the type of dysphagia to
ity in relation to feeding. In these circumstances, vary according to the type of CP [46]. Cerebral
frequent GER may disrupt or delay normal feed- palsy with hypertonicity may be associated with
ing, or lead to post-feeding irritability, sleep dis- tongue thrusting, tonic biting and hyperactive
ruption and/or loss of nutrients with overt gagging. Children with spasticity may present
regurgitation. Unfortunately, such “typical GER- with poor lip closure, tongue thrusting and jaw
related” symptoms are not specific for GERD instability as well thrusting. These inadequate
and may be due to other causes, such as dietary oral motor patterns hinder effective manipulation
protein allergy, and the differentiation of symp- of food in the oral cavity, appropriate bolus for-
toms due to GER from symptoms due to other mation and bolus propulsion needed for safe and
causes remains a significant challenge for most adequate swallowing. It is important to realize
clinicians. that the child’s oral motor skills observed during
Most common feeding problems associated an oral examination do not necessarily match
with GERD are feeding aversion, food refusal what is seen at functional mealtimes. Therefore
and insufficient oral intake. Pain secondary to assessment during mealtime process is essential
esophagitis may drive the child to associate in these children. The child’s ability to control
pain with feeding and therefore the child may movement their tone (hypertonia hypotonia, and/
attempt to limit the pain by eliminating eating or mixed), their stability, symmetry, degree of
or by taking small frequent feedings. Snacking independence, and most important head control
may however result in poor oral intake over must be carefully assessed [48] in the child’s nat-
24-h period [20]. ural feeding situation.
Children with diplegia and hemiplegia are less
likely to have significant dysphagia [45]. Reilly
Neurological Disability et al. [24] found that tetraplegia was associated with
moderate and severe oral-motor dysfunction, and
Cerebral palsy (CP) is a common problem, the diplegia was more commonly associated with mild
worldwide incidence being 1.5–3 per 1,000 live oral-motor difficulties. In addition, those children
births [40]. It is defined as a group of disorders of with diplegia were more likely to demonstrate
the development of movement and posture, caus- texture-specific problems, whereas children with
ing activity limitation, that are attributed to non- tetraplegia typically had some level of difficulty
progressive disturbances that occurred in the with all textures. Potential reasons for the child with
developing fetal or infant brain. The motor disor- spastic quadriplegia to be at an increased risk for
ders of cerebral palsy are often accompanied by dysphagia include the fact that they are dependent
disturbances of sensation, cognition, communi- feeders and are often unable to communicate [49].
cation, perception, and/or behavior, and/or by a Apart from the type of CP, other factors such as the
seizure disorder [41]. CP can be classified in severity of drooling, postural problems (e.g., scolio-
spasticity (79%), dyskinesia (14%), and ataxia sis) the severity of speech disorder, positive history
(4%) [42]. of seizures, episodes of pneumonia [50, 51], pres-
Children with CP may have feeding problems ence of GERD [4], developmental retardation [51],
that affect any or all phases of deglutition. The and severity of the functional impairment may have
reports on the prevalence of dysphagia in chil- an impact on the type of dysphagia. In general, the
dren with CP vary greatly between 27 and 99% more severe the functional motor impairment, the
[43–47] depending on the definition of dysphagia more severe the oral motor dysfunction is. Waterman
used and the population and comorbidities et al. [51] found that the poorer the trunk control,
19 Feeding and Swallowing Disorders 223

the higher is the risk of dysphagia. Calis et al. [43] Autism Spectrum Disorders
reported that the severity of dysphagia was posi-
tively related to the Gross Motor Function Autism Spectrum disorders (ASD) are a group of
Classification System Level (GMFCS), but nega- neurodevelopmental disorders of unknown etiol-
tively related to the body mass index. ogy with onset before 3 years of age and character-
Due to recent advances in instrumental evalu- ized by severe impairment in reciprocal social
ation of dysphagia in children, oropharyngeal interaction and communication with a pattern of
patterns of dysphagia are being differentiated in repetitive or stereotyped behavior [57]. A recent
patients with neurological disability. Apart from population based study by Ibrahim et al. showed
oral motor disorders such children are often noted that compared to typically developing children
to present with pharyngeal hypocontractility or matched for age and gender, children with ASD
paralysis. Importantly, patients often present with have an increased incidence of feeding issues, food
not only pharyngeal but also with oesophageal selectivity and constipation [58]. It was suggested
dysmotility that prevents them from eating orally. that these problems result from either the behav-
Therefore, both pharynx and esophagus should ioral characteristics of children with autism such
be assessed in terms of motor function in this as ritualistic tendencies, need for routine and thus
highly affected group of children. stereotyped diets or from adverse effects of treat-
There are a number of developmental condi- ment with psychotropic medications rather than
tions that place children at risk of feeding and being associated with a primary organic gastroin-
swallowing problems. It is well known that chil- testinal pathology. Importantly, when children
dren with special needs are at higher risk of acquir- with ASD are compared to typically developing
ing feeding problems [8]. Only a few among such children matched by levels of functioning, chil-
conditions can be discussed in this chapter. dren with ASD were only marginally more likely
to have more typical feeding problems [59].
Martins et al. showed that the critical difference
Velo-Cardio-Facial Syndrome between both groups lies in the frequency with
which children with ASD exhibit the problematic
Velo-cardio-facial syndrome (VCFS) is caused feeding behaviors. They showed that children with
by a deletion 22q11.2 and is characterized by ASD are twice as likely to experience feeding
mild facial dysmorphia, palatal anomaly, problems and that more problems occur at the
conotruncal cardiac defect, immunodeficiency, same time, but they do not necessarily have other
and hypocalcaemia [52]. Children with VCFS feeding problems than those observed in a typical
most often present with feeding difficulties early developing child. These findings have important
in life [53, 54] including nasal regurgitation, clinical relevance as they indicate that ASD chil-
poor coordination of sucking, swallowing, and dren need more time to overcome difficulties since
breathing and food refusal. Palatal dysfunction their behaviors tend to be associated with prob-
may lead to nasal regurgitation during swallow- lems with adapting to change. Feeding therapy
ing due to the bolus being forced into the nasal therefore should include many steps before the
cavity. However, in these children, who are par- child with ASD should be invited to taste the food,
ticularly prone to velopharyngeal insufficiency the number depending on the child’s capacity to
[3, 11], the observed retrograde flow may also adjust to change. Once oral acceptance is feasible,
be the result of an upper esophageal dysfunction gradual and repeated taste exposure to small
rather than a palatal insufficiency alone [4, 55, amounts of food may allow the child to accept the
56]. The clinical or radiological observation of food. Their data also suggest that medical care
retrograde flow and nasal regurgitation should providers should acknowledge that these children
not automatically lead to the diagnosis velopha- are not extremely different from typically develop-
ryngeal insufficiency but require the assessment ing children in the types of feeding and swallow-
of the opening profile of the UES. ing problems [59].
224 N. Rommel and T. Omari

Regardless of the prevalence of feeding prob- 8. Field D, Garland M, Williams K. Correlates of specific
lems, the most common oral feeding problems childhood feeding problems. J Paediatr Child Health.
2003;39:299–304.
observed in children with ASD are selectivity by 9. Ancel PY, Livinec F, Larroque B, EPIPAGE Study
type and texture. More complex feeding prob- Group, et al. Cerebral palsy among very preterm chil-
lems such as oropharyngeal dysphagia and food dren in relation to gestational age and neonatal ultra-
refusal are also often seen, mostly associated sound abnormalities: the EPIPAGE cohort study.
Pediatrics. 2006;117:828–35.
with GERD. Constipation as a consequence of 10. Marlow N. Neurocognitive outcome after very pre-
poor diet is these children may potentially rein- term birth. Arch Dis Child Fetal Neonatal Ed.
force the feeding problem by decreasing appetite 2001;89:F224–8.
and thus willingness to try new foods. 11. Hawdon JM, Beauregard N, Slattery J, et al.
Identification of neonates at risk of developing feed-
ing problems in infancy. Dev Med Child Neurol.
2000;42:235–9.
Summary 12. Bach D, Pouoget S, Belle K. An integrated team
approach to the management of patients with oropha-
ryngeal dysphagia. J Allied Health. 1989;18:459–68.
Although many classifications of feeding prob- 13. Bryan D, Pressman H. Comprehensive team evalua-
lems and swallowing difficulties in infants and tion. In: Rosenthal S, Sheppard J, Lotze M, editors.
children are available, it remains important, Dysphagia and the child with developmental disabili-
regardless of the primary medical pathology, to ties. San Diego: Singular Publishing Group, Inc.;
1995. p. 15–29.
assess the pure biomechanics of swallow physiol- 14. Ravich W, Donner M, Kashima H, Buchholz D, Marsh
ogy in pharynx and esophagus and to do this with B, Hendrix T, Kramer S, Jones B, Bosma J, Siebens
assessment techniques which are as objective as A, Linden P. The swallowing center: concepts and
possible. Linking clinical signs and symptoms to procedures. Gastrointest Radiol. 1985;10:255–61.
15. Logemann J. Evaluation and treatment of swallowing
the objective dysphagic “signature” of the patient disorders. Austin, TX: Pro Ed; 1983. p. 1–249.
is the only way to achieve a proper differential 16. Arvedson J, Lefton-Greif M. Anatomy, physiology
diagnosis of dysphagia and to provide effective and development of deglutition. In: Arvedson J,
treatment. Lefton-Greif M, editors. Pediatric videofluoroscopic
swallow studies. San Antonio, TX: Communication
Skill Builders; 1998. p. 13–30.
17. Arvedson J. Assessment of pediatric dysphagia and
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 Esophageal Motor Disorders:
Achalasia, Diffuse Esophageal 20
Spasm, Nonspecific Motor
Disorders, Eosinophilic Esophagitis

Hayat Mousa and Ann Aspirot

posterior 2 cm and laterally to 3 cm. Primary

General Background Physiology peristalsis is initiated by either wet or dry swal-
lows and facilitates esophageal clearance [4].
The esophagus is a collapsible organ in the Secondary peristalsis occurs in response to
digestive tract with the main function of trans- refluxed materials or esophageal distention and
porting contents from the mouth to the stom- contributes to the esophageal clearance [5].
ach. The muscle layer is composed of circular, Central and neural circuitry must coordinate in
longitudinal, striated, and smooth muscle to order for peristalsis to continue through the
assist peristalsis. Its three primary parts are the esophagus. The LES, comprising the gastroe-
upper esophageal sphincter (UES), esophageal sophageal junction, works to prevent gastroe-
body (EB), and lower esophageal sphincter sophageal reflux (GER) episodes, though
(LES). The UES is made of three muscles and allowing gaseous reflux contents.
cricoid cartilage which prevent inspired air Manometry is the primary assessment method
from entering the digestive tract as well as for esophageal motor activity, specifically con-
esophageal contents from refluxing into the tractions [6]. It measures UES and LES pressures,
hypopharynx [1, 2]. Anterior to the EB are the esophageal body contraction amplitude, and peri-
larynx and trachea; the EB descends along the staltic sequences [7, 8]. Manometry is a diagnos-
front of the vertebral column [3]. During swal- tic tool recommended for use only after endoscopy
lows it collapses, distending to the anterior– and fluoroscopy have ruled out organic pathology
[9]. Typically a manometry catheter is inserted
from the pharynx to the stomach. The catheter
has sensors which detect pressure and muscle
contractions as the patient swallows, although it
can be difficult to perform in the presence of pha-
ryngeal or upper esophageal obstructions, severe
H. Mousa, M.D. (*) coagulopathy cardiac conditions causing intoler-
Division of Gastroenterology, Nationwide Children
ance to vagal stimulation, and patient noncompli-
Hospital, J West 1985, Columbus, OH, 43205, USA
e-mail: [email protected] ance [6, 7, 10]. Accurate diagnosis is obtained
with proper instrumentation, standard technique
A. Aspirot, M.D.
Pediatric Surgery Division, Department of Surgery, and evaluation. Interpretation of the manometric
Sainte-Justine University Health Center, University tracings can be altered by the patient activity,
of Montreal, Montreal, QC, Canada body position, age, and gender [8, 11, 12]. More

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 227

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_20, © Springer Science+Business Media New York 2013
228 H. Mousa and A. Aspirot

details about the different methods used to mea- Esophageal Impedance

sure esophageal manometry are addressed in and pH Monitoring
chapter 8.
Another method involves esophageal impedance
and pH monitoring. When combined, these tech-
niques can assess bolus transit, clearance, and
Evaluation of Esophageal Bolus chemical content of the bolus or refluxate. Similar
Transit and Clearance to manometry, a catheter with several sensors is
utilized for assessment. Several liquid and vis-
There are several options to evaluate bolus transit cous swallows are required. Impedance demon-
and clearance: strates 97% concordance with fluoroscopy,
though only fluoroscopy can study swallows with
a solid bolus [20]. Among its many advantages,
impedance can be (repeatedly) employed on
Cineradiography pregnant women and children because it does not
involve radiation; it also relates to esophageal
Cineradiology or video fluorography (VFG), is mucosal integrity [21]. However, swallowed air
a method examining different phases of swal- can make brief changes in impedance unrelated
lowing to identify motor abnormalities [13]. In to bolus transit.
this test, the patient digests, or is injected with,
various concentrations of barium while altering
body position to evaluate esophageal mucosa, Esophageal Function Testing
motility, and structures [14–16]. The swallows
are followed by several radiographs which Esophageal function testing (EFT) is a union of
detect esophageal clearance. Abnormal peristal- manometry and multichannel intraluminal
sis identified in at least two swallows defines impedance monitoring. EFT gathers information
abnormal motility [15]. VFG is generally used on bolus transit patterns, swallow associated
as a screening tool with high sensitivity, though events, nonobstructive dysphagia, chest pain, and
affected by number of swallows and body posi- general motility disorders [22, 23]. It is also a
tions [16, 17]. helpful evaluation tool before antireflux surgery.
Again, catheters are used for evaluation and sev-
eral types are available depending on how many
Esophageal Transit Scintigraphy channels, sensors, pressure transducers, are
needed [24]. In one exam, EFT provides infor-
Scintigraphy focuses on esophageal emptying, mation previously gathered in separate exams
evaluates bolus transit in segments, and identifies from manometry and fluoroscopy, even though it
reflux episodes [18]. In this test, the patient is typically used after both of those methods pro-
ingests a radio-labeled bolus and several images duce negative results [22]. By evaluating the
are taken to inspect bolus transit and clearance transit time, EFT classifies esophageal dysmotil-
[19]. The study measures the level of radioactiv- ity into two categories: either abnormal manom-
ity as it relates to clearance. Use of liquidized etry with abnormal transit or abnormal manometry
bolus is more standardized than semisolid bolus. with normal transit. Abnormal manometry with
Also, patients usually usually lie in the supine abnormal transit includes conditions such as
position to eliminate gravity as a source of error achalasia, scleroderma, ineffective esophageal
[18]. Scintigraphy is more sensitive than VFG, motility, and distal esophageal spasm. Abnormal
though the necessary equipment is not as widely manometry with normal transit includes condi-
available. More details about esophageal transit tions such as nutcracker esophagus, hypertensive
scintigraphy are addressed in Chap. 14. LES, hypotensive LES, and poor relaxing LES.
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 229

motility when esophageal dysphagia is suspected

Esophageal Dysmotility [26, 27]. In infants, parents may additionally be
provided a questionnaire and/or a physician may
Prevalence of Esophageal Dysmotility observe the child while feeding.
in Children and Adolescents
Chest Pain
As reported previously by Glassman et al., up to Noncardiac chest pain can be indicative of esoph-
25% of children and adolescents who present ageal dysmotility in infants and children. Because
with chest pain, dysphagia, and vomiting have the heart and esophagus have similar neural pain
abnormal esophageal motility study [25]. The pathways, it can be difficult to determine cardiac
most common patterns of esophageal dysmotility and noncardiac chest pain [29]. Compared to
in symptomatic children with dysphagia, chest other sources to noncardiac chest pain (i.e., mus-
pain, and vomiting are diffuse esophageal spasm culoskeletal pain and asthma), studies indicate
(33%), achalasia (19%), hypotensive lower that gastrointestinal diseases represent less than
esophageal sphincter (14%), aperistaltic distal 10–15% of cases [30]. Glassman et al. reviewed
esophagus (14%), nutcracker esophagus (10%), the cases of 83 children aged 1–20 years with
and hypertensive lower esophageal sphincter in chest pain and vomiting or dysphagia for preva-
(10%) [25]. lence of esophageal motility disorders. Of the 83,
47 had normal esophageal manometry and endos-
copy [25]. The remaining 36 patients had evi-
Clinical Presentation of Esophageal dence of esophageal disease, indicated by either
Dysmotility abnormal endoscopy, abnormal manometry, or
both. Among the 21 patients with abnormal
Dysphagia manometry, diffuse esophageal spasm was the
Swallowing is an important developmental pro- most common diagnosis followed by achalasia,
cess for human life. It requires the coordination hypotensive LES, aperistalsis, nutcracker esoph-
between the mouth, pharynx, and esophagus for agus, and hypertensive LES. Most of these
successful completion. Esophageal dysphagia or patients (16 of 21) were symptomatic of their dis-
difficulty swallowing can be the result of behav- ease. Berezin et al. performed a similar study of
ioral, developmental, neurological, respiratory, 51 children, aged 8–20 years, of which 27 were
GER, and inflammatory diseases [26, 27]. It is found to have idiopathic chest pain [29]. Twenty-
observed in 25–45% of developing children and one of those patients were diagnosed with
even more in those with developmental disorders esophagitis or diffuse esophageal spasm using
[28]. Dysphagia can occur with solid foods and/ manometry and histology; though only five had
or liquids. Exclusively experiencing solid food abnormal motility. Additionally, Glassman et al.
dysphagia is more characteristic of a mechanical found that with treatment chest pain was more
rather than a neurological disorder, whereas solid easily resolved than esophageal symptoms.
and/or liquid dysphagia is characteristic of neu-
romuscular disorder [27]. A child may indicate Foreign Body Impaction
dysphagia by demonstrating little interest in food Children ingest materials that become impacted
or eating, displaying straining or extension of in the esophagus, usually in the upper esophagus,
muscles during feedings, taking extensive time to and obstruct esophageal transit; by comparison
complete feeding, spilling food or liquid out of ingested items rarely enter the tracheobronchial
the mouth, emesis, coughing or gagging during tree [31, 32]. Children primarily ingest nonfood
feeding, struggling with breathing/stridor when items such as coins and small toys, whereas adults
feeding, and failing to thrive [26]. Patients undergo tend to have impacted meat and bones [32].
barium esophagogram or upper GI endoscopy to Children with meat impactions should be evalu-
evaluate UES function, or manometry to assess ated for either anatomic esophageal malforma-
230 H. Mousa and A. Aspirot

tion, motility/functional disorders or eosinophilic noted only in case series and retrospective stud-
esophagitis [31]. ies. An incidence of less than 0.1/100,000 has
been found in children in England and Wales
[35]. Most of the cases are diagnosed between 7
Classification: The Chicago and 15 years. Infants are rarely affected (6%), but
Classification 2009 symptoms are described to be present during the
first year of life in 18% [36]. Infantile achalasia is
High-resolution esophageal pressure topography reported as case reports in the literature [37].
(HROPT) is a novel technical development in the Diagnosis may not be as rigorous in young chil-
study of motility. Traditionally, manometry was dren as it is in adults [35], many published cases
used to examine esophageal motility but did not were not confirmed by esophageal manometry,
report pressures within the organ; this was a task the gold standard diagnostic tool.
reserved for pressure topography. HROPT pro-
vides the benefits of manometry and pressure Pathophysiology
topography in one technique. The Chicago Acquired degeneration of the Auerbach’s myen-
Classification is a schema used to categorize teric plexus is the primary mechanism of achala-
results of HROPT used in clinical evaluations. It sia. Loss of nitrergic inhibitory enteric neurons
is based on a study of 400 patients and 75 con- occurring prior to loss of cholinergic neurons
trols by Kahrilas et al. [33]. In summary, HROPT results in an imbalance between excitatory and
classifies nonspecific esophageal motility disor- inhibitory input leading to ineffective esophageal
ders, diffuse esophageal spasm, nutcracker peristalsis and incomplete lower esophageal
esophagus subtypes, vigorous achalasia, and sphincter relaxation [38]. Nitric oxide (NO) is the
functional obstruction. Among its advantages, predominant inhibitory neurotransmitter but oth-
HROPT is easily interpreted and standardized, ers have been described such as vasopeptide
saves time, provides high-quality data, and allows intestinal peptide (VIP). Studies on resected
for more specific diagnoses. specimen have demonstrated decreased number
of myenteric ganglia, lymphocytic infiltrate, and
collagen deposition within ganglia. Some speci-
Esophageal Motility Disorders mens had normal number of myenteric ganglion
cells, but myenteric fibrosis was observed.
Esophageal Achalasia Preservation of cholinergic excitatory neurons
could explain the occurrence of vigorous achala-
Esophageal achalasia is a primary motor disorder sia which has been hypothesized to be an earlier
presenting with dysphagia secondary to func- form of the disease [39]. These findings suggest a
tional obstruction due to the dysfunction of the progressive immune mediated destruction of neu-
body of the esophagus and the lower esophageal ronal cells. The pathologic findings could be dif-
sphincter. It is characterized by the absence of ferent in childhood achalasia where less neuronal
peristalsis and incomplete relaxation of the lower inflammation was found [40].
esophageal sphincter.
Etiology
Epidemiology and Incidence Achalasia can be primary (idiopathic) or second-
Achalasia is an infrequent adult disease with an ary. The etiology of primary achalasia remains
incidence of 1.63/100,000 and a prevalence of unknown. Numerous hypotheses have been pro-
10.8/100,000, based on a recent population-based posed including infection, hereditary, and auto-
study [34]. Because of the relative rarity of child- immunity. Chagas disease is the prototype of
hood and adolescent achalasia, much of the liter- secondary achalasia that is caused by the parasite
ature on achalasia is based on the adult population, Trypanosma cruzi. The disease is common in
with information by pediatric gastroenterologists South and Central America. Whether the disease
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 231

is similar to idiopathic achalasia remains contro- symptoms occur in 44% which is more frequent
versial [41]. Because of the associated than in the adult population. In children, regurgi-
inflammatory infiltration mainly composed of tation, respiratory problems, and failure to thrive
lymphocytes, viruses such as measles, HSV-1, are frequently attributed to gastroesophageal
and VZV have been suspected as a cause of idio- reflux (GER) which is much more predominant
pathic achalasia. A cause–effect relationship than achalasia in this population. Extraesophageal
between viruses and achalasia has yet to be complications of achalasia include recurrent pul-
identified. Studies have associated achalasia with monary aspirations and tracheal compression by
trisomy 21 [42], Hirschsprung’s disease [43], the megaesophagus. Sudden death has also been
Allgrove’s syndrome, and familial dysautonomia, reported.
which suggest a genetic link. However, familial
history is the exception in achalasic patients even Differential Diagnosis
in the pediatric age [36]. Allgrove’s or 4 “A” syn- Apart from GER, differential diagnosis includes
drome, which presents with achalasia, alacrima, mechanical obstruction by foreign body, intrinsic
autonomic disturbance, and corticotrophin esophageal pathology (esophageal stenosis, leio-
(ACTH) insensitivity, is the only condition asso- myomas), and extrinsic compression of the
ciated with achalasia that has been linked to a esophagus (foregut duplication, mediastinal
specific chromosomal anomaly which is the tuberculosis). Malignant neoplasms are more fre-
AAAS gene on chromosome 12q13 [44–46]. quently seen in the adult population but need to
Because of the rarity of achalasia in childhood, it be included in the differential diagnosis even in
is important to refer younger patients to Genetics children. Chagas disease is always a possibility
and screen for adrenal insufficiency. The third in patients coming from endemic regions.
broad hypothesis is autoimmunity that could pre- Achalasia has also been mistaken as eating disor-
cipitate an immune reaction directed to the ders [50], emphasizing the importance of a thor-
esophageal myenteric ganglia. Studies are con- ough evaluation of the upper gastrointestinal tract
tradictory in demonstrating a link between anti- anatomy and function in patients suspected of
neuronal antibodies and achalasia [38, 47]. having primary anorexia nervosa.

Clinical Presentation Diagnosis

Achalasia presents with progressive dysphagia Diagnosis is often delayed because of the poor
(first for liquids and eventually for solid food), specificity of symptoms and the overlap with
chest pain, and regurgitation of undigested food, other more frequent pathologies such as gastroe-
not mixed with gastric secretions [48]. Nurko and sophageal reflux disease. The specific workup
Rosen [49] summarized the clinical symptoms in includes radiographic studies, upper endoscopy,
528 pediatric patients from 23 series. The most and esophageal manometry to confirm the diag-
common symptoms are vomiting (80%) and dys- nosis of achalasia.
phagia (75%). Weight loss is reported in 64% and
failure to thrive in 31%. Chest pain and Radiography
odynophagia are sometimes present (45%), but Plain chest radiograph may show an air-fluid
less common in younger children. Diagnosis is level in the lower chest, a widened mediastinum,
often delayed in children because of multiple fac- and an absent gastric bubble [51]. Contrast esoph-
tors including lower incidence of achalasia, inca- agogram will demonstrate the stagnation of con-
pacity to verbalize complaints, and unspecific trast in the distal esophagus and possibly absent
symptoms, such as food refusal and failure to or tertiary peristalsis. The typical dilated esophagus
thrive. Parents will sometimes report that their tapering smoothly at its distal end (“bird’s beak”) is
child is a slow eater. Children additionally present not necessary to make the diagnosis, but is highly
nocturnal symptoms such as choking and regur- suggestive of the disease. Using manometry as
gitated food on the pillow (21%). Respiratory the gold standard, Parkman found a positive pre-
232 H. Mousa and A. Aspirot

dictive value of 96%, a sensitivity of 100% and a than 30 mmHg in ³20% of swallows
specificity of 98% [52]. However, the correlation (Fig. 20.1.)
of severity as assessed by esophagogram and • Type III: Spastic achalasia. Mean IRP
patient’s symptoms is poor, which can also lead ³15 mmHg, absent peristalsis and spasm (con-
to a delayed diagnosis [53]. Barium esophago- tractile front >8 cm−1) in ³20% of swallows
gram is also useful to monitor the success of with or without compartmentalized pressur-
treatment. ization (Fig. 20.2).
These subtypes have different prognosis impli-
Endoscopy cation with type II having the best response to
Upper endoscopy may show retained food in a any therapy (pneumatic dilation, Heller myo-
dilated esophagus. The gastroesophageal junction tomy, botulinum toxin) while type III have the
may appear tight (difficult to distend with air worst response to all treatments. This informa-
insufflation) but it is usually possible to reach the tion can be brought in the discussion with the
stomach. The main goal of upper endoscopy is to patients and parents and also may guide the clini-
rule out mechanical obstruction at the gastroe- cian in the therapeutic decision.
sophageal junction (pseudoachalasia) [54]. If
pseudoachalasia is suspected, further investiga- Treatment
tion with ultrasound, endoscopic ultrasonography, Achalasia affects permanently the esophageal
and other imaging studies will help to differenti- motility. Treatments for achalasia, similar to
ate between the numerous neoplastic and non- other esophageal disorders, focus on relieving
neoplastic causes of pseudoachalasia [55]. symptoms [59]. The three primary types of treat-
ment are pharmacologic, endoscopic, and surgi-
Manometry cal. The therapy of choice in children is still
The diagnosis of achalasia is confirmed by esoph- debated [60]. Proper treatment of achalasia is
ageal manometry. Absence of peristalsis in the important to prevent progression toward dilated
esophageal body is the sine qua non criteria to mega-esophagus where esophagectomy may
diagnose esophageal achalasia [48]. Frequently, become inevitable. Barium esophagogram can
the lower esophageal sphincter relaxation is help monitor success of the treatment plan
incomplete (residual pressure above 8 mmHg) (Table 20.1).
[56, 57]. Hypertensive lower esophageal sphinc- Pharmacologic treatments include nitrates,
ter (resting pressure above 45 mmHg) is some- calcium channel blockers, and phosphodiesterase
times seen as well as an increased esophagogastric inhibitors. Although significant decrease of lower
gradient. Recently, high-resolution esophageal esophageal sphincter pressure has been observed
manometry has been used more frequently and by manometry, symptom improvement occurred
has permitted a better understanding of the motil- in 53–87% of patients [61]. In some cases, these
ity abnormalities found in achalasia. Based on medications are used temporarily while deter-
topographic plot characteristics, Pandolfino [58] mining a more effective means of treatment.
has proposed a classification of achalasia in three Pharmacologic interventions are also the treat-
subtypes: ment of choice for patients who are not candi-
• Type I: Classic achalasia: Mean integrated dates for or do not wish to receive more aggressive
LES relaxation pressure (IRP) ³15 mmHg, therapy. These medications have frequent side
absent peristalsis, no or minimal distal esoph- effects (headache, hypotension). Experience in
ageal pressurization. children is limited to calcium channel blockers
• Type II: Achalasia with esophageal compres- and nitrates and consists mainly of case reports
sion: Mean IRP ³15 mmHg, absent peristalsis, [62–64]. Isosorbide dinitrate patch (long acting
with panesophageal pressurization to greater nitrate) has been used in an 8-year-old [63] with
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 233

Fig. 20.1 Type II esophageal achalasia (with compression)

234 H. Mousa and A. Aspirot

Fig. 20.2 Type III esophageal achalasia (spastic)

good short-term success. Nifedipine (10 mg) high rate of recurrence. The data are however
before meal was used in four adolescents with insufficient to conclude to the same certitude as
good clinical response and a decrease of LES in the adult population. Botulinum toxin injec-
pressure on manometry but there was recurrence tion can also be used as a diagnostic tool in
of symptoms when the medication was stopped patients with early and unclear diagnosis [72].
[62]. Long-term pharmacologic therapy is not However, submucosal fibrosis resulting from
actually recommended. Short use can be useful intrasphincteric injections may complicate the
while waiting for definitive therapy (establishing subsequent surgical myotomy [73]. Esophageal
weight gain, awaiting school vacation). dilation is the oldest treatment modality [48].
Endoscopic therapies include botulinum toxin Balloon dilation is preferred over rigid bougien-
injection into the LES, pneumatic dilation, and age because it is thought to permit a controlled
stenting. The use of intrasphincteric botulinum tearing of the muscle fibers, even though it was
toxin was first reported by Pasricha et al. [65]. not proven in animal studies [74]. It is less inva-
This potent neurotoxin blocks the release of ace- sive than surgical treatment and is considered the
tylcholine at the neuromuscular junction leading most effective nonsurgical treatment of achalasia
to decreased lower esophageal sphincter pres- in adults [75, 76], and the first-line treatment in
sure. A double-blind placebo-controlled trial some pediatric centers [60]. The main complica-
demonstrated a good initial response in adults tion is esophageal perforation which was reported
[66]. Long-term results showed that it is neces- in 1.6% of patients [75, 76]. Long-term efficacy
sary to repeat the injection and the response of pneumatic dilation ranges from 40 to 60%
decreases with repeated injections [67]. [77–79]. Pediatric results are variable and difficult
Experience in children is once again limited to to compare because of the nonstandardization of
retrospective case series [68–71], but shows simi- the technique [49]. Pneumatic dilation can also
lar results of good initial clinical response and serves as a rescue therapy after an incomplete
 20

Table 20.1 Analysis of selected esophageal motility disorder treatment methods

Method of treatment Associated disorders Advantages Disadvantages Success
Acid suppression DES, NE, NEMDs, SSc Relieves GERD symptoms May only treat GERD symptoms Low success in children
Antibiotics Caustic ingestion, CIIP, SSc
Botox injection Achalasia Suitable for long-term use May contribute to fibrosis at
injection site
Elemental diet Caustic ingestion, EoE, DES, Quick resolution of symptoms Formulas not palatable Compliance difficult for children
NE, SSc Lower quality of life
Cost/insurance coverage
Elimination diet EoE, CIIP Still allows for some food intake Requires careful review of all food Must continue elimination for
by mouth choices for allergens long-term resolution
Does not always indicate specific
food allergen at fault
Esophageal dilation Achalasia, caustic ingestion, Highly effective when strictures Chest pain Common treatment in adults
DES, EoE, NE are also present Esophageal perforations
Other surgical procedures Achalasia, caustic ingestion, Complications may further compli- Usually successful with rare
DES, HD, NE cate disease complications
Systemic or topical EoE, SSc Direct administration to eosino- Low bioavailability Satisfactory symptom resolution
corticosteroids philia (topical) May not fully penetrate eosinophilia High rate of symptom relapse
Variety of administration (topical) upon discontinuation
(swallowed or inhaled)
Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor...
235
236 H. Mousa and A. Aspirot

myotomy [51]. Temporary self-expanding metal- of fundoplication [102], and type of fundoplica-
lic stent is a new therapeutic option that has been tion if performed. Complications after Heller
used in patients as young as 12 years old but more myotomy include esophageal perforation, phrenic
studies and long-term experience is needed before nerve paralysis, hemorrhage, herniation of stom-
recommending it [80]. ach. Long-term complications are persistent dys-
Surgical treatment usually consists of a longi- phagia and GER. The intra-operative use of
tudinal division of the muscle fibers of the lower endoscopy [103] and esophageal manometry
esophageal sphincter and proximal stomach cou- [104] have been suggested to decrease the rate of
pled or not with an antireflux procedure. The incomplete myotomy. It is important to empha-
name of Heller myotomy comes from the first size that while myotomy should improve the
description of this procedure by Ernest Heller in bolus transit by reducing the LES pressure, inef-
1913 [59]. Laparoscopic Heller myotomy is now fective peristalsis can still remain an issue
the most commonly performed surgical treatment (Fig. 20.3) [105].
of achalasia because it reduces the morbidity An approach to the child with persistent dys-
compared to the open approach. It has been phagia after myotomy has been proposed since it
shown to be as effective as open approaches [81] is a frequent and debilitating problem [106].
and superior to thoracoscopic approach [82, 83]. Differential diagnosis of this problem include
Clinical response after myotomy ranges from 83 esophageal dysmotility, incomplete myotomy,
to 100% [84] and the benefits persists in 67 to fibrosis at the distal end of the myotomy, obstruc-
85% in long-term (more than 10 years) studies tive fundoplication, esophageal stricture and pre-
[85, 86]. Randomized controlled trials compared operative error in diagnosis [107–109]. A
favorably laparoscopic Heller myotomy to pneu- thorough evaluation is the basis of management,
matic dilation [87, 88]. Clinical deterioration starting with a good clinical history. Contrast
over time has been associated with GER [89] esophagogram and esophageal manometry com-
which has led to randomized controlled studies plete the initial work up. Depending on the
comparing Heller myotomy with and without findings, endoscopy with pneumatic dilation may
fundoplication [90]. Recently, it has been sug- be indicated as the first therapeutic step. Surgical
gested that a more aggressive balloon dilatation treatment is reserved for persistent significant
results in comparable results to myotomy [91, obstruction of the distal esophagus [106].
92]. Based on long-term success rates of 47–82%
at 10 years, laparoscopic Heller myotomy with Outcome
partial fundoplication is considered by many the Regardless of the elected therapy, patients must
surgical procedure of choice [75, 93, 94]. continue with regular follow-up to prevent pro-
However, a study has reported that up to 30% of gression toward a more serious disease. A rare,
myotomized patients will require re-treatment yet critical complication of achalasia is squamous
within the first 12 years [95]. Pandolfino has cell carcinoma in the esophagus. It is thought to
reported different response to therapy according result from stasis and uncontrolled bacterial
to the type of achalasia. According to his growth [110]. Based on a review of the literature,
classification, type I (classic) achalasia responds Dunaway has reported a mean prevalence of 3%
best to Heller myotomy, type II (with compres- which represents of 50-fold increased risk over
sion) responds to any therapy, and type III (spas- the general population [111]. Chronic gastroe-
tic) has a poor response to any therapy [58]. sophageal reflux resulting from the successful
Laparoscopic Heller myotomy has also been treatment of achalasia is also a risk factor for the
found safe and effective in children [96]. Rates of development of adenocarcinoma [112, 113].
good to excellent results of 90.9% have been More recently, a prospective cohort study of 448
reported [97–99]. As in the adult literature [100], achalasia patients reported esophageal cancer in
the same surgical controversies exist which 3.3% with an annual incidence of 0.34 and,
include extension of the myotomy [101], addition despite structured endoscopic surveillance, most
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 237

Fig. 20.3 Postoperative esophageal manometry after Heller myotomy

neoplastic lesions were detected at an advanced Diffuse esophageal spasm (DES) and nut-
stage [114]. However, the overall life expectancy cracker esophagus (NE), also known as hyperten-
of patients with achalasia does not appear to be sive peristalsis, are benign and very rare,
significantly decreased [115] and up to now, no representing less than 10% of abnormal adult
cases of esophageal carcinoma have been reported manometry diagnoses [117–119]. The etiology
in patients who had achalasia diagnosed as chil- and pathogenesis of both conditions remain
dren [49]. Routine diagnostic tests are not recom- unknown [117]. Both DES and NE share symp-
mended but patients developing recurrence or toms of intermittent dysphagia and chest pain,
development of new symptoms should be investi- with or without swallowing [16, 117, 120, 121].
gated thoroughly. Symptoms are usually experienced while eating
or drinking [117, 120]. DES tends to present co-
morbidly in infants and children [122]. Infants
Diffuse Esophageal Spasm may additionally present with apnea and brachy-
and Nutcracker Esophagus cardia and younger children with aspiration
pneumonia; symptoms of older children most
The incidence in children is not known and the resemble those observed in adults [123]. Because
literature is scarce, limited to case reports and symptoms are intermittent, it is easy to distin-
small case series [25, 116]. In a retrospective guish these two conditions from more progres-
study of 83 children with chest pain investigated sive diseases (i.e., achalasia and esophageal
by esophageal manometry and endoscopy, cancer) [120].
Glassman identified 4 patients with DES.
238 H. Mousa and A. Aspirot

There is controversy regarding the diagnosis exact incidence and prevalence of EoE remains
and treatment of DES and NE. Both can be diag- unknown. Dohil et al. suggest a prevalence of 30
nosed using manometry; however, only clinical in 100,000 people [134]. It is postulated that 10%
symptoms are helpful to diagnose DES [120, 121]. of children with GER, unresponsive to acid sup-
pH monitoring can determine whether gastroe- pression therapies have EoE [128]. Overall, prev-
sophageal reflux disease (GERD) is present alence tends to be higher in individuals with a
which identifies need for anti-GERD therapies in history of dysphagia and pre-diagnosed/existing
treatment [124]. Barium esophagograms are cases of GERD, reflux esophagitis, and food
often normal in DES and NE patients [120]. impaction [130].
Possible treatment options for DES and NE Etiopathogenesis of EoE remains unknown,
include pharmaceutical interventions, surgery, though researchers suggest infiltration is related to
and anti-GERD therapies [120]. Nitrates, calcium food allergen hypersensitivity in non-idiopathic
channel blockers, and botulinum toxin, all cases of EoE [128]. GERD, aperistalsis, dysphagia,
decrease LES pressure; though esophageal func- and poor esophageal clearance are described as
tion is further complicated when the LES becomes complications of EoE [128, 133, 135].
too relaxed due to medications [124–126]. Mechanisms responsible for esophageal dys-
Anxiolytics may be used in DES patients diag- motility associated with EoE are somewhat
nosed with anxiety or depression [120, 121]. The uncertain. Eosinophils contain substances that
use of visceral analgesics (tricyclic antidepres- cause inflammation and may damage surround-
sants, serotonin reuptake inhibitors (SSRIs)) ing tissue when released [136]. A suggested trig-
improved global symptoms scores in individuals ger of inflammation in epithelial cells of the
with esophageal contraction abnormalities and esophagus is eotaxin-3, an eosinophil chemoat-
DES. There is no evidence on the effect of vis- tractant [133]. This inflammation subsequently
ceral analgesics on NE. Medical and surgical penetrates other cell layers. For instance, it may
approaches are intended to alleviate pain and lead to inflammation of the epithelium which fur-
decrease severity of symptoms [120]. Patients thers dysmotility [130, 133]. Axonal necrosis is
may undergo pneumatic dilation to relieve symp- thought to result from eosinophilic degranulation
toms but the procedure is not consistently effec- creating damaged nerve tissue and consequently
tive because the balloon can be difficult to place. weak esophageal contractions. Increased eosino-
Surgery is usually reserved for those patients phil cationic protein (ECP) is shown to result
with dysphagia and hypertensive sphincter. from the co-culture of eosinophils and fibroblasts;
Selecting a treatment option should be used based ECP encourages abnormal fibroblast contractions
on bolus transit and manometry findings [9]. [133, 136].
The following are symptoms of EoE in adults:
dysphagia, food impaction and retrosternal pain
Eosinophilic Esophagitis with or without swallowing [129, 132, 133, 137].
Pediatric patients may additionally experience
Eosinophilic Esophagitis (EoE) is a condition in vomiting, abdominal pain, failure to thrive, food
which the esophagus becomes inflamed due to aversion, feeding difficulties, and other symptoms
infiltration by eosinophils. Detection of ³15–21 imitating GERD [128, 137, 138]. Normal fre-
eosinophils/HPF in squamous epithelium is pos- quency of reflux episodes, an allergic history, and
tulated as qualifying criterion for EoE diag- poor response to acid suppression are also charac-
nosis though some controversy remains teristic of EoE patients [128]. Due to symptom
[127–131]. Eosinophilic infiltration is common overlap between EoE and GERD, diagnosis must
in the GI tract in cases of eosinophilic gastroen- be confirmed by endoscopy [139, 140].
teritis, allergic colitis, IBD, and GER [132, 133]. The diverse array of EoE symptoms speak to
EoE is now appreciated as a condition separate the variety of treatment options available to EoE
from GERD and reflux esophagitis [128]. The patients: diet management, fluticasone inhalants,
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 239

Table 20.2 Summary of EoE treatment methods

Method of treatment Advantages Disadvantages Success
Elimination diet Still allows for some food Requires careful review of all Must continue elimination
intake by mouth food choices for allergens for long-term resolution
Does not always indicate
specific food allergen at fault
Elemental diet Quick resolution of Formulas not palatable Compliance difficult for
symptoms Lower quality of life children
Cost/insurance coverage
Acid suppression Can distinguish between May only treat GERD Low success in children
EoE and GERD symptoms
Topical Direct administration to May not fully penetrate High rate of symptom
corticosteroids areas with eosinophilia eosinophilia relapse
Systemic Variety of administration Low bioavailability Satisfactory symptom
corticosteroids (swallowed or inhaled) resolution
Esophageal dilation Highly effective when Chest pain Common treatment in adults
strictures are also present Esophageal perforations

acid suppression, topical and systemic corticos- [146]. Of those 135 cases, under 50% (n = 63)
teroids, and esophageal dilation [138]. Esophageal involved the esophagus [146].
dilation is a surgical treatment option more com- A study of SSc revealed that childhood-onset
mon in adults with strictures, but is also used for is sometimes preceded by trauma in the area of
pediatric EoE [138, 141]. The primary, yet rare deposition; a unique phenomenon compared to
risks associated with esophageal dilation are wall adult cases of scleroderma [145]. In the presence
disruption and perforation [138]. Patients may of SSc, esophageal manometry reveals an incom-
prefer this method of treatment after seeing no petent LES and low-amplitude smooth muscle
improvement with dietary or other medical inter- contractions of the esophagus [142]. The retro-
vention (Table 20.2). grade movement of gastric contents, related to
low LES pressure, exposes the esophagus to acid-
ity, which can further compromise peristalsis.
Collagen Vascular Disorders Frequent contact between acidic gastric contents
and esophageal mucosa degrades tissue quality;
Among collagen vascular disorders, scleroderma esophagitis, bleeding, and strictures are other
is the most severe and commonly manifests in the known complications. However, studies have
gastrointestinal tract. Other collagen vascular noted that many who experience esophageal dys-
disorders with esophageal manifestations are sys- motility secondary to SSc are sometimes asymp-
temic lupus erythematosus (SLE), mixed connec- tomatic [142, 147]. Aside from manometry,
tive tissue diseases (MCTDs), Sjörgen syndrome, barium esophagram, 24-h ambulatory pH, and
and rheumatoid arthritis. Scleroderma consists of endoscopy are also used to diagnose the extent of
the hardening of tissues resulting from an auto- esophageal disturbance secondary to SSc [142].
immune response. Systemic scleroderma (SSc) is Autoimmune markers such as the anti-endonu-
characterized by collagen deposition in body tis- clear antigens anti-ScL-70 and anti-centromere
sue, especially the esophagus. SSc affects esoph- antibodies may be present.
ageal tissue and motility in 75–90% of adult cases Common symptoms of SSc with esophageal
[142, 143]; pediatric studies indicate lower prev- involvement are dysphagia, chest pain, weight
alence [144, 145]. In a multi-center study, loss, food impaction, and early satiety [142, 148].
Foeldvari et al. reported 65% (88/135) of pediat- Weber et al. reported reflux events in over 60% of
ric SSc patients presented GI tract involvement pediatric patients with SSc [147]. Overall mortal-
240 H. Mousa and A. Aspirot

ity for SSc with esophageal involvement is very ined esophageal involvement in children with HD,
rare; death is usually a consequence of multi- in comparison to those with idiopathic megacolon
system involvement [145, 146]. Treatment of SSc and healthy controls with no esophageal or colonic
primarily involves immunosuppressants (predni- diseases. Abnormalities in the amplitude and fre-
sone, methotrexate, mycophenolate mofetil, quency of distal esophageal body contractions
tumor necrosis factor-alpha, cyclophosphamide) were significantly higher in HD patients than other
[145, 149]. However, there is no specific treat- groups [157]. The severity of HD in this group was
ment for SSc esophageal involvement. unrelated to esophageal involvement.
Gunawardena and McHugh suggest proton pump
inhibitors, bulking agents, nutritional supple-
ments, and antibiotics as additional treatment Caustic Ingestion
options [148, 150].
Caustic ingestion of harmful substances is a com-
mon accident among young children, especially in
Chronic Idiopathic Intestinal Pseudo- developing countries. Common signs and symp-
Obstruction toms include salivation, oropharyngeal burns,
vomiting, bleeding, epigastric and retrosternal
Chronic idiopathic intestinal pseudo-obstruction pain, and malignant transformation [158, 159]. A
(CIIP) is a rare primary disorder that involves the recent study examined the extent of esophageal
entire gastrointestinal tract. Esophageal involve- damage in 94 toddlers (mean age 38 months) who
ment is very common [151, 152]. Non-idiopathic experienced caustic ingestion [159]. Over 80% of
intestinal pseudo-obstruction is usually secondary cases had second to third degree esophageal burns
to systemic, metabolic, genetic or mitochondrial eti- which were highly associated with the develop-
ologies. CIIP is often diagnosed during infancy and ment of esophageal strictures. Strictures occurred
childhood and symptoms are usually both severe in 46 cases overall (49%) and were associated with
and frequent at onset. Patients with esophageal development of dysphagia, contributing to poor
involvement present clinical symptoms of GER, nutrient intake, and dysmotility.
dysphagia, nausea and vomiting, and weight loss Esophageal manometry has revealed hypoperi-
[153]. Dysphagia, however, is usually a chief com- stalsis, usually with normal UES and LES func-
plaint when CIIP is secondary to another disorder. tion, in cases of caustic ingestion [160, 161].
Abnormal manometry findings include unco-
ordinated or low-amplitude contractions with
swallowing [152, 154]; these findings are more Ineffective Esophageal Motility
common than aperistalsis. Decreased LES pres-
sure is also a common finding. Pharmacologic Spechler and Castell defined ineffective esopha-
treatment of CIIP is similar to that of other esoph- geal motility (IEM) as having low or normal
ageal motility disorders, involving antiemetics, esophageal sphincter pressure, normal LES relax-
prokinetics, and antispasmodics. ation, and greater than 30% low-amplitude waves
characterized by the following: wave amplitude
<30 mmHg, peristalsis that does not travel the
Hirschsprung’s Disease length of the esophagus, simultaneous contrac-
tions <30 mmHg, or aperistalsis [162]. Currently
Lack or poor formation of the enteric nervous sys- there is little data regarding IEM in the pediatric
tem defines Hirschsprung’s Disease (HD). Though population. Literature suggests IEM as a predictor
primarily a disease of the small and large bowel, for GERD in adults, though the nature of the asso-
HD is occasionally associated with abnormal ciation is controversial. It has not yet been deter-
esophageal motility indicated by poor peristaltic mined whether IEM is a rare primary disorder or
wave propagation [155, 156]. Staiano et al. exam- merely secondary to increased acid exposure. IEM
20 Esophageal Motor Disorders: Achalasia, Diffuse Esophageal Spasm, Nonspecific Motor... 241

hypocontractions and incomplete peristalsis of the 120, 124]. NEMDs are rarer than other primary
esophagus may be diagnosed using manometry esophageal motility disorders, such as achalasia and
and/or high-frequency intraluminal ultrasound DES. In a cohort of 154 children with upper GI
(HFIUS). Pioneered by Mittal [163], HFIUS pro- symptoms, 30 were not diagnosed with GER. Of
vides real-time images of esophageal function those 30 patients, 43% (n = 13/30) were found to
which has proven especially beneficial during have NEMDs, representing 8% of the entire cohort
manometry. Using HFIUS, Kim et al. sought to [168]. In addition to normal esophageal pH, many
examine esophageal muscle thickness in patients of those diagnosed demonstrated normal endo-
diagnosed with IEM [164]. Of 283 eligible patients, scopic appearance and esophageal histology; thus
46 (16%) had IEM, with just over half of those clinical findings (i.e., food impaction) are of great
cases associated with GERD (n = 26). The non- significance with regard to NEMDs [168]. Palliative
GERD IEM group had greater LES muscle thick- treatment interventions for NEMDs usually involve
ness than the GERD group, supporting an antispasmodic agents, prokinetics, antacids (when
association, but not causal relationship between GER is present), and/or PPIs [118, 120].
the two. HFIUS, coupled with manometry, will Improvement with these methods is variable; some
likely become an increasingly utilized examina- patients may even improve without pharmacologic
tion and diagnostic tool for gastroenterologists as intervention [168].
more data is collected on IEM [162, 165].

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 Gastric Motor Disorders:
Gastroparesis and Dumping 21
Syndrome

Miguel Saps and Ashish Chogle

Introduction Gastroparesis

Normal gastrointestinal function relies on the Gastroparesis is a gastric motor disorder charac-
coordinated action of motor, sensory, digestive, terized by delayed emptying of gastric contents
secretory and excretory function. Coordinated into the duodenum in the absence of mechanical
motility is essential for the orderly digestion, obstruction. The pathogenesis and pathophysiol-
absorption, and elimination of waste. Adequate ogy of gastroparesis are often complex and poorly
gastrointestinal motility requires integration of understood. Multiple processes affecting the
the autonomic nervous system (intrinsic and extrinsic motor neurons, enteric motor neurons,
extrinsic sympathetic and parasympathetic interstitial cells of Cajal, and smooth-muscle cells
nerves), neurotransmitters, and enteric smooth may lead to altered physiological mechanisms
muscle cells. Sensory extrinsic neurons respond resulting in gastroparesis. Pathophysiological
to various stimuli, including the presence of food mechanisms vary and include exaggerated relax-
in the gastrointestinal tract by triggering complex ation of the fundus, poor antral contractility, unco-
reflex mechanisms with final effectors in the ordinated antro-pyloro-duodenal function and
smooth muscle cells in the gut wall, blood ves- persistent pylorospasm. The pathophysiological
sels, and glandular cells. Alterations at any level mechanisms and etiological agents involved in
of these complex processes may result in altered development of gastroparesis are sometimes
motility. identified but it is not infrequent that despite thor-
ough diagnostic studies the etiologic causes and
pathophysiological mechanisms of gastroparesis
remain unknown. Gastroparesis may present with
a variety of symptoms including early satiety,
bloating, abdominal discomfort or pain, anorexia,
M. Saps, M.D. halitosis, nausea, and vomiting of “old” undigested
Pediatric Gastorenterology, Hepatology and Nutrition food and weight loss but can also be paucisymp-
Division, Pediatrics Department, Children’s Memorial tomatic or asymptomatic. Diagnosis is based on
Hospital, Northwestern University, Chicago, IL, USA the clinical presentation, exclusion of other causes
A. Chogle, M.D., M.P.H. (*) of persistent vomiting, and the objective demon-
Division of Gastroenterology, Hepatology and Nutrition, stration of delayed gastric emptying (Fig. 21.1).
Children’s Memorial Hospital, 2300 Children’s Plaza,
Box 65, Chicago, IL 60614-3363, USA Etiological factors (Table 21.1) associated with
e-mail: [email protected] gastroparesis vary with the child’s age.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 247

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_21, © Springer Science+Business Media New York 2013
248 M. Saps and A. Chogle

Fig. 21.1 Gastric emptying scan showing delayed gastric emptying with greater than 60% and 10% Tc 99 m sulfur
colloid activity in the stomach at 2 and 4 h respectively

Immaturity throughout the abdomen without evidence of

obstruction and failure to pass stools in seven
Gastric electrical and motor activity matures with infants with an average gestational age of 30
gestational age [1, 2]. Extreme preterm birth is weeks that recovered after several weeks [3].
associated with immature gastric function. Mature patterns of motor contractile activity are
Premature neonates may present transient mani- only achieved in late stages of gestation. Normal
festations of intestinal ileus that mimic intestinal gastric electrical rhythm and mature patterns of
pseudo-obstruction. A case series reported gastric liquid emptying have been shown in
abdominal distension, dilated loops of bowel infants of 32 weeks of gestational age [1]. Normal
21 Gastric Motor Disorders: Gastroparesis and Dumping Syndrome 249

Table 21.1 Etiology of gastroparesis in children decade of life [5]. Small enteral feedings lead to
Idiopathic a rapid increase in motility, digestion, and absorp-
Post-infectious tive capacity of the immature gastrointestinal
Rotavirus tract [6]. Early life experiences including envi-
EBV ronmental and nociceptive factors affecting the
CMV
Norwalk virus
digestive tract and airway may delay postnatal
Parvo-virus like agents gastro-enteric motor maturation.
Mycoplasma
Borellia
Postsurgical Post-Infectious
Thoracic and abdominal surgeries
Vagotomy
Partial gastrectomy Post-infectious gastroparesis is common in chil-
Metabolic dren [7]. Multiple pathologic agents including
Diabetes mellitus type I rotavirus, EBV, CMV, Norwalk virus, parvo-virus
Hypothyroidism like agents, mycoplasma, and Lyme disease have
Hyperthyroidism been associated with gastroparesis in children
Hyperparathyroidism
Addison’s disease [7–9]. Symptoms usually present days or months
Hypopituitarism following an acute intercurrent illness.
Chronic renal failure Consultation is often late and the etiologic agents
Amyloidosis are rarely isolated. Post-viral gastroparesis in
Immune/inflammatory children is transient and tends to resolve sponta-
Cow milk protein allergy
neously over several months. Follow-up studies
Eosinophilic gastroenteropathy
Celiac disease of children diagnosed with post-infectious gas-
Crohn’s disease troparesis have shown resolution of symptoms in
Autoimmune dysautonomia 6 months to 2 years in all cases [7, 9].
Drug induced
Anticholinergics
Opioids
Tricyclic antidepressants Peripheral Neuropathies
Proton-pump inhibitors
H2 receptors antagonists Peripheral neuropathies may involve different
Antacids nerve groups. A subgroup of these patients man-
Diphenhydramine
Sucralfate ifests with a more prominent and selective
Octreotide involvement of the autonomic nervous system.
Beta-adrenergic agonists Some of these patients can have an identifiable
Calcium channel blockers cause such as diabetes, amyloidosis, or inher-
Levodopa
ited autonomic neuropathy while others have no
Other
identifiable cause and are considered as having
GERD
Hirschsprung’s disease an idiopathic autonomic neuropathy.
Neuronal intestinal dysplasia
Peripheral neuropathies
Mitochondrial disorders
CNS or other chronic illnesses
Diabetes Mellitus
Caustic ingestions
Radiation Diabetes as a cause of gastroparesis is commonly
Portal hypertension reported in adults but rarely investigated in chil-
Marijuana consumption
dren. The pathophysiology of diabetic gastropa-
resis is multifactorial and includes hyperglycemia,
gastric motility is fully developed by 34 weeks of electrolyte imbalances, vagal parasympathetic
gestational age [4]. Gastric electrical activity pro- dysfunction, loss of neuronal nitric oxide expres-
gressively acquires the adult pattern in the first sion and enteric neurons, gastric smooth muscle
250 M. Saps and A. Chogle

abnormalities, and disruption of interstitial cells broad and patients can have presence of one or
of Cajal [10–14]. Antral hypomotility is the most more autoantibodies and localized or generalized
common motor abnormality in children with gastrointestinal dysmotility and dysautonomic
IDDM [15–18]. Gastric electrical dysrhythmias, manifestations. Patients typically present with
gastrointestinal symptoms and delayed gastric gastroparesis, constipation, abnormal pupillary
emptying have been demonstrated in diabetic light response, anhidrosis, marked dry eyes and
children few years after diagnosis [15, 17]. A dry mouth (sicca complex), neurogenic bladder,
study in children with IDDM and gastrointesti- and orthostatic hypotension that usually reach
nal complaints has shown that autonomic neu- peak autonomic failure within 3 months [21].
ropathy was not an etiological factor of More commonly, autoantibodies related gastroin-
gastrointestinal symptoms in this group of chil- testinal dysmotility disorders are limited to
dren [19]. Glycemic control and delayed gastric specific areas and may manifest as isolated
emptying are closely related. Gastroparesis can foregut dysmotility such as achalasia, esophageal
contribute to worsening glycemic control due to dysmotility or pyloric stenosis. Symptoms may
the slow and erratic gastric emptying while blood include dysphagia, odynophagia, early satiety,
glucose levels measured 180 min after meals postprandial epigastric discomfort, nausea, vom-
have been correlated with prolonged gastric iting, unexplained weight loss with malnutrition,
emptying time [15]. The study has also shown a abdominal pain, and intractable constipation or
significant increase in gastric electrical dysrhyth- diarrhea. High titers of antibodies specific for the
mias in diabetic children compared with healthy neuronal ganglionic nicotinic acetylcholine
controls. Gastrointestinal symptoms, delayed receptor (nAChR) are frequently found in patients
gastric emptying have been reported in children with severe forms of autoimmune autonomic
within 1–7 years of onset of IDDM [17]. A study ganglionopathy [22]. A decrease in antibody
on 40 consecutive children diagnosed with insu- titers is frequently associated with improved
lin-dependent diabetes mellitus (IDDM) 5 years autonomic function. Gastrointestinal dysmotili-
prior to the study has shown delayed gastric ties associated with dysautonomia have been
emptying time in 2/3 of children [15]. Children reported in patients with anti-neuronal nuclear
with IDDM have lower serum motilin concentra- autoantibody, type 1 (ANNA-1, “anti-Hu”) and
tions compared with healthy control [19]. A other neuronal voltage-gated cation channel anti-
study in children with IDDM has shown bodies (voltage-gated calcium channels (VGCCs),
improvement in gastrointestinal symptoms, gas- voltage-gated potassium channels (VGKCs), glu-
tric emptying function, and better glycemic con- tamic acid decarboxylase (GAD)) [23, 24].
trol with the use of erythromycin [17]. Autoimmune gastrointestinal dysmotility disor-
ders may sometimes be part of paraneoplastic
syndromes. No cases of autoimmune autonomic
Autoimmune Neuropathy neuropathy have been published in children,
however cation channel antibodies have been
Autoimmune gastrointestinal dysmotility is a found in some unpublished cases in adolescents
limited form of autoimmune dysautonomia. It with gastrointestinal dysmotility. Autoimmune
usually presents with subacute onset of auto- gastrointestinal dysmotility can also be associ-
nomic dysfunction, unexplained nausea and ated other autoantibodies and autoimmune disor-
vomiting and confirmed gastroparesis sometimes ders (diabetes, lupus, Raynaud, hypothyroidism,
associated with a previous illness (possibly infec- and pernicious anemia). Approximately half of
tious) [20]. Most of these cases are now consid- the patients in one study had coexistence of
ered within the spectrum of autoimmune plasma membrane cation channel autoantibodies
autonomic neuropathy and specifically as auto- with antibody markers of organ-specific autoim-
immune autonomic ganglionopathy. The spec- munity (skeletal muscle striational, GAD65, thy-
trum of autoimmune autonomic disorders is roid or gastric parietal cell specificities) [23].
21 Gastric Motor Disorders: Gastroparesis and Dumping Syndrome 251

of muscle. Both inflammatory myopathies are

Hirschsprung’s Disease frequently associated with delayed gastric and
esophageal emptying secondary to malfunction
A study on adults with a history of Hirschsprung’s of the smooth muscle of the upper gastrointesti-
disease, neuronal intestinal dysplasia or hypogan- nal tract. Gastric and esophageal dysfunctions
glionosis found abnormal esophageal, gastric and correlate with the severity of the peripheral skel-
gut motility in 2 of 12 cases studied [25]. A etal muscle weakness [34].
study on 21 children who underwent GI transit
time study and a scintigraphic gastric emptying
test several years after surgery showed delayed Postsurgical
gastric emptying in 57% of patients and prolonged
total gastrointestinal time in patients with a history Gastroparesis often develops after upper abdomi-
of Hirschsprung’s disease compared with healthy nal and thoracic surgeries and is frequently associ-
controls suggesting that gastrointestinal dysmotil- ated with injury of the vagal nerve. Increases in
ity persists long after surgical correction [26, 27]. intragastric volumes, impaired proximal gastric
responses to meals and to balloon insufflation, and
heightened perception of gastric distention also
Central Nervous System Disorders have been observed after vagotomy [35]. The exact
mechanisms responsible for postsurgical gastropa-
Children with central nervous system disorders resis remain unclear but are likely to be multifacto-
and other chronic illnesses have been shown to rial. Abnormalities of antral peristalsis and fundic
have a high incidence of gastric dysrhythmias tone are demonstrable in patients with postsurgical
and gastroparesis with abnormal antroduodenal gastroparesis. In one study, eight of nine patients
motility [28–30]. Foregut dysmotility including with gastroparesis had no fasting motor activity,
esophageal dysmotility, and delayed gastric emp- whereas asymptomatic postoperative controls
tying is frequent in children with central nervous exhibited normal migrating motor complex activity
system disorders [31]. [36]. Intestinal manipulation leading to mast cells
Gastroparesis may occur as part of a mito- degranulation and altered bowel motility has been
chondrial disorder. Studies have identified accu- proposed as an important pathophysiological
mulation of mitochondrial A3243G mutation in mechanism of postoperative dysmotility. A ran-
the stomach in a group of patients with gastric domized placebo controlled study showed that the
dysmotility and gastric symptoms and a leuko- administration of mast cell stabilizers such as keto-
cytic point mutation of mitochondrial DNA at tifen prior to the surgery prevented the inflammatory
nucleotide position 3243 [32]. Mitochondrial response, and the development of postoperative
encephalomyopathy with lactic acidosis and gastroparesis [37]. Symptoms of postsurgical gas-
stroke-like episodes (MELAS) is characterized troparesis secondary to vagal injury gradually
by the involvement of skeletal muscle and central improve with time possibly due to the ability of the
nervous system and occasional urinary or gastro- enteric nervous system to adapt to the loss of vagal
intestinal symptoms. An A-to-G point mutation input or occurrence of vagal reinnervation [38].
at position 3243 of mitochondrial DNA was
found in patients with MELAS [33].
Immune and Inflammatory

Myopathies Food Allergy

Autoimmune disorders of the connective tissue Electrographic studies have shown severe gastric
such as polymyositis and dermatomyositis are dysrhythmias in infants with cow’s milk protein
characterized by inflammation and degeneration allergy [28]. Measurement of gastric half-emptying
252 M. Saps and A. Chogle

time by electrical impedance tomography has gastric emptying in a subgroup of symptomatic

shown delayed gastric emptying in children sensi- patients who complained of bloating, early sati-
tized to cow’s milk. Gastroesophageal reflux and ety, and abdominal distention [45].
cow’s milk allergy frequently coexist in infants.
Delayed gastric emptying and gastric cardiac dis-
tension associated with cow’s milk protein allergy Gastroesophageal Reflux
may elicit transient relaxations of the lower esoph- and Functional Dyspepsia
ageal sphincter (tLESR) through vagally mediated
reflexes worsening gastroesophageal reflux Studies have shown that delayed gastric emp-
symptoms. tying may play a role in the pathophysiology of
A study on a murine model of eosinophilic gas- gastroesophageal reflux in a subgroup of chil-
trointestinal inflammation has shown eosinophilic dren. Gastric emptying rate in children older
infiltration in close proximity to damaged enteric than 6 years, suffering from gastroesophageal
nerves [39]. Similar findings were described in reflux was shown to be significantly delayed as
humans. Electrogastrographic changes, mast cell compared to normal children older than 6
degranulation in proximity to the gastric nerve years. No delay was observed in children
fibers were found in patients exhibiting a positive younger than 3 years [46]. Thus gastroparesis
food challenge [40]. Although the mechanism could be a contributory factor in the pathophys-
remains unclear, it has been proposed that the iology of gastroesophageal reflux in older chil-
release of the major basic protein by eosinophils dren. Gastric motor disorders and characteristic
may induce muscarinic receptor dysfunction, altera- motility patterns may be present in functional
tion of smooth muscle contraction leading to gastric gastrointestinal disorders such as functional
dysmotility and delayed gastric emptying [41]. dyspepsia and rumination. An in-depth discus-
sion of these disorders can be found in other
sections of this book.
Celiac Disease and Inflammatory
Bowel Diseases
Other
Celiac disease is frequently associated with gas-
trointestinal dysmotility. Patients will celiac Gastroparesis is a recognized complication of
disease often present delayed esophageal, gas- other endocrine disorders such as hypothyroid-
tric and small intestinal transit time and acceler- ism, hyperthyroidism, hyperparathyroidism,
ated colonic transit [42]. A study comparing Addison’s disease and hypopituitarism. Fifty per-
antro-duodeno-jejunal motility of untreated cent of critically ill patients exhibit severe gastro-
celiac disease patients, celiac patients on a gluten- paresis [41, 47]. In these patients, gastroparesis
free diet and healthy controls showed upper gut can be explained by the elevation of fasting and
motor abnormalities in 80% of untreated celiac nutrient stimulated CCK and PYY and suppres-
patients [43]. Gastric emptying rate of solids is sion of fasting ghrelin [48, 49].
delayed in patients with untreated celiac disease Caustic ingestion was also shown to lead to
while prolonged gluten withdrawal normalizes delayed liquid gastric emptying even in the
gastric emptying time in all celiac disease absence of symptoms [50]. Various drugs includ-
patients [44]. A case series of five patients with ing anticholinergics, opioids, tricyclic antide-
clinically inactive inflammatory bowel disease pressants, proton-pump inhibitors, H2 receptors
and persistent symptoms of nausea, vomiting antagonists, diphenhydramine, antacids, sucral-
and weight loss in the absence of strictures have fate, octreotide, beta-adrenergic agonists, cal-
shown evidence of upper gut dysmotility. A cium channel blockers, and levodopa among
study on gastric emptying in adult patients with others may delay gastric emptying [51–53]. Even
nonobstructive Crohn’s disease, revealed slow after thorough diagnostic studies the etiologic
21 Gastric Motor Disorders: Gastroparesis and Dumping Syndrome 253

causes and pathophysiological mechanisms of fluids does not prevent clinical manifestations of
gastroparesis frequently remain unknown. early dumping syndrome [57]. Late dumping
Marijuana consumption slows down motility occurs 1–2 h after a meal and is characterized
and delays gastric emptying. Cannabinoid recep- predominantly by systemic vascular symptoms,
tors are expressed in the enteric nervous system. including hypoglycemia, perspiration, palpita-
Cannabinoid signaling modulates synaptic activity tions, hunger, fatigue, confusion, aggression,
in the nervous system. Activation of CB1 recep- tremor, and syncope. Physical examination may
tors on myenteric neurons results in presynaptic reveal orthostatic changes, including a fall in
depression inhibiting neuronal activity, synaptic blood pressure and increased heart rate. The rapid
transmission, and axonal mitochondrial transport delivery of gastric contents to the small bowel
[54, 55]. leads to the rapid absorption of glucose into the
circulation and hyperglycemia, which subse-
quently stimulates the rapid release of insulin
Treatment followed by reactive hypoglycemia [56].
Uncontrolled severe dumping can result in the
Treatment of gastroparesis include dietary and fear of food or eating and subsequent weight loss.
lifestyle modifications, prokinetics agents, intrapy- Clinical manifestations of one or both of these
loric injection of botulinum toxin, and gastric elec- phases may be present in each patient. It is esti-
trical stimulation, an intervention that although mated that manifestations of early phases of
does not consistently improve emptying has been dumping occur in 75% of all affected patients
shown to help alleviate symptoms and improve [58]. Dumping syndrome may be seen after sur-
quality of life. Diagnostic testing and specific gical procedures such as esophagectomy, gast-
treatment modalities of gastric motility disorders rectomy, vagotomy with pyloroplasty, bariatric
are covered in other chapters of this book. surgery, and fundoplication. It has been reported
to occur in up to 30% of children undergoing
anti-reflux surgery [59]. In a recent study, 35%
Dumping Syndrome adult patients with cyclic vomiting syndrome,
13% with diabetes mellitus and 10% with irrita-
Dumping syndrome is characterized by the onset ble bowel syndrome were found to have dumping
of gastrointestinal and vasomotor symptoms fol- syndrome [60]. A provocative test for assessing
lowing the ingestion of a meal. The underlying dumping syndrome can be used to confirm clini-
gastrointestinal motor abnormality in dumping cal suspicion. This test is a modification of the
syndrome is acceleration of gastric emptying oral glucose tolerance test and involves the inges-
leading to fluid shifts and changes in glucose tion of 50 g or 75 g glucose in solution after an
homeostasis. Early symptoms comprise both overnight fast. Immediately before and up to
gastrointestinal and vasomotor symptoms. 180 min after ingestion of this solution, the blood
Gastrointestinal symptoms include abdominal glucose concentration, hematocrit, pulse rate, and
pain, diarrhea, borborygmi, nausea and bloating. blood pressure are measured at 30 min intervals.
Vasomotor symptoms consist of fatigue, a desire The provocative test is considered positive if late
to lie down after meals, facial flushing, palpita- (120–180 min) hypoglycemia occurs, or if an
tions, perspiration tachycardia, hypotension and early (30 min) increase in hematocrit of more
syncope. The rapid emptying of hyperosmolar than 3% occurs. The best predictor of dumping
contents into the small intestine results in a fluid syndrome seems to be a rise in the pulse rate of
shift from the intravascular compartment into the more than 10 beats per minute after 30 min
intestinal lumen, leading to small bowel disten- [61]. Assessments of gastric emptying might
tion. This initiates release of various humoral and show that this process occurs rapidly in patients
neural mediators and increased intestinal con- with dumping syndrome—especially for liquid
tractility [56]. The administration of intravenous nutrients—but this test does not seem to have
254 M. Saps and A. Chogle

good diagnostic sensitivity or specificity, proba- 2. Riezzo G, et al. Gastric electrical activity and gastric
bly because rapid emptying occurs early after emptying in term and preterm newborns.
Neurogastroenterol Motil. 2000;12(3):223–9.
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closely or separately in many protocols of gastric obstruction syndrome in premature infants. Arch Fr
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diabetes-associated depletion of interstitial cells of
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 Chronic Intestinal
Pseudo-Obstruction 22
Paul E. Hyman and Nikhil Thapar

Chronic intestinal pseudo-obstruction (CIPO), and colonic myoelectrical activity and contrac-
far from a single entity, represents a heterogenous tions as well as histologic abnormalities in nerve
group of disorders affecting gut neuromuscular and muscle. The genetics for most CIPO condi-
function. Such conditions are rare and vary in tions is poorly characterized. Although these dis-
cause, severity, course, and response to therapy eases have distinctive pathophysiologic
[1–6]. Most are severe, disabling and character- characteristics, they are considered together
ized by repetitive episodes or continuous symp- because of their clinical and therapeutic similari-
toms and signs of bowel obstruction, including ties (See Table 22.1 for list of heterogeneity).
radiographic documentation of dilated bowel
with air-fluid levels, in the absence of a fixed,
lumen-occluding lesion [7]. At the present time, Etiology
CIPO remains largely a clinical diagnosis based
on phenotype, rather than pathology or manom- CIPO may occur as a primary disease or as a sec-
etry. The most common signs are abdominal dis- ondary manifestation of a large number of other
tention and failure to thrive, and the most common conditions that transiently (e.g., hypothyroidism,
symptoms are vomiting, constipation or diarrhea phenothiazine overdose) or permanently (e.g.,
and abdominal pain. Heterogeneity in pseudo- scleroderma, amyloidosis) alter bowel motility
obstruction includes, but is not limited to, a wide (Table 22.2) [8–40].
spectrum of abnormal gastric, small intestinal, Most congenital forms of neuropathic and
myopathic CIPO are both rare and sporadic.
There is no family history of pseudo-obstruction,
P.E. Hyman, M.D. (*) no associated syndrome, and no evidence of other
Gastroenterology Division, Children’s Hospital,
Louisiana State University, 200 Henry Clay Ave,
predisposing factors such as toxins, infections,
New Orleans, LA 70118, USA ischemia, or autoimmune disease. Such condi-
e-mail: [email protected] tions are likely to represent new mutations. More
N. Thapar, B.Sc.(hon), B.M.(hon), M.R.C.P., rarely, CIPO appears to show familial inheritance
M.R.C.P.C.H., Ph.D. and a number of genes have been implicated.
Gastroenterology Unit, University College London, This is discussed in detail elsewhere in the book.
Institute of Child Health, Division of
Neurogastroenterology and Motility ,
Briefly, there are reports of autosomal-dominant
London, UK [41, 42] and -recessive [43–46] neuropathic, and
Department of Paediatric Gastroenterology, Great
dominant [47, 48] and recessive [49, 50] myo-
Ormond Street Hospital for Children, pathic patterns of inheritance. In the autosomal-
London, UK dominant diseases, expressivity and penetrance are

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 257

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_22, © Springer Science+Business Media New York 2013
258 P.E. Hyman and N. Thapar

Table 22.1 Features of chronic intestinal pseudo- Table 22.2 Causes of secondary acute, subacute, and
obstruction in pediatric patients chronic intestinal pseudo-obstruction in children
Onset Toxic
Congenital Ketamine
Acquired Carbamazepine
Acute Clonidine
Gradual Atropine and other anticholinergics
Presentation Theophyllin
Megacystis—microcolon intestinal hypoperistalsis Fludarabin
syndrome Vinblastin and other vinca alkaloids
Acute neonatal bowel obstruction, with or without Neuroleptics
megacystitis Antidepressants
Chronic vomiting and failure to thrive Phenothiazine
Chronic abdominal distention and failure to thrive Opiates
Calcium channel blockers
Cause
Fetal alcohol syndrome [8]
Sporadic
Metabolic
Familial
Toxic Electrolyte imbalance (hypo K+, hyper Mg2+, hypo Ca2+)
Ischemic [9]
Viral Hypothyroidism
Inflammatory Hypoparathyroidism
Autoimmune Carnitine deficiency [10]
Vitamin E deficiency (“brown-bowel syndrome”) [11,
Area of involvement
12]
Entire gastrointestinal tract Infectious
Segment of gastrointestinal tract Viral: CMV [13], EBV [14, 15], Herpes Zoster [16],
Megaduodenum Rotavirus [17]
Small bowel
Trypanosoma cruzei (young adults)
Colon
Lyme disease [18]
Pathology
Immune
Myopathy
Neuropathy Celiac disease
Lymphocytic or eosinophilic ganglionitis Systemic sclerosis [19]
Absent neurons Lupus (myopathy) [20]
Immature neurons Autoimmune leiomyositis [21, 22]
Degenerating neurons Autoimmune enteric ganglionitis (with anti-enteric
Absent cells of Cajal neurons antibodies, anti-PCNA antibodies) [23, 24]
Intestinal neuronal dysplasia Guillain-Barré syndrome [25]
No microscopic abnormality Tumoral
Neural crest cell tumor: neuroblastoma, ganglioneuro-
variable; some of those affected die in childhood, blastoma [26]
but those less affected are able to reproduce. An Pheochromocytoma [27]
Thymoma (with anti-acetylcholine receptor antibodies)
X-linked recessive form of neuropathic pseudo- [28]
obstruction has been mapped to its locus, Xq28 Striated myopathy
[51]. A recessive form of CIPO is described in Myotonic dystrophy [29, 30]
mitochondrial neurogastrointestinal encephalop- Duchenne muscular dystrophy [31]
athy (MNGIE) [52]. When counseling families, a Desmin myopathy [32]
Mitochondrial myopathy [33, 34]
thorough family history is essential, and screen-
Central or peripheral generalized neuropathy
ing tests of relatives should be considered to seek
Degenerative process: diabetes, amyloidosis (not
milder phenotypic expression. reported in children)
CIPO may result from exposure to toxins dur- Mitochondrial neurogastrointestinal encephalopathy
ing critical developmental periods in utero. A few (MNGIE) [35]
children with fetal alcohol syndrome [52] and a Familial dysautonomia [36]
few exposed to narcotics in utero have neuro- Acquired cholinergic dysautonomia or acquired
pandysautonomia [37]
pathic forms of CIPO. Presumably, any substance
(continued)
22 Chronic Intestinal Pseudo-Obstruction 259

Table 22.2 (continued) and the chronic enterocolitis associated with

Miscellaneous Hirschsprung’s disease some patients develop
Angioedema [38] dilated bowel and symptoms due, not to anatomic
Postradiation enteropathy [39] obstruction, but to a neuromuscular disorder pre-
Kawasaki [40] sumably related to the effects of inflammatory
mediators on mucosal afferent sensory nerves or
motor nerves in the enteric plexuses. Other causes
that alters neuronal migration or maturation of CIPO associated with inflammation include
might affect the development of the enteric plex- myenteric neuritis associated with antineuronal
uses and cause CIPO. antibodies [23] and intestinal myositis [22, 57].
Children with chromosomal abnormalities or
syndromes may suffer from pseudo-obstruction.
Children with Down syndrome have a higher inci- Pathology (See Chap. 17)
dence of Hirschsprung’s disease than the general
population and may have abnormal esophageal There may be histologic abnormalities in the
motility [53] and neuronal dysplasia in the myen- muscle or nerve or, rarely, both [58]. More
teric plexus. Rare children with Down syndrome recently there have also been descriptions of
have a myenteric plexus neuropathy so general- CIPO due to mesenchymopathies or deficiencies
ized and so severe that they present with pseudo- in interstitial cells of Cajal [59]. Assessment of
obstruction. Children with neurofibromatosis, such pathology in motility disorders is not stan-
multiple endocrine neoplasia type IIB, and other dardized and therefore mesenchymopathy as a
chromosome aberrations and autonomic neuropa- distinct entity remains unclear [24]. Histology is
thies may suffer from neuropathic constipation. normal in about 10% of cases that are studied
Children with Duchenne’s muscular dystrophy appropriately, although there is great variability
sometimes develop pseudo-obstruction, especially in available expertise and protocols. Moreover, it
in the terminal stages of life [54]. Esophageal is often difficult to determine what changes are
manometry and gastric emptying are abnormal in primary, and what changes in nerve cell dropout
Duchenne’s dystrophy, suggesting that the myopa- and muscle fibrosis are caused by chronic disten-
thy includes gastrointestinal smooth muscle even sion and consequent ischemia. Recent initiatives
in asymptomatic children [31]. Acquired pseudo- are attempting to address this variability [60–62].
obstruction may be a rare complication of infec- In cases of normal gross neuromuscular histopa-
tion from cytomegalovirus [13] or Epstein-Barr thology there may be an abnormality in neuronal
virus [14]. Most recently, JC virus (JCV) a polyo- diversity (subtype dropout) or some biochemical
mavirus that can infect brain glial cells to cause aspect of stimulus-contraction coupling.
severe illness has been shown to be present in the When laparotomy is imminent for a child with
myenteric plexuses of adult patients with CIPO. pseudo-obstruction, there must be timely com-
JCV in enteroglial cells suggested a pathological munication between the surgeon and the patholo-
role for this virus in enteric neuropathy [55]. This gist. Although a laparotomy is not generally
is yet to be shown in pediatric CIPO. undertaken for biopsy alone, increasing expertise
Immunocompromised children and immunosup- with laparoscopy has facilitated it’s use for the
pressed transplant recipients seem at higher risk assessment of histopathology where confirmation
than the general population for acquired myenteric is required prior to definitive surgery or to inform
plexus neuropathy. Acquired CIPO might result prognosis. When surgery is indicated (e.g., for
from myenteric plexus neuritis from persistent colectomy, cholecystectomy, or creation of an
viral infection or an autoimmune inflammatory ileostomy) a plan should be made to obtain a full-
response. Mucosal inflammation causes abnormal thickness bowel biopsy specimen at least 2 cm in
motility. With celiac disease [56], Crohn’s disease, diameter. As discussed in Chap. 17 the tissues
260 P.E. Hyman and N. Thapar

should be processed for routine and specialized or disseminated. Other children may have neu-
histopathology studies including H&E, tinctorial ronal dysplasia associated with prematurity, pro-
stains, immunohistochemistry (IHC) and also for tein allergy, chromosome abnormalities, MEN
enzyme histochemistry and electron microscopy. IIB, and neurofibromatosis; however, intestinal
Muscle disease may be inflammatory but more neuronal dysplasia is an occasional incidental
often is not. In light microscopy of both familial finding in bowel specimens examined for reasons
and sporadic forms of hollow visceral myopathy, unrelated to motility. Intestinal neuronal dyspla-
the muscularis appears thin. The external longitu- sia correlates poorly with motility-related symp-
dinal muscle layer is more involved than the toms [66]. Thus, a pathologic diagnosis of
internal circular muscle, and there may be exten- intestinal neuronal dysplasia neither predicts
sive fibrosis in the muscle tissue. By electron clinical outcome nor influences management.
microscopy there are vacuolar degeneration and
disordered myofilaments.
Neuropathic disease used to be examined with Clinical Features
silver stains of the myenteric plexus [63, 64] and
routine histologic techniques but the former has Presentation
largely been superceded by IHC. The presence of
neurons in the submucous plexus of a suction More than half the affected children develop
biopsy specimen eliminates Hirschsprung’s dis- symptoms at or shortly after birth. A few cases
ease as a diagnostic possibility but is inadequate are diagnosed in utero, by ultrasound findings of
for the evaluation of other neuropathies. There polyhydramnios and megacystis and marked
may be maturational arrest of the myenteric abdominal distention. Intestinal malrotation is
plexus. This hypoganglionosis is characterized by found in both neuropathic and myopathic con-
fewer neurons, which may be smaller than nor- genital forms of pseudo-obstruction. Of children
mal. Apart from abnormal development pheno- who present at birth, about 40% have an intesti-
types other pathologies include neuronal nal malrotation. In the most severely affected
degeneration, inflammation, and inclusion bodies. infants symptoms of acute bowel obstruction
Maturational arrest can be a primary congenital appear within the first hours of life. Less severely
disorder or can occur secondary to ischemia or affected infants present months later with symp-
infection. Changes can be patchy or generalized. toms of vomiting, diarrhea, and failure to thrive.
Intestinal neuronal dysplasia [65], or hyper- A few patients have megacystis at birth and insid-
ganglionosis, is a histologic diagnosis defined by ious onset of gastrointestinal symptoms over the
these findings: (1) hyperplasia of the parasympa- first few years. More than three quarters of the
thetic neurons and fibers of the myenteric (and children develop symptoms by the end of the first
sometimes submucous) plexus, characterized by year of life, and the remainder present sporadi-
increases in the number and size of ganglia, cally through the first two decades.
thickened nerves, and increases in neuron cell Although there is individual variation in the
bodies; (2) increased acetyl cholinesterase-posi- number and intensity of signs and symptoms, it
tive nerve fibers in the lamina propria; (3) may be useful to note the relative frequencies in
increased acetylcholine esterase-positive nerve this population (Table 22.3). Abdominal disten-
fibers around submucosal blood vessels; (4) het- tion and vomiting are the most common features,
erotopic neuron cell bodies in the lamina propria, complaints of about three quarters of the patients.
muscle, and serosal layers. The first two criteria Constipation, episodic or intermittent abdominal
are obligatory. pain, and poor weight gain are features in about
Children with intestinal neuronal dysplasia 60% of cases. Diarrhea is a complaint in one
are a heterogeneous group. Children with pri- third. Urinary tract smooth muscle is affected in
mary pseudo-obstruction due to neuronal dyspla- those with both hollow visceral neuropathy and
sia may have disease that is limited to the colon hollow visceral myopathy, about one fifth of all
22 Chronic Intestinal Pseudo-Obstruction 261

Table 22.3 Clinical symptoms in children with chronic intestinal pseudo-obstruction

Study Abdominal Vomiting Constipation Failure Abdominal Diarrhea Dysphagia
distension to thrive pain
Faure et al. [1] n = 105 100 94 70 64 46 29 9
Vargas et al. [2] n = 87 73 50 51 23 NA 21 2
Granata et al. [3] n = 59 59 31 27 NA NA 26 NA
Schuffler et al. [4, 5] n = 30 23 19 20 15 NA 16 NA
Heneyke et al. [6] n = 44 31 40 31 NA NA – NA
Total n = 325 286 (88%) 234 199 (61%) 102 – 92 11 (3%)
(72%) (31%) (28%)
NA not available

pseudo-obstruction patients. Often these children Table 22.4 Differential diagnosis of CIP in children
are severely affected at birth and are described by Aerophagia
the phenotype megacystis-microcolon intestinal Gastroparesis
hypoperistalsis syndrome [2]. Functional constipation
The majority of children’s clinical course is Cyclic vomiting syndrome
characterized by relative remissions and exacer- Chronic abdominal pain with psychological dysfunction
bations. Factors that precipitate deteriorations (pain-associated disability syndrome)
include intercurrent infections, general anesthe- Bacterial overgrowth of various origins (lactase
deficiency, disaccharidase deficiency, intestinal
sia, psychological stress, and poor nutritional
duplication)
status. Aerodigestive fistula
The radiographic signs are those of intestinal Pediatric illness falsification (Munchausen-by-proxy
obstruction, with air-fluid levels, dilated stom- syndrome, fabricated or induced illness imposed on a child)
ach, small intestine, and colon, or microcolon in
those studied because of obstruction at birth [6].
There may be prolonged stasis of contrast mate- [67]. Well-meaning clinicians inadvertently
rial placed into the affected bowel, so it is pru- cocreate disease as they respond to a caretaker’s
dent to use a nontoxic, isotonic, water-soluble symptom fabrications by performing tests and
medium to prevent barium from solidifying. procedures, including parenteral nutrition sup-
Children who feel well still show radiographic port, repeated surgery, and even small bowel
evidence of bowel obstruction. The greater prob- transplantation [68]. Adolescents with disabling
lem arises when children develop an acute dete- abdominal pain arising from psychiatric diseases
rioration. Radiographs demonstrate the same such as pain disorder, posttraumatic stress disor-
patterns of bowel obstruction that are seen when der, and Asperger’s syndrome may also confuse
the child feels well. In children who previously gastroenterologists [69]. A differential diagnosis
had surgery, it can be difficult to discriminate for CIPO is provided in Table 22.4.
between physical obstruction related to adhesions Diagnostic testing provides information about
and an episodic increase in CIPO symptoms. the nature and severity of the pathophysiology.
Manometric studies are more sensitive than
radiographic tests to evaluate the strength and
Diagnosis coordination of contraction and relaxation in the
esophagus, gastric antrum, small intestine, colon,
An incorrect CIPO label can result from misdiag- and anorectal area.
nosis of infant and toddler victims of pediatric In affected children scintigraphy demonstrates
illness falsification, known in the United Kingdom delayed gastric emptying of solids or liquids and
as Fabricated or Induced Illness, formerly reflux of intestinal contents back into the stom-
known as Münchausen’s syndrome by proxy ach. Dilated loops of bowel predispose to bacterial
262 P.E. Hyman and N. Thapar

overgrowth, so breath hydrogen testing may Table 22.5 Antroduodenal manometric features from
reveal elevations in fasting breath hydrogen and a studies of 300 children
rapid increase in breath hydrogen with a carbohy- Normal features
drate meal. Migrating motor complex (MMC) (fasting)
Esophageal manometry is abnormal in about Postprandial (phase 2-like) pattern
Abnormal features in duodenum
half those affected by CIPO. In children with Absent MMC phase 3
myopathy, contractions are low amplitude but Sustained tonic contractions
coordinated in the distal two-thirds of the esopha- Retrograde propagation of phase 3
gus. Lower esophageal sphincter pressure is low, Giant single-propagating contractions
Absent phase 2 with increased phase 3 frequency
and sphincter relaxation is complete. When the Persistently low-amplitude or absent contractions
esophagus is affected by neuropathy, contraction Prolonged nonpropagating clusters
amplitude in the esophageal body may be high, Postprandial abnormalities
normal, low, or absent. There may be simultane- Antral hypomotility after a solid nutrient meal
ous, spontaneous, or repetitive contractions Absent or decreased motility
Failure to induce a fed pattern (MMC persists)
[70, 71]. Relaxation of the lower esophageal
a
Each of these features is recognized by visual inspection
sphincter may be incomplete or absent.
of the recording. From Tomomasa T, DiLorenzo C,
Antroduodenal manometry findings are always Morikawa A, et al. Analysis of fasting antroduodenal
abnormal with intestinal pseudo-obstruction manometry in children. Dig Dis Sci. 1996;41:195–203.
involving the upper gastrointestinal tract; how-
ever, manometry is often also abnormal in partial
or complete small bowel obstruction. Although never organized into migrating motor complexes
the manometric patterns of true obstruction differ (MMCs), fed patterns, or even bursts or clusters
from those of CIPO in adults [72, 73], such a dis- of contractions but are simply a monotonous pat-
tinction is not always clear. Contrast radiography tern of random events. Children with such a pat-
and, as a last resort, exploratory laparotomy are tern are dependent on total parenteral nutrition
best for differentiating true obstruction from (TPN). More than 80% of children with MMCs
pseudo-obstruction. Antroduodenal manometry are nourished enterally, but more than 80% of
should not be used as a test to differentiate true children without MMCs require partial or total
bowel obstruction from pseudo-obstruction. parenteral nutrition [75].
Manometry may help to determine the physio- Normal antroduodenal manometry and
logic correlates for the symptoms, to assess drug absence of dilated bowel in a patient with CIPO
responses, and for prognosis [70, 74–76]. symptoms shifts the emphasis from medical to
Intestinal myopathy causes low-amplitude coor- psychological illness [78]. It is often difficult for
dinated contractions, and neuropathy causes families to consider and engage in psychological
uncoordinated contractions [77]. Pain with each intervention, especially when the decision is
high-amplitude antral contraction suggests gas- based on a “lack of medical findings.” Thus it is
tric hyperalgesia. Interpretation of antroduodenal important to interpret the antroduodenal manom-
manometry requires recognition of normal and etry as a positive prognostic indicator, especially
abnormal features (Table 22.5). when the results are normal.
The abnormalities in pseudo-obstruction are Colon manometry is abnormal in colonic
commonly discrete and easily interpreted by eye pseudo-obstruction [79]. The normal features of
(see Chap. 9). They contrast markedly with nor- colon manometry in children include (1) high-
mal features of antroduodenal manometry. amplitude propagating contractions (phasic con-
In most cases the manometric abnormality tractions stronger than 60 mmHg amplitude)
correlates with clinical severity of the disease. propagating over at least 30 cm; (2) a gastrocolic
For example, children with total aganglionosis response (the increase in motility that follows a
have contractions of normal amplitude that are meal); and (3) an absence of discrete abnormalities.
22 Chronic Intestinal Pseudo-Obstruction 263

With neuropathic disease contractions are normal nutrition (TPN). One third require total or partial
or reduced in amplitude, but there are no high- tube feedings, and the rest eat by mouth. In those
amplitude propagating contractions or gastro- with intestinal neuropathies about 30% need
colic response. With myopathy there are usually TPN. In those with enteric myopathies over 70%
no colonic contractions (see Chap. 10). need TPN. TPN is the least desirable means of
There are several pitfalls with intestinal and achieving nutritional sufficiency because of the
colonic manometry. In dilated bowel no con- potential for life-threatening complications. In
tractions are recorded and manometry is not the absence of enteral nutrients, the gastrointesti-
diagnostic. Recordings filled with respiratory nal tract does not grow or mature normally. In the
and movement artifacts from agitated, angry, absence of the postprandial rise in trophic and
crying patients are uninterpretable. Acute stimulant gastrointestinal hormones, bile stasis
pseudo-obstruction is usually associated with and liver disease develop [81]. TPN-associated
ileus, so that an absence of contractions may not cholelithiasis [82] and progressive liver disease
reflect the underlying abnormality. Manometry are important causes of morbidity and mortality
is most likely to be helpful when performed in a in children with pseudo-obstruction. The mini-
cooperative patient at a time when the patient is mal volume, composition, and route of enteral
feeling well. Anorectal manometry is usually support required to reverse or prevent the pro-
normal in CIPO. There is an absence of the rec- gression of gastrointestinal complications have
toinhibitory reflex only in Hirschsprung’s dis- not been determined. It seems likely that a com-
ease and in some patients with intestinal plex liquid formula containing protein and fat,
neuronal dysplasia. In a few specialized centers, given by mouth or gastrostomy tube, and contrib-
electrogastrography is a noninvasive screening uting 10–25% of the child’s total calorie require-
test for evaluation of children thought to have ment would be sufficient to stimulate postprandial
CIPO [80]. Skin electrodes are placed over the increases in splanchnic blood flow and plasma
stomach, just as surface electrodes are placed concentrations of gastrin and other trophic fac-
over the heart to perform electrocardiography. tors. Every effort should be extended to maximize
The electrical slow-wave rhythms of the gastric enteral nutritional support in parenteral nutrition-
body and antrum are recorded. Gastric slow dependent children.
waves normally occur at a rate of 3 per minute. Continuous feeding via gastrostomy or
Gastric neuropathies are characterized by jejunostomy may be effective when bolus feed-
decreases (bradygastria) or increases (tachygas- ings fail. Most children with visceral myopathy
tria) in slow-wave frequency. Gastric myopa- and a few with neuropathy have an atonic stom-
thies are characterized by reduced power, a ach and almost no gastric emptying. In these chil-
measure of signal amplitude. dren, a feeding jejunostomy may be helpful for
the administration of medications and for drip
feedings [83]. Care must be taken to place a
Treatment jejunostomy into an undistended bowel loop.

Nutrition Support
Drugs
The goal of nutrition support is to achieve normal
growth and development with the fewest possible Drugs to stimulate intestinal contractions are
complications and the greatest patient comfort. In helpful in a minority of children with CIPO.
children with CIPO, motility improves as nutri- Bethanechol, neostigmine, metoclopramide, and
tional deficiencies resolve and worsens as malnu- domperidone have not been useful. Perhaps the
trition recurs. best documented benefit of pharmacoptherapy
Roughly a third of affected children require for CIPO has come from serotonergic drugs. The
prolonged periods of partial or total parenteral combined 5HT4 agonist and 5HT3 antagonist
264 P.E. Hyman and N. Thapar

cisapride’s mechanism of action is to bind to steatorrhea, fat-soluble vitamin malabsorption,

serotonin receptors on the motor nerves of the and malabsorption of the intrinsic factor—vitamin
myenteric plexus, facilitating release of acetyl- B12 complex. It is possible that bacterial over-
choline and stimulating gastrointestinal smooth growth contributes to bacteremia and frequent
muscle contraction. It appeared most likely to episodes of central venous catheter-related sepsis
improve symptoms in children with MMCs and and to TPN-associated liver disease. Bacterial
without dilated bowel [84] and acted by increas- overgrowth, mucosal injury, malabsorption, fluid
ing the number and strength of contractions in secretion, and gas production may contribute to
the duodenum of children with CIPO. It did not chronic intestinal dilatation, which may further
initiate the MMC in patients without it or inhibit impair motility. Chronic antibiotic use may result
discrete abnormalities. Cisapride was withdrawn in the emergence of resistant strains of bacteria or
from the commercial marketplace in much of overgrowth with fungi. Thus, treating bacterial
the world in the early 2000s because of concerns overgrowth must be considered on an individual
related to rare fatal cardiac arrhythmias. In the basis.
USA today cisapride is available at no cost to Excessive gastrostomy drainage may result
individual patients after successful application from retrograde flow of intestinal contents into
to the Federal Drug Administration for an the stomach or from gastric acid hypersecretion.
Investigational New Drug application, and Gastric secretory function or gastric pH should
approval by a local Human Subjects Committee. be tested before beginning antisecretory drugs.
The pure 5HT4 agonist tegaserod held similar Histamine H2-receptor antagonists may be used
promise for CIPO, but was also withdrawn for to suppress gastric acid hypersecretion. Tolerance
cardiovascular concerns similar to those about develops after a few months of intravenous use
cisapride. Newer serotonergic agents are being [89], so the drug should be given orally when
tested but their effect in CIPO is not yet studied. possible. When a drug is added to TPN, gastric
Erythromycin, a motilin receptor agonist, pH should be assessed at regular intervals to
appears to facilitate gastric emptying in those monitor drug efficacy. Induction of achlorhydria
with neuropathic gastroparesis by stimulating is inadvisable because it promotes bacterial over-
high-amplitude 3-min antral contractions, relax- growth in the stomach.
ing the pylorus, and inducing antral phase 3 epi- Constipation is treated initially with oral poly-
sodes in doses of 1–3 mg/kg intravenously [85] ethylene glycol solutions, suppositories, or ene-
or 3–5 mg/kg orally. Erythromycin does not mas. Oral lavage solutions often cause abdominal
appear to be effective for more generalized motil- distention because of delayed small bowel transit
ity disorders [85], is ineffective for stimulating in children with pseudo-obstruction. For consti-
colonic contractility [86]. pation and small bowel disease, cecostomy or
Octreotide, a somatostatin analogue, given appendicostomy may simplify management by
subcutaneously, induces small intestinal phase bypassing the small bowel [90]. If colon manom-
3-like clustered contractions and suppresses etry shows no colon contractions, the most
phase 2 [87]. However, the clusters may not efficient course is ileostomy and colon resection.
propagate, or may propagate in either direction An ileostomy takes the resistance of the anal
and intestinal transit and nutrient absorption sphincter out of the system, and facilitates flow
are optimal during phase 2. Augmentin, a combi- of chyme from the higher pressures from gastric
nation of amoxacillin and clavulinate, increases contractions to the absence of pressure at the
contractions in the small bowel [88]. Augmentin stoma.
may be useful in selected CIPO cases to Acute pain due to episodes of pseudo-obstruction
increase the contractions and treat bacterial is best treated by decompressing distended bowel.
overgrowth. Opioids are rarely needed if the bowel is promptly
Antibiotics are used for bacterial over- decompressed. It is appropriate to consider non-
growth. Bacterial overgrowth is associated with steroidal anti-inflammatory agents (e.g., ketorolac)
22 Chronic Intestinal Pseudo-Obstruction 265

and epidural anesthetics as alternatives to, or in time there is a new obstructive episode: (3)
combination with, systemic opioids. Adhesions following laparotomy may distort nor-
Chronic pain can be a problem in children mal tissue planes and make future surgery riskier
with congenital pseudo-obstruction and is com- in terms of bleeding and organ perforation. After
mon in adolescents who have autoimmune or several laparotomies turn up no evidence of
inflammatory disease and progressive loss of mechanical obstruction, the surgeon may choose a
intestinal function. Pain consists of a nociceptive more conservative management plan for subse-
component and an affective component. Patients quent episodes, including pain management, nutri-
with chronic pain benefit from a multidisciplinary tional support, and abdominal decompression.
approach including not only attention to gastroin- Gastrostomy was the only procedure that
testinal disease but also mental health assessment reduced the number of hospitalizations in adults
and treatment for the affective pain component. with pseudo-obstruction [95], and the experience
Collaboration with pain management specialists with children seems to be similar [96].
is beneficial for optimizing the care of pseudo- Gastrostomy provides a quick and comfortable
obstruction patients who complain of chronic means of evacuating gastric contents and relieves
pain. Multiple modalities for pain relief are use- pain and nausea related to gastric and bowel dis-
ful: cognitive behavioral therapy, massage, relax- tention. Continued “venting” may decompress
ation, hypnosis, psychotherapy, yoga, and drugs more distal regions of small bowel, precluding
all have shown positive effects. Drugs that reduce nasogastric intubation and pain medication.
afferent signaling, improving chronic visceral Gastrostomy is used for enteral feeding and
pain, include the tricyclic antidepressants, cloni- enteral administration of medication. Gastrostomy
dine, and gabapentin [91]. Opioid use is inadvis- placement should be considered for those receiv-
able, because opioids disorganize intestinal ing parenteral nutrition and for children who will
motility, tolerance to opioids develops rapidly, need tube feedings longer than 2 months. In many
and opioid withdrawal can simulate the visceral patients, endoscopic gastrostomy placement is
pain of acute pseudo-obstruction. ideal. In those with contraindications to endo-
Sympathetic plexus neurolysis, by interrupt- scopic placement, surgical placement is appro-
ing sympathetic efferent (and inhibitory) activity priate. Care must be taken to place the ostomy in
on upper digestive tract, improved symptoms in a suitable position, above the gastric antrum in
CIPO patients [92–94]. the midbody.
Fundoplication is rarely indicated for pseudo-
obstruction. After fundoplication, symptoms
Surgery change from vomiting to repeated retching [97].
In children with pseudo-obstruction, vomiting is
One of the management challenges in pseudo- reduced by venting the gastrostomy. Acid reflux
obstruction is the evaluation and reevaluation of is controlled with antisecretory medication.
newborns and children with episodic acute obstruc- Results of pyloroplasty or Roux-en-Y gas-
tive symptoms. Although most acute episodes rep- trojejunostomy to improve gastric emptying in
resent pseudo-obstruction, it is important to pseudo-obstruction have been poor; gastric emp-
intervene with surgery when the episode is a true tying remains delayed. Altering the anatomy
bowel obstruction, appendicitis, or another surgi- rarely improves the function of the dilated fundus
cal condition. Many children with episodes of and body. Small bowel resections or tapering
acute pseudo-obstruction undergo repeated explor- operations may provide relief for months or even
atory laparotomies. It is important to avoid unnec- years; however, when the lesion is present in
essary abdominal surgery in children with other areas of bowel those areas gradually dilate
pseudo-obstruction for several reasons: (1) They and symptoms recur.
often suffer from prolonged postoperative ileus: Ileostomy can decompress dilated distal small
(2) Adhesions create a diagnostic problem each bowel and provide further benefit by removing
266 P.E. Hyman and N. Thapar

from the circuit the high-pressure zones at the pseudo-obstruction. The abdomen distends, but
end of the bowel namely the colon and the anal the colon does not empty.
sphincter. Transit of luminal contents is always There is increasing experience with the pace-
from a high-pressure zone to a lower-pressure makers in gut motility disorders although the expe-
one. In pseudo-obstruction patients with gastric rience is limited to gastroparesis, not CIPO [100].
antral contractions but no effective small bowel Failed medical management may signal a
contractions, bowel transit improves with the cre- need for total bowel resection. Rarely, a
ation of an ileostomy because of the absence of mucosal secretory disorder complicates the
resistance to flow at the ostomy site. management of pseudo-obstruction. Several
Colectomy is sometimes necessary in severe liters of intestinal secretions drain from enteric
congenital pseudo-obstruction to decompress an orifices each day. When secretions cannot be
abdomen so distended that respiration is controlled with loperamide, anticholinergics,
impaired. In general, colon diversions are inad- antibiotics, steroids, or somatostatin analogue,
visable because of a high incidence of diversion it may be necessary to resect the entire bowel
colitis [98]. Diversion colitis can cause abdomi- to avoid life-threatening electrolyte abnormali-
nal pain, tenesmus, hematochezia and may ties and nutritional disturbances caused by the
worsen motility of the proximal intestine as large volume losses. Total bowel resection may
chemical by-products of inflammation circulate reduce episodes of bacterial transmigration
to vulnerable tissues. across dilated bowel to eliminate repeated life-
Subtotal colectomy with ileoproctostomy threatening central venous catheter infections
cures rare children with neuropathic pseudo- [101]. Total bowel resection should be consid-
obstruction confined to the colon. Typically these ered alone or in combination with small bowel
children are able to eat normally and grow, but transplantation. Small bowel or combined liv-
they are unable to defecate spontaneously. They er–bowel transplants have the potential to cure
differ from children with functional constipation children with pseudo-obstruction. Transplant
in that their stools are never huge or hard, there is results in CIPO children are similar to results
no retentive posturing, the history of constipation in children undergoing transplantation for short
begins at birth, and there are often extrarectal bowel syndrome or intractable diarrhea [102].
fecal masses. Colon pathology may show neu- (See also Chap. 46.)
ronal dysplasia, maturational arrest, or no diag-
nostic abnormality, but colon manometry is
always abnormal, without high-amplitude propa- Outcomes
gating contractions or a postprandial rise in motil-
ity index. Before colectomy for constipation, The prognosis of children with CIPO remains
antroduodenal manometry may be necessary to guarded, with risk of mortality as high as 30%
determine whether the upper gastrointestinal tract in the first year of life. Complications of paren-
is involved. Abnormal antroduodenal manometry teral nutrition are the cause of death in a major-
is a relative contraindication to colectomy because ity of children [103, 104]. Thus, TPN is life
upper gastrointestinal symptoms appear after saving, but measures to avoid TPN and, once
colon resection [99]. Before surgery, a psycho- started, to discontinue TPN are appropriate.
logical evaluation may help to assess the possi- Children with lower socioeconomic status tend
bility of psychiatric disease and somatization to be on TPN longer than children from high
masquerading as colon disease and to prepare the socioeconomic status, suggesting that those
patient for the procedures. with better health care access are aggressively
A cecostomy using a small “button” ostomy moved away from parenteral nutrition [103].
appliance for regular infusion of colonic lavage The quality of life for surviving children with
solution has not been effective for severe colonic pseudo-obstruction and their families is
22 Chronic Intestinal Pseudo-Obstruction 267

reduced compared to others with chronic dis- 9. Golzarian J, Scott Jr HW, Richards WO.
ease [103]. The factors responsible for reduced Hypermagnesemia-induced paralytic ileus. Dig Dis
Sci. 1994;39:1138–42.
quality of life in CIP were chronic pain and the 10. Weaver LT, Rosenthal SR, Gladstone W, et al.
caretaker’s time commitment for participating Carnitine deficiency: a possible cause of gastrointes-
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96. Michaud L, Guimber D, Carpentier B, Sfeir R, come of congenital intestinal pseudo-obstruction.
Lambilliotte A, Mazingue F, Gottrand F, Turck D. Dig Dis Sci. 2002;47:2298–305.
Gastrostomy as a decompression technique in chil- 104. Schwankovsky L, Mousa H, Rowhani A, et al. Quality
dren with chronic gastrointestinal obstruction. of life outcomes in congenital chronic intestinal pseu-
J Pediatr Gastroenterol Nutr. 2001;32:82–5. do-obstruction. Dig Dis Sci. 2002;47:1965–8.
 Hirschsprung Disease
23
Robert O. Heuckeroth

There are many excellent articles on Hirschsprung aganglionosis) in the myenteric and submucosal
disease (HSCR) that provide detailed information plexus of the distal bowel. In the absence of gan-
about the clinical presentation, epidemiology, genet- glion cells, the bowel tonically contracts causing
ics, diagnosis, and associated medical problems a functional intestinal obstruction. Many, but not
[1–9]. This chapter summarizes and simplifies the all, clinical manifestations of HSCR result from
complex HSCR literature. Percentages in the text the tonic contraction of aganglionic bowel.
and tables are estimates, since widely divergent Nomenclature describing the extent of agangli-
numbers are presented in different manuscripts. onosis in HSCR is not consistent. However, most
The enteric nervous system (ENS) is an inte- affected individuals have “short segment” disease
grated network of neurons and glia that controls where aganglionosis is restricted to the rectosig-
most aspects of intestinal function. This includes moid region of the colon [7, 8, 10]. “Long-
intestinal motility, response to luminal and intra- segment” HSCR aganglionosis extends proximal
mural stimuli, regulation of epithelial activity to the sigmoid colon and is usually distinguished
and control of blood flow. To perform these tasks, from “total colonic” aganglionosis. In a small per-
neurons are distributed along the entire length of centage of cases, aganglionosis extends into the
the bowel in a well-ordered and finely regulated small bowel leading to very serious life-long dis-
manner. When the ENS is absent or defective in ability often requiring total parenteral nutrition
any region of the bowel, profound problems with (Table 23.1) [7, 8]. Although some authors have
intestinal function occur causing significant mor- suggested that clinical presentation varies with the
bidity and in some cases death. length of aganglionosis [4], others claim that clini-
cal symptoms are not related to the extent of dis-
ease [1]. From a practical standpoint, it is best to
Introduction assume that the extent of aganglionosis and the
severity and character of symptoms are unrelated.
Hirschsprung disease, the most well understood
intestinal motility disorder, is characterized by
the complete absence of enteric neurons (i.e., Clinical Presentation

R.O. Heuckeroth, M.D., Ph.D. (*) HSCR is debilitating and can be fatal. Clinical pre-
Department of Pediatrics, Division of Gastroenterology, sentation is highly variable and diagnosis requires
Hepatology, and Nutrition, Washington University School a high index of suspicion (Table 23.2). Recognizing
of Medicine, 660 South Euclid Avenue, Campus Box
8208, St. Louis, MO 63110, USA HSCR is important since surgical management
e-mail: [email protected] dramatically reduces disease morbidity and mortality.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 271

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_23, © Springer Science+Business Media New York 2013
272 R.O. Heuckeroth

Table 23.1 Extent of aganglionosis “gastroenteritis” that were actually a mani-

Short segment 74–89% festation of HSCR associated intestinal
Long segment 12–22% obstruction. A key clinical distinction is that
Total colon 4–13% gastroenteritis may cause severe vomiting, but
Small bowel 3–5% does not typically cause as much abdominal
Adapted from Haricharan and Georgeson [8] distension as HSCR. Vomiting associated with
infectious enteritis is also usually followed by
Table 23.2 Presenting symptoms in HSCR diarrhea, whereas intestinal obstruction should
Symptom Comment be accompanied by reduced stool passage.
Abdominal distension Very Common in HSCR or A distended abdomen occurs in 57–93% of
anatomic bowel obstruction infants with Hirschsprung disease and bilious
Bilious emesis Common and suggests HSCR emesis occurs in 19–37% [1, 8, 17–19].
or anatomic defects 2. Neonatal bowel perforation
Constipation Common in older children with HSCR presents with bowel perforation about
HSCR but also in healthy
toddlers and infants
5% of the time [20, 21] and HSCR causes about
Diarrhea Foul smelling, bloody or 10% of all neonatal bowel perforations [22].
“explosive” diarrhea suggests Symptoms may not be specific and include
enterocolitis (HAEC) poor feeding, emesis, abdominal distension,
Delayed Meconium Common in HSCR, but many constipation, diarrhea, and lethargy. In two
infants with HSCR do not have
series with 55 cases reported [20, 21] only one
delayed passage of meconium
Bowel perforation Should raise concern for HSCR
child was more than 2 months old. The major-
ity of the perforations were in the cecum or
ascending colon and 15% were in the appendix.
In the current era, most people with HSCR are Many of the children with bowel perforation
diagnosed by 6 months of age [11–13], but it is not had long-segment disease (34% total colonic
unusual to diagnose HSCR in older children and aganglionosis, with an additional 23% having
HSCR has been diagnosed in adults up to 73 years aganglionosis proximal to the splenic flexure).
of age [14]. HSCR needs to be considered in any- Since long-segment HSCR is less common
one with severe chronic constipation that began in than short segment disease (see Table 23.1),
early infancy, especially if suppositories or enemas proximal colon perforation in a young infant
are needed for stool passage. However, because should dramatically raise concern for long-segment
constipation is common, affecting up to 35% of all HSCR. In 55% of reported cases, the perforation
children [15, 16], and HSCR is rare (1/5,000 peo- was proximal to the transition zone and occurred
ple), recognizing distinct features that suggest in ganglion cell containing bowel. In 13% the
HSCR is important for diagnosis. Furthermore, perforation was at the transition zone. In 30%,
constipation is only one feature of HSCR. Typical however, the perforation occurred in aganglionic
presentations for HSCR include: bowel distal to the transition zone.
1. Neonatal intestinal obstruction 3. Delayed passage of meconium
Infants present with marked abdominal dis- Delayed passage of meconium should suggest
tension and bilious emesis. Distension may be the diagnosis of HSCR, but defining HSCR risk
severe enough to cause respiratory compro- in infants with delayed passage of meconium is
mise. Obstruction may occur on the first day challenging because the timing of meconium
of life, but children may also initially have passage reported for healthy infants is variable.
apparently normal bowel movements or “mild In a study of 979 infants older than 34 weeks
constipation” and then present acutely with gestational age in the United States, 97% passed
abdominal distension and vomiting at an older meconium by 24 h of life, and 99.8% passed
age. Because HSCR requires a high index of meconium by 36 h of life [23]. Breast feeding or
suspicion for diagnosis, some infants are hos- bottle feeding did not influence the timing of the
pitalized repeatedly for episodes of presumed first bowel movement and multivariate analysis
23 Hirschsprung Disease 273

demonstrated that only prematurity was a also appears to be an uncommon presentation

significant predictor of delayed passage of of HSCR in infants. In particular, the wide
meconium. A similar study in Turkey [24] also range of normal bowel movement frequency in
demonstrated that 724/743 (97%) passed meco- healthy infants makes it difficult to use consti-
nium by 24 h after birth and 740/743 (99.6%) pation as the only indication to evaluate for
passed meconium by the time that they were HSCR. In a study of 911 healthy children in
48 h old. However, a smaller study in the Turkey (Tunc 2008) between 2 and 12 months
Netherlands, reported only 56/71 (79%) of term of age, mean stool frequency was once a day,
infants passed meconium by 24 h after birth but at 2 months of age stool frequency varied
[25] and in a study of 267 healthy infants in from once a week to eight times per day.
Nigeria, only 92% passed their first bowel 5. Abdominal distension relieved by rectal
movement by 48 h after birth [26]. In the stimulation or enema
Nigerian study, 5% of the infants were preterm, In children with HSCR, rectal exam or other
but even if the preterm infants are excluded, the forms of rectal stimulation may cause a sud-
data suggest that at most 97% of the healthy full den “explosive” release of intraluminal con-
term infants studied passed their first bowel tents and relieve abdominal distension. This is
movement by the time they were 48 h old. uncommon in other conditions and should
Excluding premature infants from the analysis raise concern about HSCR. Rectal exam is,
is important since prematurity predisposes to however, not otherwise useful in identifying
delayed passage of meconium. A study of 611 children with HSCR. In particular, “anal tone”
infants reported that only 57% of infants less is not a reliable indicator of disease.
than 29 weeks EGA, 66% of infants between 29 6. Enterocolitis
and 32 weeks EGA, and 80% of infants between Defining when children have enterocolitis
32 and 37 weeks EGA [27] passed meconium presents its own challenges (see below for
by the end of their “second calendar day” and symptoms), but enterocolitis is a dangerous
1% of premature infants did not pass meconium and common presentation for HSCR. When
until after day of life 9. In children with enterocolitis occurs, children with HSCR have
Hirschsprung disease, delayed passage of meco- diarrhea instead of constipation.
nium is much more common than in healthy
infants. Nonetheless, up to 50% of children with
HSCR pass meconium by 48 h after birth [17, Who Should be Biopsied to Evaluate
28, 29], so passage of meconium within 48 h of for Hirschsprung Disease?
birth does not exclude a diagnosis of HSCR.
4. Chronic severe constipation Rectal biopsy is the “gold standard” diagnostic
HSCR causes constipation, but constipation test for HSCR (see below). Unless another diag-
unrelated to HSCR is very common and HSCR nosis is evident, children with the following clini-
is rare, so constipation alone usually does not cal presentations should undergo rectal biopsy to
indicate HSCR. “Severe” constipation and con- evaluate for Hirschsprung disease:
stipation beginning within the first few months 1. Neonates with significant abdominal disten-
of life does increase concern for HSCR and the sion, especially in combination with bilious
likelihood of disease. For example, in one study, vomiting or delayed passage of meconium.
rectal biopsy was performed on all children 2. Neonates with bowel perforation.
over a year of age who were referred to a spe- Also consider rectal biopsy for Hirschsprung
cialty center for consultation and who had con- disease in children with:
stipation refractory to more than 6 months of 1. Neonatal bloody diarrhea. Given the low inci-
medical management. 19 out of 395 biopsies dence of infectious enteritis in breast fed or
demonstrated HSCR (5%), a 250-fold increased formula fed neonates, bloody diarrhea in neo-
risk compared to the population prevalence of nates is concerning for HSCR associated
HSCR (1/5,000) [30]. Constipation in isolation enterocolitis (see below).
274 R.O. Heuckeroth

2. Healthy appearing full term infants with high morbidity and mortality in untreated HSCR,
delayed passage of meconium even in the evaluation for HSCR should be performed in
absence of other symptoms. Since Hirschsprung many children who do not end up having this dis-
disease occurs in 1:5,000 infants, but delayed ease to avoid missing this potentially life threaten-
passage of meconium for more than 48 h after ing medical problem.
birth probably happens in at least 1:1,000
healthy infants, most children (i.e., >80%) who
have delayed passage of meconium for 48 h Diagnostic Strategies
will not have HSCR, but the risk of HSCR is
probably 5–20%. Given the risks associated HSCR by definition means that affected individuals
with untreated HSCR, I usually recommend do not have ganglion cells in the distal bowel. Rectal
biopsy in this setting. Assuming that 97% of biopsy is therefore required to make the diagnosis
healthy full term infants pass meconium by and is considered the “gold standard” approach
24 h of life, only about 1:150 children with pas- [31]. A number of other strategies for diagnosing
sage of meconium >24 h after birth, but <48 h HSCR are used, but each has problems.
after birth will have HSCR. The value of rectal 1. Rectal suction biopsy
biopsy in this setting is more questionable, This is a simple procedure taking only a few
unless other symptoms of HSCR are present. minutes using an instrument designed to take
3. Young children with constipation refractory small pieces of the rectal mucosa (e.g., Noblett
to oral medication. Constipation beginning or rbi2 instrument) to reduce the risk of bowel
after a year of age is rarely due to HSCR. perforation or hemorrhage [32]. Because there
Constipation that improves dramatically with are no sensory nerve endings that respond to cut-
oral medication is also unlikely to be due to ting in the area of the rectum where the biopsies
HSCR. Remember too that the common form are obtained, sedation and pain medicines are
of functional constipation that occurs in tod- not required, but sedation is sometimes used in
dlers may be challenging to treat, so it can be older children. Biopsies should be obtained at
challenging to know if toddlers are truly 2–3 cm from the dentate line (i.e., the transition
“refractory to oral medication.” between rectal and squamous mucosa) because
Red Flags (conditions that should raise suspicion there is a physiological submucosal agangliono-
for HSCR): sis in the terminal rectum. From a practical
1. Constipation with episodes of abdominal dis- standpoint, however, some authors advocate
tension or vomiting. Constipation does not obtaining biopsies at multiple levels (e.g., 1, 2,
cause vomiting, but many disorders cause both and 3 cm from the dentate line) because precise
vomiting and reduced bowel movement fre- positioning of the biopsy can be difficult. Biopsy
quency including HSCR. tissues obtained are sectioned, stained and exam-
2. Growth failure. This is a common feature of ined by a pathologist to identify ganglion cells.
untreated HSCR. There is some controversy about the optimal
3. Trisomy 21. HSCR occurs in 1:100 children staining method, but hematoxylin and eosin and
with Down syndrome so HSCR should be more acetylcholinesterase are commonly used tech-
readily suspected in children with trisomy 21. niques [31, 32]. A meta-analysis analyzing data
4. The presence of additional anomalies also from 993 patients indicated that the mean sensi-
increases the likelihood of HSCR, but remem- tivity of rectal suction biopsy for HSCR is 93%,
ber that most children with HSCR do not have and the mean specificity is 98% [33]. A more
other medical problems. recent manuscript documents 935 cases of
Given the diverse presenting symptoms of HSCR diagnosed by rectal mucosal biopsy (a
HSCR, it remains difficult to decide who to evalu- total of 19,365 biopsies in 6,615 children) with
ate. The more “classic” features of HSCR present, no false positive or false negative diagnoses (i.e.,
the more likely the child has HSCR. Given the 100% sensitivity and specificity) [34]. Serious
23 Hirschsprung Disease 275

bleeding and bowel perforation are uncommon 4. Full thickness rectal biopsy
with rectal suction biopsy, but can occur. One Deeper biopsies can be performed by a sur-
series of 1,340 biopsies [35] reported three bowel geon under general anesthesia if the diagnosis
perforations (0.2%), one death (0.07%), and remains uncertain after rectal suction biopsy.
three rectal hemorrhage (0.2%) requiring blood
transfusion. More recent studies also document
low but non-zero rates of serious bleeding or Epidemiology/Genetics Overview
bowel perforation (no complications in 297 chil-
dren [36]; no complications in 88 infants [37]; HSCR is a multigenic disorder that affects approxi-
and 2 episodes of bleeding requiring transfusion mately 1/5,000 infants. At least 10 specific gene
(0.7%) plus one episode of rectal perforation and defects are associated with HSCR. For short seg-
sepsis (0.035%) in 272 children [38]). The most ment disease there is an approximately 4:1 male to
common problem with rectal suction biopsies, female ratio, but for total colonic aganglionosis, the
however, is that they are so small that they are male to female ratio is near 2:1. HSCR has been
“inadequate” 6–26% of the time requiring repeat reported throughout the world in many ethnic
biopsy to make a diagnosis [36, 38, 39]. groups. There are geographic and racial differences
2. Anorectal manometry described in HSCR incidence, but these data are
This method tests for the rectoanal inhibition difficult to evaluate. Most reports have not been rep-
reflex using a small balloon attached to a tube licated over extended time periods and the difficulty
inserted into the rectum [33]. This reflex is absent in HSCR diagnosis increases uncertainty in inter-
in children with HSCR. Sensitivity and specificity preting regional data. Furthermore, it is often not
of anorectal manometry are 91 and 94% respec- possible to determine from large-scale epidemio-
tively, but this test is not required to diagnose logical studies the number of affected individuals
HSCR [33]. Furthermore, the equipment needed who share mutations by common descent, so data
to do this test is expensive, patient cooperation is may be skewed by families with multiple affected
needed, and significant experience is needed to members, such as has been described in some
evaluate results in infants less than a year of age, Mennonite communities [40]. HSCR incidence per
so the test is not widely available. 10,000 live births in California were reported as 1.0,
3. Contrast enema 1.5, 2.1, and 2.8 for Hispanics, Caucasian-
This is a radiology test where images are obtained Americans, African-Americans and Asians respec-
as contrast is infused into the colon via the anal tively [41]. HSCR incidence was reported as 1.4 per
canal to look for evidence of the distal bowel con- 10,000 in Denmark, 1.8–2.1 per 10,000 in Japan
traction that occurs in areas of aganglionosis. The [7], and 2.3 per 10,000 in British Columbia [42].
change in bowel caliber between contracted dis- Considerably higher rates of HSCR are reported in
tal aganglionic bowel and more dilated ganglion some small geographic areas or ethnic groups. For
cell containing bowel is called the “transition example, HSCR incidence is 2.9 per 10,000 in
zone” and suggests HSCR. Although contrast Tasmania [43], 5.6 per 10,000 for native Alaskans
enema may have value in planning the surgical [44], 7.3 per 10,000 in Pohnpei State in the Federated
approach to HSCR, the radiographic and ana- States of Micronesia [45], and 5.6 per 10,000 in
tomic transition from aganglionic to ganglion cell Oman [46]. In Oman, rates of consanguinity are
containing bowel may not be in the same loca- reported to be high (75% first or second cousins).
tion. It should also be noted that in total colonic Founder effects within populations, nutritional fac-
HSCR there is no colon transition zone. tors, or environmental toxins may also account for
Furthermore, the sensitivity (70%) and specificity these differences in HSCR incidence.
(50–80%) are considerably lower using contrast Recurrence risk for siblings of children with
enema for HSCR diagnosis than other methods HSCR is dramatically elevated compared to the
[19, 33]. The role of contrast enema in HSCR general population, but HSCR is a non-Mende-
diagnosis therefore remains a matter of debate. lian disease and risk varies from 1:3 to 1:100
276 R.O. Heuckeroth

[6, 47], depending on the sex of the proband and unknown until the first successful surgical
the extent of aganglionosis. Because female sex approach was described in 1948 [52]. There are
protects against HSCR and because long-segment many modifications of the original pull-through
disease implies more serious genetic risk than surgery, but the most common procedures today
short segment disease, male siblings of females are the Swenson, Duhamel, and Soave endo-
with long-segment HSCR have a 33% chance of rectal techniques with modification of surgical
HSCR, while new sisters have only a 9% risk. approaches for total colonic HSCR [1, 2, 53].
Siblings of males with long-segment HSCR have For each of these procedures, intraoperative
a recurrence risk of 17 and 13% in new brothers biopsies are obtained to determine the extent of
and sisters respectively. For a male proband with aganglionosis. The Swenson procedure involves
short segment HSCR the risk of recurrence is 5% complete resection of the aganglionic bowel
in male siblings, but only 1% in female siblings. with reanastomosis of ganglion cell containing
For a female proband with short segment disease, bowel to a 1–2 cm rectal cuff. In the Duhamel
recurrence risk is 5 and 3% for new male and modification, ganglion cell containing bowel is
female siblings respectively. These complex epi- brought through the retrorectal space and anas-
demiologic and recurrence risk data are a direct tomosed to a segment of aganglionic rectum
reflection of the genetic underpinnings of HSCR. using a side-to-side anastomosis. In the Soave
While these “average” data are helpful in discus- procedure as modified by Boley, the rectal
sions with families, far better estimates of HSCR mucosa and submucosa are removed, the gan-
recurrence risk could theoretically be obtained glion cell containing bowel is pulled through a
using modern molecular genetic techniques. muscular cuff of distal aganglionic bowel, and
then attached within 1 cm of the anal verge.
There are innumerable studies of surgical out-
Associated Medical Problems come, but few large-scale systematic compari-
sons are available [54], so it remains unclear
HSCR is an isolated anomaly in ~70% of affected that one procedure is better than another. Over
individuals, but ~30% of children with HSCR the past decade there have been three major
have additional birth defects, including the ~12% changes in surgical management. These include
of children with HSCR who have chromosomal laparoscopic surgery, transanal surgery, and
anomalies [9, 29, 42, 48–50]. A very wide range increased use of one-step surgical procedures
of additional defects have been reported in chil- [8, 55–58]. A recent analysis of transanal versus
dren with HSCR. The most common defects are transabdominal surgery suggests that the chil-
congenital heart disease, sensory neural prob- dren who had transanal endorectal pull-through
lems, kidney and urinary tract, and skeletal anoma- procedures for HSCR had fewer complications
lies. Many different chromosomal defects have and lower rates of enterocolitis [13].
been described in people with HSCR, but trisomy
21 is by far the most common. There are also >30
genetic syndromes associated with HSCR Cost for Initial Management
(reviewed in Amiel 2008). A few HSCR associ-
ated syndromes are summarized in Table 23.3. For children with HSCR, initial hospitalization
costs average $100,000 and the hospital stay
averages almost a month [59]. Taking into account
Surgical Management HSCR incidence and birth rates, estimated costs
for initial care of children with HSCR in the
Although Harald Hirschsprung first described United States is at least $86 million/year. This
children with the disease that now bears his cost estimate does not include the expense of lost
name in 1886 [51], the pathophysiology of work time or other expenses families encounter
HSCR and management strategies remained while caring for an ill child. Estimates also do not
23 Hirschsprung Disease 277

Table 23.3 Selected HSCR associated syndromes

Syndrome name Genetic defect Comments
MEN2A = Multiple RET mutation in codons 609, ~2% of children with HSCR may have MEN2A
Endocrine Neoplasia 2A 611, 618, or 620 RET mutations; 20–30% of families with Ret 609,
611, 618, or 620 mutations have members with both
FMTC and HSCR
FMTC = Familial medullary
thyroid carcinoma
Down Syndrome Trisomy 21 1% of children with trisomy 21 have HSCR; 2–10%
of children with HSCR have Down’s
WS4 = Waardenburg WS4A = EDNRB 9% of children with HSCR have WS4
Syndrome
WS4C = SOX10 Syndrome includes HSCR, deafness and pigmentary
abnormalities
CCHS = Congenital central PHOX2B 20% of children with CCHS have HSCR; 0.5–1.5%
hypoventilation syndrome of children with HSCR have CCHS
MWS = Mowat-Wilson ZFHX1B 60% of children with MWS have HSCR; 6% of
Syndrome children with HSCR have MWS; Syndrome
includes HSCR, intellectual disability, epilepsy,
dysmorphic facial features, brain and heart defects
Goldberg-Sphrintzen KIAA1279 Syndrome includes HSCR, intellectual disability,
Megacolon Syndrome dysmorphic facial features, brain and heart defects

include the cost of ongoing care after the initial of gas and stool with rectal exam, reduced periph-
hospitalization, which in some cases may be eral perfusion, lethargy and fever. Radiographic
significant, especially in children with entero- findings include multiple air fluid levels, distended
colitis. For children with aganglionosis extending loops of bowel, sawtooth and irregular mucosal
into the small bowel, long term parenteral nutri- lining, pneumatosis and rectosigmoid cutoff sign
tion also adds dramatically to cost and disease with the absence of distal air. Laboratory findings
morbidity. Finding new ways to treat or prevent include leukocytosis and a left shift. Many of these
HSCR therefore remains desirable. features are also listed as presenting symptoms for
HSCR because HAEC is common in children with
HSCR, especially before surgery.
Enterocolitis The reason that children with HSCR develop
HAEC is not clear, but enterocolitis does not occur
Hirschsprung disease associated enterocolitis in children with “severe” functional constipation.
(HAEC) is common, can occur at any time before Possible predisposing factors for HAEC in children
or after surgery, and is the most frequent cause of with HSCR include residual partial bowel obstruc-
death in infants and children with HSCR. Death tion, defects in epithelial integrity, or abnormalities
from HAEC occurs because HSCR predisposes to in the immune system [61]. Partial obstruction may
bacterial translocation into the bloodstream that result from stricture or from intestinal dysmotility
leads to sepsis. Nonetheless, recognizing HAEC is causing increased intraluminal pressure and possi-
difficult and until recently there was no standard bly changes in gut flora. Epithelial dysfunction may
clinical definition for HAEC. In 2009 a consensus occur because enteric neurons and glia support nor-
of expert surgeons and gastroenterologists devel- mal bowel epithelial cell function and mucin pro-
oped a systematic scoring system to identify chil- duction [62–67]. Problems with intestinal immunity
dren with HSCR [60]. Components of the score may occur because the ENS directly regulates the
include “explosive” diarrhea, foul smelling diar- intestinal immune system [68–70]. Furthermore,
rhea, or bloody diarrhea. Additional components some of the genes defective in children with HSCR
include abdominal distension, explosive discharge have roles in development of the immune system.
278 R.O. Heuckeroth

For example, RET is important for Peyer’s patch

formation [71], while EDNRB is important for nor- Lessons from Mouse Models
mal spleen development [72]. Given the diverse
genetic underpinnings of HSCR, there may be more There are many mouse models with distal bowel
than one mechanism for HAEC. or total intestinal aganglionosis that mimic human
Optimal methods to treat or prevent HAEC are HSCR [82–87]. This includes mice with muta-
not yet known. Current treatment includes bowel tions in Ret, Sox10, Ednrb, Edn3, Ece1, Phox2b,
rest, nasogastric tube drainage, intravenous fluids, b(Beta)1 integrin, Ihh, and Pax3. Mutations in
decompression of dilated bowel via rectal dilation several additional genes affect ENS structure or
and/or rectal irrigation with normal saline, and the function but do not cause distal bowel agangli-
use of broad spectrum antibiotics [61]. Routine onosis including Nrtn, Gfra2, Gdnf, Shh, Nt3,
rectal irrigation [73] and the long-term use of met- Trkc, Sprty2, Dcc, and Hlx1. These model organ-
ronidazole in children at high risk of enterocolitis isms support the human genetic data that identified
may also reduce the frequency of HAEC episodes. mutations causing HSCR and also provide addi-
Because HAEC is potentially fatal, it is critical tional insight into disease pathogenesis. Mouse
that families understand symptoms of enterocolitis models are particularly valuable because they
and that plans are in place for prompt treatment provide direct evidence that specific genetic
should these symptoms arise. defects cause specific anomalies. There are a sev-
eral simple lessons from these model organisms
that are relevant to human clinical disease. First,
Long Term Outcome the ENS is often abnormal in the proximal bowel
of mice with distal bowel aganglionosis [88],
Untreated HSCR is a deadly disease, but outcome suggesting that many of the ongoing problems in
with modern surgical methods and improved med- children with HSCR occur because the “normal”
ical management strategies is dramatically better proximal bowel is not really normal. Furthermore,
than in the past. Nonoperative management leads areas in the distal bowel that contain ganglion
to very high mortality rates (e.g., >50–80%), and cells may be profoundly hypoganglionic, a prob-
reports from the 1970s describe mortality rates of lem that is not apparent with the limited biopsies
25–35% [1, 74] even with surgical treatment. that are obtained during surgery for children with
HSCR death rates today remain about 2–6%, in HSCR. Finally in some mouse models, ENS
large part attributable to enterocolitis [7, 10, 29, anatomy is nearly normal, but function is pro-
75, 76]. Enterocolitis occurs commonly both foundly abnormal [89] emphasizing that even
before and after surgery for HSCR (25–45% of sophisticated pathological methods may not pro-
children) [13, 59, 77, 78]. Long-term outcome vide the information needed to optimize intesti-
even years after surgery also remains less than nal function. There are human correlates to these
ideal with only 45–89% having normal bowel observations in mice including the observation
function. Many individuals continue to have fecal that motility problems of the stomach, small
soiling (4–29%), constipation (3–22%), or perma- bowel and esophagus are common in humans
nent stomas (7–10%) [79–81]. Normal bowel with HSCR [90–94].
function is even less common in children with
Down syndrome (34%). Bowel function appears
to improve as children get older with “normal” The Future of Hirschsprung Disease
continence in 58% at 5–10 years after surgery,
68% at 10–15 years after surgery, and 89% at Outcomes for children with HSCR today are
15–20 years after surgery in one study [79]. In this quite good, but many challenges remain. The pri-
analysis 7% had marked limitation in their social mary problems and opportunities include:
life 5–10 years after surgery, although this prob- 1. There have been major advances in our
lem improved as children became older. understanding of the genetic underpinnings
23 Hirschsprung Disease 279

of HSCR, but these fi ndings are not yet better data about the location of the anatomic
routinely incorporated into clinical practice. transition zone. These data might improve
Furthermore, there is no consensus about surgical outcomes and reduce post-surgical
what type of molecular genetic testing, if any, HAEC rates by enhancing the surgeon’s abil-
should be performed on children with HSCR. ity to evaluate the density of bowel innerva-
One reasonable argument is that all children tion intra-operatively. They could also reduce
with HSCR should be tested for RET muta- the cost of surgery.
tions that cause MEN2A, but this is still not 4. We need to determine if there are ways to
common practice. As genetic testing becomes reduce HSCR occurrence rates or to reduce
less expensive and the capacity to test for the extent of aganglionosis in affected indi-
many mutations simultaneously increases, it viduals. New data from our laboratory suggest
may become practical to perform more com- that many environmental factors, including
prehensive analysis that would provide infor- maternal vitamin A levels, may impact the
mation about the risk of other medical likelihood that children develop HSCR [96].
problems. It is important that we develop Reports of monozygotic twins discordant for
user friendly methods to understand the type HSCR also suggest that HSCR is not a purely
of complex genetic data that are relevant for genetic disease [29, 49, 97, 98]. Large-scale
children with HSCR. epidemiological studies coupled with work in
2. Enterocolitis remains a common cause of model systems should be pursued to identify
morbidity and the most common cause of maternal drugs, health conditions, or nutri-
mortality in children with HSCR. We need tional problems that could be modified to pre-
to have a more complete understanding of vent HSCR.
factors that predispose to HAEC and new 5. We need to find new ways to replace or repair
ways to prevent this problem. More research the ENS when it is damaged or when develop-
is needed to understand the impact of the ment is defective. New very exciting studies of
ENS on mucosal integrity and on immune ENS stem cells provide hope for the future, but
system function. We also need more infor- many obstacles need to be overcome for stem
mation about whether specific HSCR predis- cell replacement therapy to become a practical
posing mutations increase the risk of HAEC. treatment strategy [99–103]. Specifically, we
Most importantly we ought to know if there need to know how to differentiate stem cells
are factors that can be modified to reduce into specific types of neurons or glia, to implant
HAEC frequency or severity. Are there those cells close to where they are needed, and
changes in surgical approach that would to encourage stem cells to establish a func-
help? Would probiotics be useful? Are there tional enteric neuron network.
additional medications that could reduce
HAEC rates? Would a more systematic anal-
ysis of pathology at the time of surgery help? Summary
These questions must be investigated in
more detail. Over the past century dramatic advances have
3. We need improved methods to evaluate and been made in Hirschsprung disease diagnosis,
visualize the ENS. Recent intriguing experi- surgical management, developmental biology
ments suggest that advanced acousto-optic and genetics. Ongoing studies provide new hope
spectral imaging techniques might be useful that we will be able to reduce HSCR incidence,
during surgery [95], but these methods require prevent HAEC, replace missing enteric neurons
further development and testing. The ability using stem cells, image the ENS intra-operatively,
to visualize the ENS without biopsy could improve surgical techniques, and incorporate
potentially make surgery faster and provide genetics into clinical practice.
280 R.O. Heuckeroth

19. Diamond IR, Casadiego G, Traubici J, Langer JC,

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 Motility Problems in Developmental
Disorders: Cerebral Palsy, Down 24
Syndrome, William Syndrome,
Familial Dysautonomia, and
Mitochondrial Disorders

Annamaria Staiano and Massimo Martinelli

mentary bolus due to either uncoordinated move-

Cerebral Palsy ments of the tongue or it being contracted and
rigid. Alternatively, they had a normal bolus but
Cerebral palsy (CP) refers to a group of chronic, huge defects in its propulsion toward the orophar-
nonprogressive disorders of movement, posture, ynx, due to the lack of finely coordinated move-
and tone due to central nervous system damage ments of the tongue against the palate. Swallowing
before cerebral development is complete. The disorders have significant implications for devel-
prevalence of CP is approximately 2 per 1,000 live opment, nutrition, respiratory health, and GI func-
births. The different types of CP vary from series tion of this group of patients [3]. The development
to series, with the spastic type being the most fre- of dysphagia is associated with a progressive
quent, while periventricular leukomalacia and/or reduction of food intake and represents the main
cortical/cerebral atrophy represents the main neu- pathogenic factor for malnutrition [4]. At the same
ropathological correlates [1]. The survival of chil- time, swallowing disorders can often cause recur-
dren with severe neurological disorders, such as rent episodes of pulmonary aspiration. For all
cerebral palsy, has created a major challenge for these reasons, it is essential to diagnose these con-
medical care. Gastrointestinal motor dysfunction, ditions as early as possible. Videofluoroscopic
such as gastroesophageal reflux disease (GERD), swallow studies are considered to be a valuable
dysphagia, vomiting, and chronic constipation, is diagnostic tool for children with CP, given their
known to occur frequently in children with differ- ability to assess both pharyngeal motility and air-
ent degrees of CNS damage. The degree of GI dys- way protection during swallowing. There is grow-
motility seems to correlate with the degree of brain ing evidence that the method of feeding is an
damage [2]. Swallowing disorders are common in important variable in outcomes of children with
patients affected by CP. In the study by Del Giudice more severe CP. In those patients with dysphagia,
and colleagues, the authors found that 30 of the 35 undernutrition, and associated respiratory diseases,
patients with CP presenting with dysphagia had the adoption of gastrostomy tube feeding is rec-
swallowing disorders. The great majority of ommended [5–7]. The American Academy of
patients showed dysfunction of the oral phase of Cerebral Palsy and Developmental Medicine con-
swallowing with abnormal formation of the ali- siders gastrostomy feeding as a valuable alterna-
tive nutritional source in this group of children [6].
A. Staiano, M.D. (*) • M. Martinelli, M.D. GERD is very common in patients with a severe
Pediatric Gastoenterology Division, Pediatrics neurologic impairment. The incidence is reported
Department, University of Naples “Federico II”,
to be between 70 and 90%, depending on the dif-
Via Pansini No 5, Naples 80131, Italy
e-mail: [email protected] ferent investigations used including esophageal

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 285

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_24, © Springer Science+Business Media New York 2013
286 A. Staiano and M. Martinelli

Fig. 24.1 Examples of high-resolution esophageal manom- ageal tracing, whereas in (b) hypotensive lower esophageal
etry tracings in a control subject (a) and in two patients (b sphincter and low-amplitude contraction. In (c), marked
and c) affected by cerebral palsy. Note in (a) a normal esoph- hypomotility of the smooth muscle region is visible.

pH studies and/or upper GI endoscopy [3, 8]. The effective for symptom control and maintenance of
pathogenesis of GERD in children with CP seems remission. Baclofen is recommended to control
to relate mainly to the impaired motility of the vomiting [9]. An alternative medical approach is
esophagus. Our group demonstrated that most of represented by the use of an elemental diet. We
the neurological patients affected by GERD described a lower incidence of GERD in neuro-
showed prolonged gastric emptying and abnormal logically impaired children with refractory
esophageal motility. The main abnormalities con- esophagitis treated with amino acid-based formula
sisted of significantly low amplitudes of the lower [10]. However, conventional medical management
esophageal sphincter (LES) and esophageal con- is less effective in neurologically impaired chil-
traction waves and an increased number of simul- dren. At the same time, surgical intervention is
taneous waves, compared to control children associated with high operative risk given the poor
(Fig. 24.1) [3]. These findings, part of a more gen- physical condition of the patients. The benefit/risk
eralized dysmotility of the GI tract, together with ratio of antireflux surgery in patients with persis-
the other conditions often present in these chil- tent symptoms despite optimized medical therapy
dren, such as spasticity, prolonged adoption of is not clear. Nissen fundoplication has been associ-
supine position, scoliosis, seizures, and reduced ated with several complications in neurologically
amounts of swallowed saliva consequent to the impaired children. In addition, postoperative mor-
drooling, increase the predisposition to the devel- bidity rates are up to 50%, reoperation rates up to
opment of GERD and may be responsible for the 20%, and mortality substantial [11, 12]. Recently,
high failure rate of both medical and surgical treat- the advent of laparoscopic Nissen fundoplication
ments in this category of patients. The correct has become the procedure of choice. Esposito and
therapeutical approach to GERD in CP patients is colleagues reported a 30% rate of postoperative
still controversial. According to the recent complications and 6% rate of reoperation [13].
ESPGHAN–NASPGHAN guidelines on gastroe- Constipation represents another frequent and
sophageal reflux, antisecretory therapy should be often undiagnosed problem in patients with CP.
optimized. Long-term treatment with PPIs is often The prevalence of the chronic constipation var-
24 Motility Problems in Developmental Disorders: Cerebral Palsy, Down Syndrome, William... 287

ies from 25 to 75% of patients with CP [3]. has been observed however that neurological
Chronic constipation is the result of prolonged impairment and GI disease necessitating surgery
colonic transit, which is secondary to the under- have been independently associated with poorer
lying gut dysmotility. Colonic transit time seems development outcome [21]. With regard to esopha-
to be delayed predominantly in the left colon geal motor disorders, different cases of association
and rectum [14]. It has been suggested that dis- between achalasia and DS have been described in
ruption of the neural modulation of colonic the literature, and although achalasia remains a rare
motility may play a predominant role in the entity, it should be considered in any DS patient
development of constipation in neurologic dis- who presents with dysphagia [22]. Among the most
ease. This could explain why prokinetic drugs common motor disorders in DS children and adults,
have little impact on the delayed colonic transit unexplained chronic constipation is included [23].
seen in children with brain damage. The low In children with chronic constipation, it is important
fiber and fluid intake as well as the frequent to exclude Hirschsprung disease (HSCR), observed
delay in diagnosis certainly contribute to the in approximately 1 on 200–300 DS patients [24].
development and the reinforcement of constipa- About 30% of HSCR patients have a recognized
tion in neurologically impaired children. Our chromosomal abnormality, a recognized syndrome,
group demonstrated the efficacy of dietary fiber or additional congenital anomalies, the most fre-
glucomannan in improving bowel frequency in quent of which is DS [25]. Moore et al., studying a
children with severe brain damage, despite no population of 408 HSCR patients, reported a preva-
measurable effects on delayed transit [15]. lence of 3.2% of DS with an 85% association with
other anomalies [26]. The well-described correla-
tion between DS and HSCR indicates a possible
Down Syndrome role for chromosome 21 in the etiology of HD.
Nevertheless, the existence of trisomy 21 although
About 77% of neonates affected by Down syn- seemingly increasing the risk of developing HSCR
drome (DS) present with or develop associated GI does not invariably lead to its occurrence. In the lit-
abnormalities [16]. Cleves et al., in a recent cohort erature several studies investigating the role of chro-
study, showed, besides congenital heart defects, an mosome 21 as a potential candidate area for a
elevated relative risk for GI malformations (OR modifying gene in HSCR exist [27], but in the last
67.07) in infants with DS [17]. The most frequent few years, the possible role of genes mapping out-
GI malformation associated with DS is Hirschsprung side chromosome 21 (such as SOD1, ITGB2, pro-
disease; however, esophageal atresia, tracheoesoph- tein s-100 beta) is emerging. Also well studied has
ageal fistula, duodenal atresia or stenosis, and been the relationship between the major susceptibil-
imperforate anus were all described. Some of the ity genes associated with HSCR (RET and EDNRB)
most common functional GI symptoms reported by and the DS. Arnold et al. [28] demonstrated that the
DS patients are dysphagia for liquids and solids, RET enhancer polymorphism RET 19.7 at chromo-
vomiting/GER, and heartburn, as well as other some 10q11.2 is associated with HSCR in DS indi-
esophageal dysmotility symptoms [18]. Children viduals. Interestingly, the RET19.7 T allele
affected by DS are at high risk of GERD [19] and its frequency is significantly different between indi-
serious complications such as oropharyngeal aspi- viduals with DS alone (0.26 ± 0.04), HSCR alone
ration and pneumonia. As for other conditions with (0.61 ± 0.04), and HSCR and DS (0.41 ± 0.04), dem-
neurological impairment such as CP, treatment of onstrating an association and interaction between
GERD in DS patients should associate optimized RET and chromosome 21 gene dosage. Similarly a
antisecretory therapy to behavioral measures includ- novel EDNRB variant was identified in DS patients
ing feeding and positional changes. Despite opti- with HSCR [29]. Moreover, there appears to be a
mized medical therapy, some DS patients with significantly higher overall incidence of preopera-
GERD, especially patients with respiratory compli- tive enterocolitis and postoperative enterocolitis in
cations of GERD, need antireflux surgery [20]. It DS with HSCR [30].
288 A. Staiano and M. Martinelli

psychological stress: gastrointestinal perturba-

Williams Syndrome tions such as vomiting are the predominant part
of the constellation of symptoms seen during
Williams syndrome (WS), also known as an episode; other symptoms include hyperten-
Williams–Beuren syndrome, is due to a homozy- sion, tachycardia, diaphoresis, personality
gous deletion of a contiguous gene on the long changes, blotching of the skin, piloerection,
arm of chromosome 7 (7q11.23) [31]. The esti- functional ileus, and dilatation of pupils [38].
mated prevalence of WS is 1 in 7,500 live births Malfunction of the gastrointestinal tract is the
[32]. Most individuals with WS (99%) have a 1.5 main clinical manifestation of FD with oropha-
megabase deletion in 7q11.23 encompassing the ryngeal incoordination being one of the earli-
elastin gene (ELN) and 25–35 other genes, all of est symptoms. Discoordinated swallow is
which are detectable by fluorescent in situ hybrid- found in about the 60% of patients with FD,
ization (FISH) [33]. Clinical features of WS and it is often responsible for the development
include distinctive facial anomalies; congenital of severe feeding alteration, malnutrition, and
heart defects, in particular supravalvular aortic recurrent aspiration, which can lead to chronic
stenosis; slight to severe mental retardation; her- lung disease. Cineradiographic swallowing
niae; growth deficiency; and infantile hypercalce- studies may document the level of functional
mia [34]. Gastrointestinal symptoms such as ability [39, 40]. According to Axelrod et al., up
chronic abdominal pain, feeding problems, con- to 80% of children will require gastrostomy
stipation, and gastroesophageal reflux disease are prior to the age of 1 year [37]. However, the
seen relatively frequently in children with WS prominent GI gastrointestinal symptom is the
[35]. Hypercalcemia may contribute to irritabil- propensity to vomit. Vomiting can occur cycli-
ity, vomiting, constipation, and muscle cramps; it cally as a part of dysautonomic crises or daily
is more common in infancy but may recur in in response to stress or arousal. The efficacy of
adults [36]. diazepam in reducing vomiting during auto-
nomic crises suggests that the crisis is caused
by a central phenomenon, probably developed
Familial Dysautonomia from autonomic seizures [41]. Gastroesophageal
reflux is another common problem. Sundaram
Familial dysautonomia, also known as Riley– and colleagues found a prevalence of 95% of
Day syndrome, is an autosomal recessive dis- GERD in a sample study of 174 FD patients
order, which occurs predominantly in the [42]. A major contributor to the development
Ashkenazi Jewish population and has an inci- of GERD is represented by dysfunction and
dence of about 1 in 1,370 individuals. It is increased relaxation of the lower esophageal
associated with a complex neurological disor- sphincter. The LES is controlled by postgangli-
der that affects the sensory system and the onic parasympathetic fibers within the vagus
autonomous nervous system functions [37]. nerve and preganglionic sympathetic fibers.
Although FD is caused by one gene and the The parasympathetic circuits are able to con-
penetrance is always complete, there is a great trol both the relaxation and the contraction of
deal of variation in expression. The sensory LES, while the sympathetic system evokes
dysfunction is characterized by alterations of exclusively the contraction. The pathogenesis
small fiber neuronal populations such that FD of GERD is correlated to the reported degen-
patients have impaired sensations of tempera- eration of sympathetic nervous system and the
ture, pain, and vibration. The autonomic dys- consequent prevalence of parasympathetic
function affects multiple systems and it is firing. Medical management including H2
characterized by cyclic manifestations of a typ- antagonists should be tried; however, if symp-
ical “dysautonomic crisis”; these crises repre- toms persist and events such as hematemesis
sent systemic reactions to physiologic and occur, surgical intervention is recommended.
24 Motility Problems in Developmental Disorders: Cerebral Palsy, Down Syndrome, William... 289

acidosis, and stroke-like episodes) [51]. Other

Mitochondrial Disorders MD are characterized by nonspecific GI symp-
toms and present with dysphagia, gastroesopha-
Mitochondrial disorders (MD) refer to a clini- geal delayed gastric emptying, feeding difficulties,
cally heterogeneous group of disorders that arise gastroesophageal reflux (GER) and/or vomiting,
as a result of dysfunction of the mitochondrial diarrhea, failure to thrive, and abdominal pain.
respiratory chain. They can be caused by either Different mtDNA mutations have been associated
inherited or spontaneous mutations of nuclear with GI disorders in MD. Recently Horvath et al.
(nDNA) or mitochondrial DNA (mtDNA) which found a new heteroplasmic mutation in the anti-
lead to altered functions of the proteins or RNA codon stem of mitochondrial tRNA of a girl pre-
molecules that normally reside in mitochondria. senting with clinical symptoms of MNGIE-like
Defects in nDNA can be inherited from either GI dysmotility and cachexia [52]. In MELAS it is
parent, while defects in the genes of the mtDNA common to find an A3243G mutation in transfer
are maternally inherited. Mitochondria are pres- RNA (tRNA) Leu (UUR) [53]. Mutations in the
ent in virtually all cell types of human body and nuclear gene encoding SURF1, a mitochondrial
their damage primarily affects the main energy- protein involved in cytochrome c oxidase assem-
dependent tissues such as brain, heart, liver, skel- bly, have been noted in many patients with Leigh
etal muscles, kidney, and the endocrine and syndrome [54]. GI symptoms are predominantly
respiratory systems [43]. Mitochondrial disorders localized in the upper GI tract. Chitkara et al.
primarily affect children, but adult onset is reported six children with MD who presented
becoming more common. More than 100 mtDNA upper GI symptoms such as vomiting, food aver-
abnormalities associated with MD have been sion, GER, poor suck, and feeding intolerance
described in the literature, with some resulting in [46]. Fifteen percent of patients with Kearns–
profound disability and premature death [44, 45]. Sayre, an MD characterized by deletions in cyto-
GI symptoms are reported in 15% of MD patients chrome c oxidase deficiency, present swallowing
occurring usually in childhood, before the onset difficulties and dysphagia [55]. Shaker et al.
of more classical symptoms of MD [46]. described the manometric characteristics of a cer-
vical dysphagia in a patient with Kearns–Sayre
observing absence of pharyngeal peristalsis,
Mitochondrial Disorders Presenting abnormally low upper esophageal sphincter rest-
with Motility Problems ing pressure, and absence of proximal esophageal
peristalsis [56]. Vomiting and dysphagia have
The major MD presenting with GI symptoms are been described in patients with Leigh syndrome
mitochondrial neurogastrointestinal encephalo- [57]. Dysphagia seems to be due to primary
myopathy (MNGIE) (peripheral neuropathy, oph- esophageal dysmotility, neurogenic causes, or a
thalmoparesis, leukoencephalopathy, muscle combination of these two factors. Dysmotility
wasting, cachexia) in which GI symptoms (espe- disorders like delayed gastric emptying and intes-
cially from chronic intestinal pseudo-obstruction tinal pseudo-obstruction have been shown in child
and diarrhea) are present in 45–67% of patients [46, 58] and adult patients with MD [59].
[47–49]; Leigh syndrome (subacute necrotizing Gastroparesis has been associated with various
encephalomyelopathy resulting in hypotonia, bul- diseases and may occur as part of a MD [60].
bar paresis, abnormal eye movements, lack of There is no consensus regarding management of
coordination of extremities, and regressive psy- patients with gastroparesis who do not respond to
chomotor development) [50]; Kearns–Sayre syn- simple antiemetic or prokinetic therapy. Tatekawa
drome (chronic progressive external et al. proposed a new surgical technique in a
ophthalmoplegia, atypical pigmentary retinopa- refractory gastroparesis 12-year-old girl with
thy, ataxia, and heart block); and MELAS syn- pyruvate dehydrogenase complex deficiency [60].
drome (mitochondrial encephalopathy, lactic Intestinal pseudo-obstruction is an increasingly
290 A. Staiano and M. Martinelli

recognized clinical feature of MD, mainly in American Society for Pediatric Gastroenterology,
MNGIE and less frequently in MELAS, and Hepatology, and Nutrition (NASPGHAN) and the
European Society for Pediatric Gastroenterology,
may represent an important cause of chronic Hepatology, and Nutrition (ESPGHAN). J Pediatr
intestinal failure. The pathogenesis of intestinal Gastroenterol Nutr. 2009;49:498–547.
pseudo-obstruction in MD is still unclear. 10. Miele E, Staiano A, Tozzi A, Auricchio R, Paparo F,
Giordano et al. showed in two studies per- Troncone R. Clinical response to amino acid-based for-
mula in neurologically impaired children with refractory
formed in one and four patients suffering from esophagitis. J Pediatr Gastroenterol Nutr. 2002;35:314–9.
MNGIE, respectively, smooth muscle cell atro- 11. Richards CA, Andrews PL, Spitz L, Milla PJ. Nissen
phy, mitochondrial proliferation, and mtDNA fundoplication may induce gastric myoelectrical dis-
depletion in the muscularis propria of the small turbance in children. J Pediatr Surg. 1998;33:1801–5.
12. Richards CA, Carr D, Spitz L, Milla PJ, Andrews PL.
intestine [61, 62]. Their pathogenetic hypothe- Nissen-type fundoplication and its effects on the
sis was that in MNGIE patients the baseline low emetic reflex and gastric motility in the ferret.
abundance of mtDNA molecules may predis- Neurogastroenterol Motil. 2000;12:65–74.
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A, Bax NM. Risks and benefits of surgical management
of muscularis propria to the toxic effects of cir- of gastroesophageal reflux in neurologically impaired
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 Part IV
Motility Disorders after Surgery and
Developmental Anomalies of the
Enteric Neuromuscular System
Secondary to Anatomical
Malformations
 Esophageal Atresia
25
Julie Castilloux and Christophe Faure

Esophageal atresia (EA) with or without

tracheoesophageal fistula (TEF) is a common Clinical Symptoms
congenital anomaly, with an incidence of 1:3,500.
Since the first successful surgery in 1941, anes- Gastroesophageal Reflux
thetic, surgical, and neonatal care have improved
tremendously, and our interest is now geared GER, as assessed by pH monitoring, affects the
toward preventing short- and long-term morbid- majority of children [1, 3–5] and adults [10, 12]
ity in these children [1]. Besides pulmonary and with EA with an incidence of 22–58% and may be
orthopedic complications [2], motor disorders of very severe leading to esophagitis and worsening
the esophagus leading to gastroesophageal reflux of the pulmonary condition [10]. Using impedance
(GER) [3–8], chronic dysphagia [5, 9, 10], and testing in 24 children with EA, Fröhlich et al. dem-
esophageal stricture [3–5, 8, 11, 12] remain the onstrated an abnormal bolus index in 67% of the
most frequent long term problems. Later, compli- patients. Weakly acid reflux showed a higher ten-
cations potentially related to chronic acid and dency to be related to symptoms than did acid
pepsin exposure of the esophageal mucosa, such reflux [13]. However, the low baseline impedance,
as Barrett’s esophagus [12] and esophageal carci- secondary to the poor esophageal function and/or
noma [8] have also been reported. stasis of liquid especially in the lower esophagus,
appears to impair the capacity of MII-pH to accu-
rately capture the changes associated with reflux
in these patients [14]. EA patients are at high risk
of developing severe GER for several reasons:
esophageal dysmotility, modification of the His
angle, iatrogenic hiatal hernia, smaller portion of
the intrathoracic part of esophagus, vagal nerve
surgical injury, and anomalies of gastric motility
J. Castilloux, M.D. (*)
Division of Pediatric Gastroenterology, Pediatric [15–17]. Romeo et al. reported that 36% of patients
Department, Centre Hospitalier Universitaire Laval, with EA have delayed gastric emptying on scintig-
2705 boul Laurier, Quebec City, QC G1V 4G2, Canada raphy and 45% abnormal gastric peristalsis on
e-mail: [email protected]
manometry [18]. Because esophagitis is known to
C. Faure, M.D. provoke esophageal hypomotility, many authors
Division of Pediatric Gastroenterology, Department of
suggest that, at least in the first year of life, all
Pediatrics, Sainte-Justine, University Health Center,
Université de Montréal, 3175 Côte Sainte-Catherine, patients need antacid protection and should
Montréal, H3T1C5 QC, Canada undergo endoscopic surveillance [8, 19].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 295

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_25, © Springer Science+Business Media New York 2013
296 J. Castilloux and C. Faure

Dysphagia try, an inadequate coordination between pharyngeal

contraction and UES relaxation was found [28].
Frequent symptoms of esophageal dysfunction
such as dysphagia, episodes of foreign body
impaction, heartburn, and vomiting are often Esophageal Body
detected during purposeful interrogation [20, 21].
Studies in children [3, 5, 10] and in adults [12, 20, Esophageal body dysfunction is present in nearly
22] have reported that dysphagia is very common all patients with EA. It is found in children [13,
occurring in 45–85% of patients [5, 8, 15, 20, 21]. 15, 16, 21, 26–31] and persists all life long as
It might be caused by an anastomotic stricture or demonstrated by adult studies [12, 16, 20, 32].
rarely by eosinophilic esophagitis [23] but is most Manometric studies have so far been conducted
frequently related to esophageal dysmotility. It can with standard techniques and found a lack of
be associated with increased risk of esophageal coordination of peristalsis or no peristaltic waves
foreign body impaction and feeding difficulties [1, in the entire esophagus or limited to a segment
8, 12, 15]. A step-by-step investigation may con- [10, 15, 20, 26, 28, 29]. Amplitudes are usually
sist of a barium swallow to exclude a stricture, an low. Simultaneous contractions of low or normal
upper endoscopy to exclude peptic or eosinophilic amplitude, similar to achalasia, have been
esophagitis, then an esophageal manometry, and a reported [12, 15]. Tovar et al. used a combined
possible trial of a prokinetic. 24-h manometry and pH-metry and found a vir-
tual absence of propulsive waves leading to a uni-
form pattern of long nocturnal episodes of GER
Dumping Syndrome in those with a failing sphincteric barrier [21].
Using conventional manometric technique in 101
Dumping syndrome is often unrecognized, and adults, Sistonen et al. demonstrated non-propa-
its diagnosis delayed. In children with EA, it is gating peristalsis with weak and simultaneous
most often encountered after a fundoplication or esophageal pressure waves in 80% of patients,
in patients with microgastria [24]. It has also been with ineffective distal esophageal peristalsis in
reported in EA patients with no other precipitat- all [12]. Manometrical abnormalities were
ing factors [25]. Whether gastric motility disor- significantly worse in those with epithelial meta-
der may be primitive or secondary to vagus nerve plasia [12]. Using high-resolution manometry
injury is unknown. (HREM), a recent study was conducted on 39
patients (34 with type C EA and 5 with type A)
with a median age of 8 years. HREM results were
Esophageal Motility in Patients abnormal in all patients. Three different esopha-
with EA geal motility patterns were derived from HREM
tracing analysis: aperistalsis, pressurization, and
Esophageal dysmotility is practically universal distal peristalsis (Fig. 25.1). Five patients were
in all patients with EA. It involves mostly peri- asymptomatic and were found in each group.
stalsis and may exist even when symptoms are GERD-related symptoms predominated in the
absent [26]. aperistalsis group, and dysphagia was more prev-
alent in the distal peristalsis group [33].

Upper Esophageal Sphincter

Lower Esophageal Sphincter
The upper esophageal sphincter (UES) function has
been reported to be normal by most authors [15, 16, In most studies, lower esophageal sphincter
26], but incomplete relaxation has been described in (LES) function is generally similar to controls
newborns [27]. When evaluated by videomanome- except for occasional reduced pressure and
25 Esophageal Atresia 297

Fig. 25.1 High-resolution

esophageal manometry
tracings recorded in patients
with esophageal atresia.
Three patterns are recog-
nized: aperistalsis pattern
(A), pressurization pattern
(B), and distal (weak)
peristalsis pattern (C)

incomplete relaxation [10, 16, 20, 27, 29]. Dutta EA newborn reported profound abnormalities in the
et al. found that the LES pressure correlated with Auerbach plexus (plexus hypoplasia, abnormal
the severity of GER [26]. interganglionic network) [36]. Other studies found
hypoplasia of esophageal innervation or smooth
muscle [37] in the upper pouch [38] or in the fistula
Etiology of the Esophageal [37, 39]. Findings in an Adriamycin-induced
Dysmotility EA-TEF fetal rat model have similarly shown an
abnormal distribution of nerve tissue in the esopha-
The etiology of the esophageal motility disorder gus [40] and inherent abnormalities in the branch-
remains unclear and controversial. It may be ing pattern of the vagus nerves [41].
caused by (1) intrinsic factors related to abnormal
development of the esophageal smooth muscle
and intrinsic innervation and vagus nerve or (2) Postsurgical Dysmotility
operative maneuvers. Data indicating a key role
of congenital malformation are gaining strength. On the other hand, the dysmotility may be caused
by the dissection during surgery itself damaging
the vagal nerve and its esophageal branches [42].
Primary Motility Disorder of the Indeed, bilateral cervical vagotomy above the ori-
Esophagus gin of the pharyngoesophageal branches abolishes
peristalsis in the striated muscle esophagus [43].
Prior to surgery, esophageal manometry conducted However, unilateral vagotomy has no effect on
in 20 newborn with EA showed motor abnormali- peristalsis, presumably because of extensive cross-
ties in the proximal (pouch) and distal esophagus over of vagal innervation within the esophageal
[27]. Similarly, abnormal esophageal motility pat- wall [44]. Surgery may also result in an extensive
terns with aperistalsis have been described in adults mobilization and denervation of the esophagus.
with tracheoesophageal fistula without atresia Shono et al. demonstrated, in two patients with
before surgical repair [34, 35]. Pathological data pure EA studied before surgery, coordinated peri-
support the role of abnormal intrinsic and vagal stalsis between the proximal and the distal esopha-
innervation of the esophagus. Detailed pathological gus as well as a normal LES reflex relaxation
analysis of esophageal myenteric plexuses in dead suggesting that surgery may alter esophageal
298 J. Castilloux and C. Faure

motility [45]. However, this is not supported by 8. Taylor AC, Breen KJ, Auldist A, Catto-Smith A,
experimental animal studies where transection and Clarnette T, Crameri J, Taylor R, Nagarajah S, Brady
J, Stokes K. Gastroesophageal reflux and related
anastomosis of the esophagus did not cause severe pathology in adults who were born with esophageal
esophageal dysmotility [46]. atresia: a long-term follow-up study. Clin Gastroenterol
Hepatol. 2007;5:702–6.
9. Lindahl H, Rintala R. Long-term complications in
cases of isolated esophageal atresia treated with esoph-
Nissen and EA ageal anastomosis. J Pediatr Surg. 1995;30:1222–3.
10. Somppi E, Tammela O, Ruuska T, Rahnasto J,
Nissen fundoplication may exacerbate the dys- Laitinen J, Turjanmaa V, Jarnberg J. Outcome of
motility, and careful attention must be considered patients operated on for esophageal atresia: 30 years’
experience. J Pediatr Surg. 1998;33:1341–6.
for its indication. It is performed in about 9–28% 11. Okada A, Usui N, Inoue M, Kawahara H, Kubota A,
of cases [4, 5, 10, 47]. The fundoplication creates Imura K, Kamata S. Esophageal atresia in Osaka: a
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may worsen [48]. Some authors have suggested Sarna S, Rintala RJ, Pakarinen MP. Esophageal
that an anti-reflux procedure may be considered morbidity and function in adults with repaired
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 Anorectal Malformations
26
Jose M. Garza and Ajay Kaul

Anorectal malformations (ARM) are a spectrum cloaca and the two tracts are separated (Fig. 26.1b),
of congenital abnormalities of distal hindgut devel- and during the tenth week, the perineal body is
opment in which the gastrointestinal tract ends formed and the cloacal sphincter is separated by the
blindly or opens ectopically with a fistula to the perineal body into urogenital and anal portions
skin or into the genitourinary tract. ARM affect (Fig. 26.1c) [3]. It has been postulated that failures
about 2–5 per 10,000 live births, an incidence sim- in this process of normal development lead to the
ilar to that of Hirschsprung’s disease [1]. Males are various forms of anorectal malformations, from
affected more frequently than females [2]. The simple to complex. Prenatal demonstration of the
most frequent malformation in males involves a fetal anal sphincter on ultrasound is consistently
rectourethral fistula and in girls a vestibular fistula. possible at 23–24 weeks and has been shown to
The term ARM is often erroneously used synony- develop in a predictable pattern [4]. Although pre-
mously with “imperforate anus.” natal diagnosis is possible, most of these malforma-
tions are diagnosed at or soon after birth.
ARM have been associated with many differ-
Embryology and Genetics of ARM ent genetic or inherited conditions such as Townes-
Brocks syndrome, Currarino triad, Pallister-Hall
The distal colon, the rectum, and the anal canal syndrome, Johanson-Blizzard syndrome, Down
above the dentate line are all derived from the syndrome, trisomies 18 and 12, as well in indi-
hindgut. Before the fifth week of gestation, the viduals with VACTERL association [1]. There are
intestinal and urogenital tracts terminate in a com- several reports of increased incidence of nonsyn-
mon cavity called cloaca (Fig. 26.1a). At the sixth dromic or isolated ARMs in family members,
week, the urorectal septum migrates caudally in the especially in siblings. Recurrence rates of up to
3–4% in full siblings and approximately 2% in
first-degree relatives have been reported [1].
J.M. Garza, M.D., M.S.
Gastroenterology, Heptology and Nutrition Division,
Pediatrics Department, Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA Classification of ARM
A. Kaul, M.D. (*)
Professor of Clinical Pediatrics, There is currently no consensus on the classification
Director of Neuro-Gastroenterology Program, of ARMs. The Wingspread classification of anorec-
Director of GI Operations at Liberty Campus, tal malformations has been the most common
Cincinnati Children’s Hospital Medical Center,
3333 Burnet Ave (ML 2010), Cincinnati, OH 45229, USA classification described internationally. ARMs are
e-mail: [email protected] usually categorized according to the level of the

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 301

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_26, © Springer Science+Business Media New York 2013
302 J.M. Garza and A. Kaul

Fig. 26.1 Embryology

rectal pouch relative to the levator ani muscles into orly and connects with the urethra, most frequently
high, intermediate, and low anomalies, with special the bulbar urethra. Quality of muscle is usually
groups established for cloacal and rare malforma- good in bulbar urethra with a better potential
tions [5]. An international conference for the devel- because it has already passed through much of the
opment of standards in the treatment of anorectal levator ani and muscle complex mechanism [2].
malformation was organized at Krickenbeck Castle,
Germany, and a modification of the classification
was proposed [5]. The major clinical groups were Rectum-Bladder Neck Fistula
classified as perineal (cutaneous) fistulas, rectoure- (Fig. 26.2d)
thral fistulas (prostatic and bulbar), rectovesical
fistulas, vestibular fistulas, cloacal malformations, In this defect, the levator ani muscle complex and
patients with no fistula, and anal stenosis. Rare and external sphincter are usually underdeveloped
regional variants were subclassified as pouch colon, with a high association with abnormal sacrum
rectal atresia/stenosis, rectovaginal fistulas, H-type and flat bottom. About 90% of infants with this
fistulas, and others [5]. anomaly have other congenital defects.
Continence is usually poor [2].

Perineal (Cutaneous) Fistula (Fig. 26.2a, b)

Vestibular Fistula (Fig. 26.2e)
This is a very low malformation in which the rec-
tum passes normally through much of the sphinc- This is the most common ARM in females. The
ter complex. The lowest part of the rectum is rectum is anteriorly deviated at a higher level and
anteriorly deviated and ends as a perineal fistula opens immediately behind the hymen into the ves-
anterior to the center of the external sphincter. In tibule. Most patients have a normal appearing
males, this fistula can open anywhere between sacrum, adequate innervations, and normal-look-
the anus to the ventral portion of the penis. In ing perineum. This malformation is frequently
females, the anterior rectal wall and the posterior misdiagnosed as a rectovaginal fistula. This defect
vaginal wall are completely separated [2]. has excellent potential for bowel control [2].

Rectourethral Fistula (Fig. 26.2c) Persistent Cloaca (Fig. 26.2f)

The rectum descends partially through the sphinc- Cloacae represent a wide array of defects with
ter muscle, but at some point, it deviates anteri- presence of a single perineal orifice as the
26 Anorectal Malformations 303

Fig. 26.2 Anorectal

malformations (a) perineal
fistula in a male, (b) perineal
fistula in a female, (c)
rectourethral fistula, (d)
rectum-bladder neck fistula,
(e) vestibular fistula, (f)
persistent cloaca, (g)
rectovaginal fistula

common denominator. The length of the common perforate [6]. The diagnosis of cloaca is a clinical
channel varies from 1 to 10 cm with an average of one made by identifying a single perianal orifice
approximately 3 cm. It is unclear why 30% have with no evidence of vagina or rectum. Sometimes,
a dilated vagina filled with fluid, urine, or mucus one finds hypertrophic folds of skin in the area of
(hydrocolpos) since the common channel is the single perineal orifice, which gives a false
almost never atretic. Hydrocolpos can compress impression of a phallus which is likely why some
the trigone of the bladder anteriorly producing patients are misdiagnosed with disorders of sex-
ureterovesical obstruction, megaureter, and ual development. Associated congenital defects
hydronephrosis. Alternatively, it may become are common, and it is vital to recognize urologi-
infected leading to pyocolpos and potentially cal abnormalities [6].
304 J.M. Garza and A. Kaul

Rectovaginal Fistula (Fig. 26.2g) term morbidity associated with these disorders.
Traditionally, long-term prognosis was based on
Very unusual malformation in females, the higher the type of defect: best prognosis with low defects
the malformation is, the shorter the common wall and worst with high defects and cloacal malfor-
between the rectum and vagina; one cannot see mations. While this may be a good rule of thumb,
the fistula orifice by inspection, and the meco- predicting prognosis in children with ARM is
nium seems to come from within the vagina [2]. often complicated. In addition to the type of
defect, there are other factors that potentially
impact outcomes. These include surgical tech-
Anorectal Agenesis Without Fistula nique and experience, immediate postsurgical
care, presence of other comorbidities, child’s
This defect is relatively less common and con- level of cognitive functioning and coping skills,
stitutes about 5% of anorectal malformations. ongoing medical care, and social support.
About half of these children have Down syn- Constipation and fecal soiling are common
drome. Over 90% of children with Down syn- long-term defecatory problems reported in chil-
drome who have an anorectal malformation dren after ARM repair. The etiologies include
have this particular defect. Of these, 80% tend anal sphincter dysfunction (congenital or
to have voluntary bowel control later in life acquired), megarectum (associated with sacral
and usually have good muscle quality and a anomalies or acquired), and colonic dysmotility
well-developed sacrum [2]. (hyperactivity or ineffective colonic contractions)
[8–11]. Untreated constipation can lead to mega-
rectum and overflow incontinence (“pseudo-
Anal Stenosis incontinence”). It is important to distinguish
constipation with overflow incontinence from
In this type of defect, there is a ring of fibrous true fecal incontinence as the underlying etiol-
tissue located at the anal verge that causes a stric- ogy, and therefore their management, is different
ture resulting in varying degrees of functional [12, 13]. The evaluation of such a patient should
abnormality. The presenting symptom is consti- include radiographic studies to define anatomy,
pation with “thin” feces. Most of these only need anorectal, and colonic manometry to study anal
to be serially dilated and generally have a good sphincter and colonic function [14–17]. On occa-
outcome [2]. sion, imaging studies of the lower spine and pel-
vis may be indicated.
The long-term outcomes data on children with
Long-Term Outcomes in ARM ARM are inconsistent at best. Additionally,
definitions and methodologies used to study this
Anorectal malformations include a spectrum of complex issue vary widely between studies, so
rare congenital defects involving the developing correlations between defecatory functioning and
hindgut. It is estimated that about 64% of chil- quality of life are conflicting. From a review of
dren with ARM have other defects, and 15% have published studies, Hartman et al. tried to examine
a chromosomal abnormality [7]. The most com- disease-specific functioning and quality of life in
mon associated abnormalities involve the urinary patients with ARM across different developmen-
tract (40%). The underlying etiology for these tal stages. They concluded that even though ado-
varied defects is not known. Improved surgical lescents reported better fecal functioning, they
techniques and care after reconstruction have had more psychosocial quality of life problems
improved survival to nearly 100%. The primary than their younger counterparts [18]. In an earlier
goal for the surgeon during reconstruction of study, the same group reported that even though
these anomalies is to preserve fecal and urinary patients with ARM and Hirschsprung’s disease
continence. Despite this, there is variable long- had comparable quality of life, those with an
26 Anorectal Malformations 305

Table 26.1 Initial work-up Due to the potential involvement of multiple

Place an NG tube to r/o esophageal atresia organ systems in a child born with an ARM, a
Echocardiogram to rule out cardiac conditions multidisciplinary approach to evaluation and
Kidney or bladder US to r/o presence of hydronephro- management is imperative for best outcomes
sis and megaureters (Table 26.1). Since surgical reconstruction may
Pelvic US, rule out hydrocolpos need to be done in a step-wise manner and involve
Spinal US to evaluate for tethered cord several surgical disciplines, including colorectal
Plain abdominal X-ray sacrum and sacral ratio
surgeons, urologists, and gynecologists, a coordi-
nated effort to plan surgeries is critical. Additional
ARM reported additional pain and limitations in medical specialists may need to be engaged after
role functioning due to physical problems [19]. the initial reconstruction to address any potential
Another study on 10-year outcomes of children complications with long-term effects. These per-
that had posterior sagittal anorectoplasty for sonnel include primary care providers, gastroen-
ARM reported fecal continence in 58–90% of terologists, and psychologists. Even though
patients depending upon the severity of the anom- outcomes of children born with ARM have
aly [20]. A long-term outcome study from Japan significantly improved over the recent decades,
reported that only 21% adolescents who had cor- even better long-term outcomes are possible and
rective surgery for Hirschsprung’s disease had may be accomplished by standardizing their care
completely normal bowel function [21]. In a at specialized centers.
review of one of the largest series of 1,192
patients with ARM, Pena and Hong reported that
only 37% had complete continence [22]. References
With regard to urinary and renal function, com-
mon anomalies include renal dysgenesis, ectopic 1. Mundt E, Bates MD. Genetics of Hirschsprung dis-
ease and anorectal malformations. Semin Pediatr
and duplex kidneys, vesicoureteric reflux, fistulae,
Surg. 2010;19:107–17.
and neurogenic bladder. Inadvertent injury to the 2. Pena A, Levitt M. Pediatric surgical problems. In:
urinary tract during surgery, especially in males Corman ML, editor. Colon and rectal surgery.
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 Small Bowel and Colonic
Dysfunction After Surgery 27
Roberto Gomez, H. Nicole Lopez,
and John E. Fortunato

motility disorders observed in children after small

Introduction bowel and colonic surgery.

Surgery of the small intestine and colon is com-

monly performed in children for a variety of indi- Small Bowel Motility After Resection
cations ranging from congenital anatomic
abnormalities to need for enteral feeding access to Resection of all or part of the small bowel may be
underlying motility disorders. Under most circum- necessary for conditions including surgical emer-
stances, nonemergent operations allow time for a gencies such as bowel ischemia or necrosis from
multidisciplinary team approach between surgeons volvulus and perforation; congenital anomalies
and gastroenterologists to devise a thorough pre- such as intestinal atresia, malrotation, and gastro-
operative diagnostic strategy. Unfortunately, schisis; or acquired etiologies encompassing
abdominal catastrophes such as malrotation with stricturing Crohn’s disease, ulcerative colitis,
volvulus often preclude the luxury of time before severe necrotizing enterocolitis, intestinal pseu-
surgery necessitating a strong relationship between doobstruction, or abdominal trauma. Preservation
surgeon and gastroenterologist to address the of bowel length, particularly the small intestine,
potential consequences of such an event. Under is critical to insure adequate absorption of nutri-
both circumstances, the motility of the small bowel ents, fluids, and electrolytes but is contingent on
and colon remains a critical feature that often pre- circumstances such as extent of the necrosis or
dicts the success of an operation and, most impor- ischemia. The consequences of a more extensive
tantly, the prognosis of the patient. This chapter resection of small bowel include symptoms such
aims to address several of the more prevalent as frequent diarrhea, malnutrition, and bloating
due to bacterial overgrowth and may result in the
need for parental nutrition with its associated
R. Gomez, M.D. complications.
Pediatric Gastroenterology Department, Wake Forest Small intestinal resections are classified into
University, Winston-Salem, NC, USA three categories based on length of residual small
H.N. Lopez, M.D. bowel: short resection with 100–150-cm length
Pediatrics Department, Wake Forest University School of remaining, large resection with 40–100 cm remain-
Medicine, Winston-Salem, NC, USA
ing, and massive resection with 40 cm or less
J.E. Fortunato, M.D. (*) remaining. In general, massive resections particu-
Department of Pediatrics, Wake Forest University,
larly in the context of an absent ileocecal valve are
Medical Center Blvd, Winston-Salem, NC 27157, USA
e-mail: [email protected] associated with inability to wean completely from

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 307

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_27, © Springer Science+Business Media New York 2013
308 R. Gomez et al.

parenteral nutrition [1]. The absence of ileocecal extent and location of resection. For example, after
valve has been associated with increased diarrhea extensive distal small bowel resection, postopera-
and small bowel bacterial overgrowth (SBBO). tive changes such as decreased MMC velocity and
While mucosal adaptation has been exten- longer intervals between MMCs during fasting
sively studied, there is a paucity of data regarding with slight recovery of propagation frequency in
changes in motility after small intestinal resec- the chronic phase have been observed [5, 6].
tion. A better functional outcome is associated Findings such as shorter phase I duration and dis-
with proximal compared to distal resection, coordinate clustered MMC activity have also been
which may be related to both the adaptive capac- seen using the same model [7]. There are very lim-
ity and intrinsic properties of the jejunum and ited motility studies in humans after small bowel
ileum. Adaptation involves all layers of the bowel resection [8–10]. With extensive distal resection,
wall, including intestinal smooth muscle. The motility changes include shorter duration and more
intestinal smooth muscle is coordinated by both frequent MMCs as well as a reduction in phase 2
hormonal and neuronal components which regu- activity; however, limited ileal resection does not
late the transit of intestinal contents through the result in detectable manometric changes of jejunal
gastrointestinal tract [2]. Activation of this com- motility [9]. The postprandial motor response is
plex circuitry allows changes in the peristaltic not well defined, but appears to be shorter in
reflex to modulate the intestinal motility pattern patients after resection [10].
from propagative to segmenting. This is accom-
plished through a complex integration of signals
that trigger a jejunal and ileal break mechanism Intestinal Lengthening
in response to nutrients, most notably fats.
Mediators involved in this response include pep- Various surgical procedures, including Bianchi
tide YY, chemosensitive afferent neurons, nora- intestinal lengthening and serial transverse entero-
drenergic nerves, myenteric serotonergic neurons, plasty (STEP), have been developed to address the
and opioid neurons [3]. Following proximal anatomic and physiological consequence of short
resection of small bowel, for example, it has been bowel syndrome [11, 12]. These consequences
demonstrated that the postprandial motilin include reduced intestinal length, decreased
response is decreased, whereas transient increases mucosal surface area, rapid intestinal transit, and
in neurotensin and peptide YY have been noted ineffective peristalsis. Bianchi isoperistaltic bowel
after distal resection [4]. lengthening entails longitudinal division of the
After intestinal loss, a combination of shorter bowel with isoperistaltic end-to-end anastomosis
bowel length and disruption of normal physiolog- effectively doubling the length of that portion of
ical mechanisms may lead to poor absorption and the bowel. The STEP procedure involves the
malnutrition. Increased contractile response and sequential linear stapling of the dilated small
proliferative changes in intestinal smooth muscle bowel from alternating directions perpendicular to
cells may contribute to the compensatory adap- the long axis of the intestine [12].
tive mechanism to slow intestinal transit and Both the Bianchi and STEP have been shown to
improve nutrient absorption. While the cellular successfully result in increased caloric absorption
mechanism for this process is not well defined, and improved intestinal motility [13, 14]. After
mechanisms such as epidermal growth factor Bianchi, increased tolerance of enteral feeds,
receptor signaling have been shown to play a role improved growth, and decreased frequency of cath-
in adaptation of the smooth muscle cellular com- eter infections have been reported [15]. Significant
partment [2]. improvement in stool counts, intestinal transit time,
Little is known about changes in the migrating d-xylose absorption, and fat absorption resulting in
motor complex (MMC) after resection. Animal discontinuation of parenteral nutrition has also been
studies often reveal conflicting results with a broad observed [15, 16]. Longitudinal intestinal lengthen-
spectrum of motility changes depending on the ing and tailoring has also been associated with nor-
27 Small Bowel and Colonic Dysfunction After Surgery 309

malization in liver enzymes in patients weaned from Small bowel or multivisceral organ transplan-
parental nutrition [17]. Limitations of the Bianchi tation is often necessary for children after mas-
procedure include its technical difficulty, involve- sive intestinal resection including those with less
ment of at least one intestinal anastomosis, and risk than 25 cm of small bowel without ileocecal
to the mesenteric blood supply. It is also best per- valve, congenital intractable mucosal disorders,
formed if the bowel is symmetrically dilated. Some persistent hyperbilirubinemia, and diminishing
complications such as ileal valve prolapse and venous access, often associated with recurrent
recurrent small bowel dilatation have been reported episodes of sepsis [23, 24]. The role of perform-
after the operation [14]. ing small bowel motility studies as a gauge to
STEP has become widely accepted among determine whether intestinal transplantation
pediatric surgeons as it is technically easier to should be undertaken is unclear, but has been
perform than longitudinal bowel lengthening and proposed as a potential prognostic tool [25]. Most
preserves the natural mesenteric vasculature to studies have focused on the impact on intestinal
the intestine [18]. STEP has been shown to motility after transplantation [26].
improve weight retention, nutritional status, and After intestinal transplantation, maintenance
intestinal absorptive capacity in an animal model of intestinal motility with coordinated smooth
[19]. Phase III of the MMC appeared to be pre- muscle function and adequate absorptive capabil-
served in animals with STEP after resection and ity is paramount. Animal models have confirmed
anastomosis with the same mean amplitude and that intrinsic nerves are generally preserved after
frequency after octreotide as well as motility transplantation [27, 28]. The consequence of
index compared to controls [12]. Nonspecific extrinsic denervation from the small bowel may
abnormalities observed in both groups included lead to poor functioning of the grafted intestine.
simultaneous or tonic contractions as well as In a canine model, for instance, body weight and
contractions present in only proximal or distal serum albumin levels remain stable after auto-
segments. The duration of phase III after oct- transplantation. However, transplanted animals
reotide was also increased in STEP animals [12]. demonstrated significant defects in fat and
In patients with severe ischemia even after the d-xylose absorption compared to controls, possi-
STEP procedure, the intestinal motility continues bly attributed to overgrowth in fecal flora [27]. In
to be affected, and it correlates with feeding intol- a similar model, dogs undergoing autotransplan-
erance and TPN dependency (Fig. 27.1). tation experienced rapid intestinal transit com-
pared to short-gut animals which may suggest
that adaptive responses of the transplanted intes-
Intestinal Transplantation tine may be impaired by neuromuscular injury
associated with denervation or ischemia [29].
Intestinal transplantation has become an increas- Intestinal motility after small bowel transplan-
ingly accepted treatment for children with intesti- tation has been studied in children using antrodu-
nal failure with 3- and 5-year survival rates of odenal manometry [26]. Interdigestive phase III
84% and 77%, respectively, with most patients motor activity with normal manometric charac-
becoming independent of TPN [20]. The most teristics was seen as early as 3 months post trans-
frequent cause of intestinal failure is short-gut plantation in the majority of patients. However,
syndrome (SGS) defined by malabsorption, mal- disruption of an orderly MMC was noted across
nutrition, and growth retardation secondary to the anastomosis as well as abnormal postprandial
extensive loss of intestinal length or functional motility, which may in part be responsible for
gut mass [21, 22]. Gastroschisis, volvulus, necro- abnormal intestinal transit and poor absorption
tizing enterocolitis, intestinal atresia, chronic [26]. These studies emphasize how little is known
intestinal pseudoobstruction, and congenital about the effect of small bowel transplantation on
enteropathy are frequent conditions associated motility and underscore the need for future pro-
with SGS [20]. spective research.
Fig. 27.1 Small bowel and colonic motility in a 4-year- in the first eight channels. (b) HAPCs in the sigmoid after
old boy with a medical history of NEC, small bowel syn- bisacodyl stimulation (arrow). Courtesy of Dr. Carlo Di
drome, and post-STEP procedure. (a) Presence of Lorenzo and Dr. Hayat Mousa Nationwide Children’s
simultaneous contractions in the antrum and small bowel Hospital
27 Small Bowel and Colonic Dysfunction After Surgery 311

with other anatomic malformations in 30% of the

Roux-en-Y Jejunostomy and Bariatric patients resulting in increased mortality [37, 38].
Surgery Long-term gastrointestinal problems, most nota-
bly refractory gastroesophageal reflux disease
Roux-en-Y gastrojejunostomy has been employed (GERD), have been described in patients with
in both children and adults for a variety of indica- prior CDH repair [39]. In a recent multivariate
tions including postgastrectomy for peptic ulcer analysis, the incidence of GERD was shown to be
disease, as a component of bariatric surgery, and 39% immediately after repair and 16% 12–18
for jejunal feeding access [29]. The technique years after repair. Patients with an intrathoracic
limits reflux of bile into the gastric remnant and stomach and patch closure of the diaphragm
esophagus. Common postoperative symptoms seemed to demonstrate the most significant reflux
attributed to secondary dysmotility include symptoms in the early postoperative period [40].
abdominal fullness, distension, pain, nausea, and Reports of intestinal motility disorders in
vomiting [30]. These symptoms are likely the patients with CDH are limited. However, foregut
result of interrupted slow-wave electrical con- dysmotility has been postulated after CDH repair
duction which occurs after transecting the jeju- as evidenced by persistent upper GI symptoms
num resulting in shortened phase III MMC noted in association with abnormal gut fixation
duration and abnormal motor response to meals seen in nearly 10% of patients [41]. For example,
[31]. The consequence of disruption of the enteric antral hypomotility with low-amplitude and pro-
nervous system may include serious conditions longed phase III contractions has been observed
such as ascending cholangitis due to stasis of after CDH repair manifesting as symptoms of
bowel contents in the proximal limb of the roux severe gastroesophageal reflux and delayed gas-
segment, known as blind-loop syndrome [32]. tric emptying scintigraphy testing [42].
It has been shown in both adults and animals
that using an “uncut” Roux-en-Y technique may
avoid the problems observed with jejunal Gastroschisis
transection by prolonging the phase III MMC,
thereby enhancing digestive clearance [32]. Gastroschisis is a full-thickness defect in the
While gastrectomy is uncommon in children, abdominal wall usually adjacent to the insertion
there has been an increase in pediatric gastric of the umbilical cord with an incidence between
surgery to treat obesity particularly in adoles- 0.4 and 3 per 10,000 births [43]. A variable
cents [33]. Both laparoscopic adjustable gastric amount of intestine and abdominal organs may
banding and laparoscopic Roux-en-Y gastric herniate through this defect without the protec-
bypass have been performed in children, but tive covering of the peritoneal sac [44]. Ten per-
there is a paucity of data examining the effects cent of infants with gastroschisis develop
of these operations on gut motility. Overall, ischemic injury to the bowel due to vascular
there seems to be an improvement in health- insufficiency which may result in intestinal
related quality of life based on early studies, stenosis or atresia [43, 45]. Gastroschisis repre-
which may suggest limited disturbances in sents one of the major causes of intestinal fail-
motility in these patients [34]. ure often necessitating consideration of intestinal
transplantation. Approximately 40% of patients
with gastroschisis require parenteral nutrition
Congenital Diaphragmatic Hernia by the age of 4 months and 10% by the age of 2
years [46].
Congenital diaphragmatic hernia (CDH) is a Patients with gastroschisis tend to have per-
developmental defect present in less than 1 of sistent gut dysmotility with symptoms sugges-
1,000 live births resulting in herniation of abdom- tive of intestinal pseudoobstruction [47]. Even
inal viscera into the chest [35, 36]. It is associated after repair with adequate bowel length, these
312 R. Gomez et al.

patients have evidence of profound feeding small bowel obstruction due to atresia or
problems, increased hospitalizations, and mor- malrotation can lead to severe refeeding prob-
tality [48, 49]. Many of these patients with feed- lems in the neonatal period. Cezard et al.
ing problems may have neuropathic predominant described a form of postobstructive enteropathy
changes based on antroduodenal manometry (POE) of the apparently normal small intestine
(Gomez et al. unpublished case series). segment proximal to the obstruction. POE
Interestingly, in postnatal autopsy studies, there patients showed significant abnormal peristalsis
is no evidence of ganglion cell or generalized as characterized by barium and carmine transit
myenteric nervous system abnormalities to times. Small bowel manometric recordings are
explain the motility disorders that often accom- characterized by an absence or abnormal phase
pany cases of gastroschisis [50]. III of the migrating motor complex and decreased
motility index of the small intestine above the
obstruction [55, 56].
Motility Disorders After Repair of
Malrotation and Intestinal Atresia
Colectomy and Partial Colonic
Malrotation is defined by the absence of midgut Resection
rotation before reentering the abdominal cavity
during the 12th week of gestation [51]. By this Colonic resection in children is reserved for
time in embryonic development, the neurons chronic conditions such as refractory ulcerative
forming the ENS have already migrated from the colitis, Crohn’s colitis, familial adenomatous
neural crest to the intestine. Surgical correction polyposis, severe constipation, Hirschsprung’s
(Ladd’s procedure) involves division of a fibrous disease, and debilitating motility disorders such
stalk of peritoneal tissue attaching the cecum to as intestinal pseudoobstruction. Small bowel
the abdominal wall, known as Ladd’s bands; wid- and residual colonic function is contingent on
ening the small bowel mesentery; appendectomy; the region and extent of colonic resection as
and appropriate placement of the colon. Small well as the underlying pathology necessitating
bowel motility abnormalities including complete surgery. As an example, subtotal colectomy is a
absence of motor activity, low-amplitude or slow- surgical option to treat severe cases of constipa-
frequency contractions, and slow propagation of tion associated with colonic dilatation. While
phase III of the MMCs have been described after extensive resection of colon may accomplish
performing a Ladd’s procedure for these patients reduction in intestinal transit time, it may not
[52]. These manometric abnormalities have been eliminate symptoms of pain and bloating sug-
associated in some patients with histological gesting the possibility of a more generalized
changes such as distended neuronal axon hypo- motor disorder of the gut [57]. Colectomy in
ganglionosis or vacuolated nerve tracts in the these patients may also be associated with
small bowel [53]. uncontrolled diarrhea and fecal incontinence as
Intestinal atresia is a frequent cause of bowel well as relapsing constipation [58].
obstruction in neonates. Operative management The difficulties associated with subtotal
includes resection of the atresia with primary colectomy may be due to the adaptive changes
bowel anastomosis, resection with tapering in the MMC resulting in increased anaerobic
enteroplasty, temporary ostomy with intestinal bacterial colonization of the small intestine [59].
resection, enterostomy with web excision, and Partial colonic resection may alleviate some of
longitudinal intestinal lengthening procedures. symptoms observed after subtotal colectomy
After surgical correction, symptoms of adhesive particularly if performed in conjunction with
bowel obstruction occur in close to 25% of the preoperative motor assessment including Sitz
patients with prolonged adynamic ileus in 9% markers, scintigraphy, and antroduodenal and
and enterostomy prolapse in 2% [54]. Prolonged colonic manometry [60–62].
27 Small Bowel and Colonic Dysfunction After Surgery 313

Fig. 27.2 Example of two manometry catheters placed in manometry study. There is evidence of propulsive con-
a retrograde fashion from a colostomy and from the anus. tractions proximal to a diverting colostomy (top 8 chan-
The top panel shows the radiology image of the two nels in the manometry tracing) and absent motility in the
manometry catheters. The bottom panel shows the distal 4 channels in the distal colonic segment
314 R. Gomez et al.

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colonic dilatation, colonic and antroduodenal gic control of intestinal transit. Curr Gastroenterol
Rep. 2006;8(5):367–73.
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the absence of demonstrable colonic motility, a intestinal resection in the dog: an examination of
decompressive ileostomy or proximal colostomy the relative roles of mucosal adaptation, motility,
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 Gastric Function After
Fundoplication 28
Samuel Nurko

Fundoplication is one of the most common reduced gastric compliance, and significantly
operations performed in children [1–3]. It is a higher pain scores. It can be hypothesized that
very successful operation to control gastroe- the lower gastric compliance leads to stimulation
sophageal reflux, but it can be associated with of visceral efferents and heightened perception.
significant postoperative symptoms that may Zangen et al. [6] showed that in 12/14 children
limit its effectiveness [1, 2, 4]. there was a decrease in gastric volume capacity
that produced retching.
Similar findings of abnormal gastric accom-
Effect on Gastric Sensorimotor modation have been reported in adults. In a case
Function controlled study, proximal gastric function was
studied with the use of barostat in 12 adult
Fundoplication reduces the volume of the stom- patients that underwent fundoplication and com-
ach and uses most of the proximal stomach to pared with 12 controls [7]. It was found that there
create a wrap around the lower part of the esoph- was no difference between groups in compliance
agus [2, 3]. This can have a major impact on gas- during fasting. However, the adaptive relaxation
tric function and may explain some of the in the fundoplication group was significantly less
postoperative symptoms that may develop [5]. than that in controls after ingestion of a liquid
There have been a few studies that have evalu- meal [7]. The authors also showed that the fundal
ated gastric accommodation, sensation, and wrap is still functional and able to accommodate
emptying in children and adults after fundoplica- to pressure increments, that the stomach relax-
tion. Mousa et al. [3] studied gastric compliance ation after a meal occurs normally, but that there
and gastric sensory function before and after was a decrease in receptive relaxation in the
Nissen fundoplication in children. They per- patients with fundoplication. Similar findings
formed barostat studies in 13 children before related to accommodation were reported by Vu
surgery and repeated the test after surgery in 8. et al. [8] who studied with a barostat 12 adult
After fundoplication the patients had significantly patients before and after Nissen fundoplication
higher minimal distending pressure values, and compared the results with the findings on 12
healthy adults and 12 adults with GERD without
surgery. The sensation of fullness was increased
S. Nurko, M.D., M.P.H. (*) in the postoperative patients. Again, post-Nissen
Center for Motility and Functional Gastrointestinal patients had normal compliance, but reduced
Disorders, Children’s Hospital Boston,
300 Longwood Ave, Boston, MA 02155, USA
postprandial gastric accommodation and acceler-
e-mail: [email protected] ated gastric emptying.

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 317

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_28, © Springer Science+Business Media New York 2013
318 S. Nurko

Other less invasive methods that indirectly insulin-induced hypoglycemia, Vu et al. found that
assess gastric function have also been used to 11 of their 12 patients had a normal response [8].
study gastric function after surgery. By using sin- Thus, it appears that the reduced gastric accom-
gle-photon emission computed tomography with modation is probably mechanical in origin [7, 8].
three-dimensional analysis, Bouras et al. [9]
showed that patients post fundoplication had a
postprandial/fasting gastric volume ratio that was Effects on Gastric Emptying
lower than in healthy controls, again suggesting
impaired gastric accommodation. By using the Patients with GERD frequently have delayed
water load test, Remes-Troche et al. [10] found gastric emptying [8]. It has been reported that
that patients with dyspeptic symptoms after fun- fundoplication may accelerate gastric emptying
doplication had a significantly lower drinking for both solids and liquids [7, 8, 13, 14]. Faster
capacity and higher symptom scores than controls gastric emptying after a fundoplication is attrib-
with values similar to those of patients with func- uted to the loss of accommodation in the stom-
tional dyspepsia. They suggested that, as in func- ach, thereby preventing the fundus from
tional dyspepsia, severe dyspeptic symptoms after expanding to hold the liquid portion of the meal
fundoplication are associated with an impaired [15]. An acceleration of gastric emptying after
drinking capacity, reflecting visceral hypersensi- surgery in children has not been consistently
tivity or impaired gastric accommodation or both. found. Mousa et al. [3] found no significant
Visceral hypersensitivity has been associated with change in emptying for both solids and liquids
abnormal gastric accommodation and hyperalge- after surgery, although most patients had normal
sia, and contributing factors to this hypersensitiv- emptying before the surgery.
ity are likely to be wall tension and the function of A fast gastric emptying after surgery can pro-
visceral afferents [11]. duce postoperative symptoms [2, 4, 12]. Diarrhea
The exact mechanism by which these changes which can occur in up to 18 % of patients [12]
in accommodation occur is not clear. There may has been correlated with rapid gastric emptying.
be alterations in the proximal gastric wall function An exaggerated fast gastric emptying for liquids
or the abnormalities may be secondary to vagal may produce dumping syndrome [2, 4, 12]. Even
dysfunction or to the mechanical effects of the though this occurrence is more frequent when a
fundoplication per se [3, 5, 12]. The proximal gas- pyloroplasty has been performed, it has been
tric wall seems to function normally as gastric shown to occur also in children and adults in
compliance and tone have been found to be normal whom no pyloroplasty was done. The pathophys-
[7, 8]. It is then possible that the surgical manipu- iology of dumping syndrome in children is multi-
lation itself could impair autonomic pathways factorial, although its incidence and its severity
affecting the gastric sensorimotor function and appear to be proportional to the rate of emptying
that changes in postprandial relaxation after reflux [16]. Fonkalsrud et al. [1] described a postopera-
surgery could result from alterations in neurohor- tive transient dumping syndrome in 0.9 % out of
monal control [5, 12]. Vagal nerve function after 7,467 fundoplications (0–5 %), and in a prospec-
fundoplication has been evaluated by using differ- tive study of 50 pediatric patients, Samuk et al.
ent methods. By using sham-feeding-stimulated [17] diagnosed dumping syndrome in 30 %.
pancreatic polypeptide (PP) test before and after
surgery, Devault et al. [12] showed that 5/12 with
normal testing before the surgery had developed Effects on Antroduodenal Motility and
evidence of vagal dysfunction after surgery. Gastric Myoelectrical Activity
Interestingly, there was no correlation between PP
tests and the development or worsening of symp- The effect of fundoplication on antroduodenal
toms after surgery. In another study that evaluated motility has not been clearly established. No
vagal function by measuring PP serum changes to prospective studies measuring antroduodenal
28 Gastric Function After Fundoplication 319

motility before and after fundoplication have been retching, pain, feeding refusal, and diarrhea [2, 4,
reported, but studies of children and adults with 6, 12]. Dysphagia can often be corrected with
postoperative problems have shown abnormal esophageal dilation and occasionally repeated
antroduodenal motility [5, 6, 18]. In one study it surgery [4]. Inability to belch is an expected out-
was shown that 25 of 28 symptomatic children come after fundoplication and most patients learn
after fundoplication had abnormalities. The most to compensate for this symptom [4]. The devel-
common abnormality found was an absence of the opment of retching, gas-bloat syndrome, early
migrating motor complex in 12, while six had satiety, diarrhea, pain, and feeding refusal is more
postprandial hypomotility; other nonspecific difficult to explain [4, 10, 20] and is probably
abnormalities included clustered, retrograde, and related to the effects that the fundoplication has
tonic contractions [18]. Similar motility abnor- on the sensorimotor gastric function.
malities have been described in adults [5]. There are other factors that may predispose
In another study of 14 patients with food patients to have symptoms. The presence of a
refusal after fundoplication, an abnormal antrodu- fundoplication, which both strengthens the lower
odenal manometry was described in nine patients, esophageal sphincter and decreases transient
suggesting that abnormal motility after surgery lower esophageal sphincter relaxations [21], may
does not occur in all patients with symptoms. It is prevent venting of gas from the proximal stom-
unclear if the abnormalities were present before ach and cause increased abdominal distention,
the operation or are a result of it. Given that the particularly in patients with gastroesophageal
abnormalities found were similar to those seen in reflux who are known to swallow large volumes
chronic intestinal pseudo-obstruction and that not of air routinely [12]. Richards et al. found that
all children with postoperative symptoms have children, in whom gastric myoelectrical activity
motility dysfunction, it is likely that the abnor- had deteriorated after surgery, developed retch-
malities predated the operation, suggesting that ing postoperatively [19], and concluded that
those children had a more generalized gastroin- Nissen fundoplication may be followed by a pro-
testinal dysfunction, and not only gastroesopha- gression of gastric dysrhythmias that may be
geal reflux. The presence of preoperative gastric associated with retching [19]. In children, another
myoelectrical dysfunction has also been reported. prominent symptom after fundoplication can be
Richards et al. measured gastric myoelectrical food refusal which can be secondary not only to
activity before and after fundoplication with the gastric dysfunction but also be related to pain and
use of surface electrogastrography in 27 children behavioral issues [6].
(17 neurologically impaired and 10 neurologi- Given that the symptoms can originate from a
cally normal) [19]. They found abnormal gastric variety of underlying problems, it is important to
electrical activity before surgery in 65 % of the clarify the pathophysiology of the symptoms in
neurologically impaired as compared with 20 % each patient [6]. Ideally, treatment has to be tai-
of the neurologically normal group. After surgery lored accordingly, and a multidisciplinary team
an abnormal myoelectrical activity developed in may be necessary [6]. Drugs that increase gastric
six (three in each group). accommodation may be beneficial. Given that
5HT1 receptors are involved in gastric accommo-
dation, agonists such as cyproheptadine, suma-
Relation of Postoperative Symptoms triptan, and buspirone may be used [2, 6, 10].
to Gastric Dysfunction Prokinetics may be beneficial in those children
with evidence of delayed gastric emptying.
It has been reported that up to a third of patients Erythromycin has been used for this purpose but
develop symptoms after fundoplication [3]. it can cause increased pain and nausea [2]. Other
Symptoms commonly seen after antireflux sur- prokinetics, like metoclopramide, cisapride, and
gery include dysphagia, inability to belch, early domperidone, have limited use given their side
satiety, bloating, dyspepsia, gas-bloat syndrome, effect profile and lack of availability in most parts
320 S. Nurko

of the world [2, 4, 6]. Injection of botulinum 4. Nurko SS. Complications after gastrointestinal sur-
toxin into the pylorus may relieve some of the gery. A medical perspective. In: Walker WA et al.,
editors. Pediatric gastrointestinal disease. 3rd ed.
gas-bloat symptoms. Smaller meals, anticholin- Philadelphia: B.C. Decker Inc.; 2004. p. 2111–38.
ergics and pain modulators (like low-dose antide- 5. Stanghellini V, Malagelada JR. Gastric manometric
pressants or gabapentin), and behavioral abnormalities in patients with dyspeptic symptoms
techniques are often used [2, 6]. When symptoms after fundoplication. Gut. 1983;24(9):790–7.
6. Zangen T, Ciarla C, Zangen S, Di Lorenzo C, Flores
related to food ingestion are particularly severe, it AF, Cocjin J, et al. Gastrointestinal motility and sen-
may be necessary to use jejunal feedings [6]. sory abnormalities may contribute to food refusal in
medically fragile toddlers. J Pediatr Gastroenterol
Nutr. 2003;37(3):287–93.
7. Wijnhoven BP, Salet GA, Roelofs JM, Smout AJ,
Summary and Conclusions Akkermans LM, Gooszen HG. Function of the proxi-
mal stomach after Nissen fundoplication. Br J Surg.
Fundoplication has an impact on gastric sensorim- 1998;85(2):267–71.
otor function. It reduces the volume of the stomach 8. Vu MK, Ringers J, Arndt JW, et al. Prospective study
of the effect of laparoscopic hemifundoplication on
and uses most of the proximal stomach to create a motor and sensory function of the proximal stomach.
wrap around the lower part of the esophagus. Br J Surg. 2000;87:338–43.
Studies consistently show that fundoplication 9. Bouras EP, Delgado-Aros S, Camilleri M, Castillo EJ,
accelerates the rate of gastric emptying, decreases Burton DD, Thomforde GM, et al. SPECT imaging of
the stomach: comparison with barostat, and effects of
gastric accommodation, changes distribution of sex, age, body mass index, and fundoplication. Single
intragastric food with the ingested material reach- photon emission computed tomography. Gut. 2002;
ing and distending the distal stomach earlier than 51(6):781–6.
physiologically expected, and may produce vis- 10. Remes-Troche JM, Montano-Loza A, Martinez JC,
Herrera M, Valdovinos-Diaz MA. Drinking capacity
ceral hypersensitivity. Postoperative symptoms and severity of dyspeptic symptoms during a water
that may be attributed to gastric sensorimotor dys- load test after Nissen fundoplication. Dig Dis Sci.
function after surgery include inability to belch, 2007;52(10):2850–7.
early satiety, bloating, dyspepsia, gas-bloat syn- 11. Mertz H, Fullerton S, Naliboff B, Mayer EA. Symptoms
and visceral perception in severe functional and organic
drome, retching, pain, feeding refusal, diarrhea, dyspepsia. Gut. 1998;42(6):814–22.
and dumping. Given that the symptoms can origi- 12. DeVault KR, Swain JM, Wentling GK, Floch NR,
nate from a variety of underlying problems, it is Achem SR, Hinder RA. Evaluation of vagus nerve
important to clarify the pathophysiology of the function before and after antireflux surgery.
J Gastrointest Surg. 2004;8(7):883–8. discussion
symptoms in each patient in order to be able to 8–9.
tailor therapy accordingly. 13. Lindeboom MY, Ringers J, van Rijn PJ, Neijenhuis P,
Stokkel MP, Masclee AA. Gastric emptying and vagus
Acknowledgement Supported by grant NIH nerve function after laparoscopic partial fundoplica-
K24DK082792A. tion. Ann Surg. 2004;240(5):785–90.
14. Farrell TM, Richardson WS, Halkar R, Lyon CP,
Galloway KD, Waring JP, et al. Nissen fundoplica-
tion improves gastric motility in patients with
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Grosfeld JL, Tunell WP, et al. Surgical treatment of Relationship of a satisfactory outcome to normal-
gastroesophageal reflux in children: a combined hos- ization of delayed gastric emptying after Nissen
pital study of 7467 patients. [comment]. Pediatrics. fundoplication. Ann Surg. 1989;210(4):458–64.
1998;101(3 (Pt 1)):419–22. discussion 64–5.
2. Di Lorenzo C, Orenstein S. Fundoplication: friend or 16. Borovoy J, Furuta L, Nurko S. Benefit of uncooked
foe? J Pediatr Gastroenterol Nutr. 2002;34:117–24. corn starch in the management of children with
3. Mousa H, Caniano DA, Alhajj M, Gibson L, Di dumping syndrome fed exclusively by gastrostomy.
Lorenzo C, Binkowitz L. Effect of Nissen fundoplica- Am J Gastroenterol. 1998;93:814–8.
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Gastroenterol Nutr. 2006;43(2):185–9. Vinograd I. Dumping syndrome following Nissen
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fundoplication, diagnosis, and treatment. J Pediatr 20. Klaus A, Hinder RA, DeVault KR, Achem SR. Bowel
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 Part V
Functional Gastrointestinal
Disorders
 History and Definition of the Rome
Criteria 29
Andrée Rasquin

The history of the Rome criteria began in 1987, were born and published in 1991 [2, 3]. This
when Professor Aldo Torsoli proposed the use of arduous process improved the understanding of
a consensus process to define various gastrointes- FGIDs tremendously. It introduced clarity and
tinal disturbances that appeared to cluster together consistency in deriving clinical diagnoses, which
with significant prevalence, constituting disor- could now be made positively according to the
ders. Because of the lack of reproducible anatom- criteria. By selecting homogenous groups of
ical or biochemical abnormalities, these complaints patients, it became possible to make comparisons
were considered to be of functional origin. Among between different treatment approaches to the
them, irritable bowel syndrome (IBS) was a good often complex factors compounding the disorders.
example. A working team of international experts Moreover, it definitively encouraged research on
in gastroenterology was formed and its members pathophysiology.
decided to use the so-called Delphic approach, In 1993, I was faced with the decision of where
which promotes the reaching of a consensus for to spend a sabbatical year. Having spent the pre-
questions not easily addressed [1]. They applied vious 8 years working with a multidisciplinary
this method to clarify gastrointestinal conditions team to build the pediatric liver transplant pro-
that were not easily resolved by scientific research gram for the province of Quebec, I was convinced
or literature review. It took 2–3 years for the entire of the deep and effective human value that a biop-
consensus process to be completed. Five commit- sychosocial approach could bring to children
tees were each given a topic based on anatomical with chronic disease and to their families. Despite
region: esophageal, gastroduodenal, intestinal, the physical and emotional suffering that accom-
biliary, and anorectal. Within each committee, panied the journey through a liver transplant,
members were invited to apply their own experi- children and their families were coming out of
ence and knowledge of the literature to define cri- the experience with a deeper understanding and
teria, and their reports were subsequently merged appreciation of themselves and their lives.
to form a final document. Thus the Rome I symp- I decided to apply the same biopsychosocial
tom-based diagnostic criteria for functional gas- model to a group of children that we, as pediatric
trointestinal disorders (FGIDs) in adult patients gastroenterologists, had been poorly prepared to
treat, i.e., children with FGIDs. We were still
A. Rasquin, M.D. (*) conducting endoscopies that indeed revealed
Division of Gastroenterology, Pediatrics Department, negative results and were sending these families
Chu Ste Justine, University of Montreal, home saying that nothing was found. After inves-
3175 Cote Ste Catherine, Montreal, QC, Canada
tigating different centers where I could be trained,
H3T-1C5
e-mail: [email protected] I chose the gastroenterology unit at the University

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 325

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_29, © Springer Science+Business Media New York 2013
326 A. Rasquin

of North Carolina, where Douglas Drossman had The work of the pediatric working team was
been using the biopsychosocial approach with original in that for the first time, it proposed a
adult patients with FGIDs. I felt that this setting classification system and symptom-based diag-
would be the most appropriate place, despite the nostic criteria for all the gastrointestinal syn-
fact that I had not approached an adult patient for dromes considered to be functional in children. It
the last 25 years! also reviewed diagnostic guidelines and treatment
My experience at UNC in 1994–1995 pro- approaches. The effort was well received by the
vided me with new insight into the medical scientific community; to date, the publication has
approach to FGIDs. Observing Douglas Drossman been cited nearly 500 times in the medical litera-
interviewing and listening to his patients was a ture. The contact and sharing of experience among
deeply human experience, and I learned from different working groups within the Rome struc-
him how to never let them feel that they had ture was inspiring and proved to be a great asset to
“nothing.” The trust and confidence that he estab- the pediatric team. It helped place the pediatric
lished was remarkable in that his patients finally disorders within a larger perspective and reaffirmed
felt that a doctor cared and would accompany the belief that early life experiences can have
them. This was the beginning of a healing jour- important consequences in adulthood [7]. The
ney for them, despite the fact that a cure was team decided to classify the pediatric disorders
never promised [4]. according to symptoms rather than anatomical
Synchronicities do occur! In 1995, the revision regions. The disorders were grouped according to
of the Rome I symptom-based diagnostic criteria the following presenting symptoms: vomiting,
for adult FGIDs was in progress. During my stay abdominal pain, diarrhea, and defecation com-
in North Carolina, it soon became obvious that the plaints. The team tried to take different develop-
rationale for symptom-based criteria applied ment stages of childhood into account. Indeed,
equally to pediatric patients and that the participa- some digestive symptoms, such as regurgitation,
tion of pediatric gastroenterologists to the Rome may accompany normal development in an infant,
process could make an important contribution to but not at later stages of development. Some
the approach for children with FGIDs. symptoms could be indicative of maladaptive
Thanks to Douglas Drossman and Enrico behavior, as in the case of a child with retentive
Corazziari, we were allowed to form an interna- fecal soiling. Age limits were defined for certain
tional pediatric working team. It was composed syndromes, such as IBS and dyspepsia, recogniz-
of Paul E. Hyman, Jeffrey S. Hyams, David R. ing that after a certain age, the child can be a reli-
Fleisher, Peter J. Milla, Annamaria Staiano, able self-reporter of symptoms. Particular
Salvatore Cucchiara, and myself. Each member emphasis was put on the child’s psychosocial con-
produced a document that was incorporated into text; it was recognized that the decision to report
a manuscript. In 1996, the team met in Rome for symptoms generally lies with parents and that
3 days to reach a consensus. The final version of their own private issues and fears can influence
the document was sent to six independent inter- their children’s symptom presentation.
national experts before the final consensus report This effort at classification was a first attempt
on the criteria for pediatric functional gastroin- and, obviously, far from perfect. There were little
testinal disorders was presented to the adult evidence-based data available, obliging team
group. They were published in 1999 and 2000 as members to rely mainly on their experience.
part of the Rome II criteria [5, 6]. In this publica- Furthermore, at that time, the team was limited to
tion on the revised Rome criteria for adult six members, whose task was to define all func-
patients, other chapters addressed newly devel- tional disorders, and it excluded the participation
oping topics, such as gut motility and sensitivity, of several excellent experts in each domain. The
brain/gut interaction, psychosocial aspects of team was neither multinational nor multidisci-
FGIDs, recommendations for clinical trials and plinary and did not include infantile neurophysi-
designs, and questionnaires. ologists and pediatric psychologists. However,
29 History and Definition of the Rome Criteria 327

Table 29.1 Pediatric functional gastrointestinal disorders

(A) Neonates and toddlers
Infant regurgitation Functional diarrhea
Infant rumination syndrome Infant dyschezia
Cyclic vomiting syndrome Functional constipation
Infant colic
(B) Children and adolescents
Vomiting and aerophagia Abdominal pain-related FGIDs
Adolescent rumination syndrome Functional dyspepsia
Cyclic vomiting syndrome Irritable bowel syndrome
Aerophagia Abdominal migraine
Constipation and incontinence Childhood functional abdominal pain
Functional constipation Childhood functional abdominal pain syndrome
Nonretentive fecal incontinence

the team felt that it was a good starting point and lated FGIDs, but further refinement is still
that the advantages of being part of the Rome required, since inter-rater reliability among pedi-
process far exceeded its drawbacks. atric gastroenterologists remains only fair to
Studies supporting the validity of the pediatric moderate [15, 16]. The criteria have helped in the
criteria were published as early as 2001 [8, 9]. design of multicenter clinical trials and research
However, since the criteria were defined by con- on pathophysiology [17–21]. However, pediatric
sensus, validation studies were needed to confirm studies remain very modest in comparison to the
that the disorders did indeed exist in the patient recent dramatic research advances in neurosci-
population. The preliminary steps consisted of ence [22].
establishing a questionnaire based on the disor- The number of publications using the pediat-
ders and validating its use among adolescents ric Rome III criteria has been growing more
with digestive complaints and their parents. This recently in various countries and continents. This
validation was performed and published in 2005 should permit comparisons between children
[10, 11]. The development and validation of the from different cultural origins in the future, an
questionnaire promoted further research, facili- exploration that has already been promoted in the
tated clinical trials, and helped in the subsequent document of the Rome III criteria [12]. Along
revision of the pediatric criteria. with sections on pharmacology and pharmacoki-
The Rome III pediatric criteria were published netics of medications for FGIDs, a new chapter
in 2006 (Table 29.1) [12, 13]. For this task, two appeared concerning the respective influences of
pediatric working teams, consisting of six mem- gender, age, society, and culture on symptom pre-
bers each, were created. It was decided to divide sentation and clinical approaches. This topic in
pediatric FGIDs into two groups, according to particular was recently examined at our univer-
the developmental stage of their occurrence: sity in collaboration between the Departments of
(1) neonates and toddlers and (2) children and Pediatrics and Anthropology and is reported upon
adolescents. This time, experts from yet other in another chapter of this book. Suffice to say that
countries participated and a pediatric psycholo- the study of cultural aspects of abdominal pain-
gist was included. This work led to another 540 related FGIDs was very interesting. It certainly
citations in the medical literature during the fol- helped me realize the extent to which my own
lowing years. The use of the Rome III criteria has interviews were devoid of cultural inquiry.
been encouraged and the biopsychosocial Using the Rome criteria and a biopsychoso-
approach has been highly recommended [14]. cial approach will undoubtedly help physicians
The Rome III criteria were shown to be more caring for children. Recently, I have become
inclusive for children with abdominal pain-re- deeply concerned by the increasing level of
328 A. Rasquin

diffuse anxiety in children in general and in those 6. Hyman PE, Rasquin-Weber A, Fleisher D, et al. Childhood
with FGIDs in particular. Children are increas- functional gastrointestinal disorders. In: Drossman D, edi-
tor. The functional gastrointestinal disorders. McLean,
ingly aware of global violence, threats, and catas- VA: Degnon Associates; 2000. p. 533–75.
trophes, and many experience these events 7. Milla PJ. Irritable bowel syndrome in childhood.
through different forms of media. Children’s Gastroenterology. 2001;120:287–90.
involvement in saving the planet is regularly 8. Van Ginkel R, Voskuijl WP, Benninga MA, et al.
Alterations in rectal sensitivity and motility in child-
addressed at school, and their concerns and anxi- hood irritable bowel syndrome. Gastroenterology.
eties are growing. I am convinced that physicians 2001;120:31–8.
must address this issue as well as better under- 9. Di Lorenzo C, Youssef NN, Sigurdsson L, et al.
stand how cultural origins influence children’s Visceral hyperalgesia in children with functional
abdominal pain. J Pediatr. 2001;139:838–43.
and families’ ways of coping. 10. Caplan A, Walker L, Rasquin A. Development and
Advances in neurogastroenterology, which preliminary validation of the questionnaire on pediat-
explore the brain/gut axis and the transfer of ric gastrointestinal symptoms to assess functional
information through the autonomic, neuroendo- gastrointestinal disorders in children and adolescents.
J Pediatr Gastroenterol Nutr. 2005;41:296–304.
crine, and immune systems, have brought new 11. Caplan A, Walker L, Rasquin A. Validation of the
knowledge about the influence of psychosocial pediatric Rome II criteria for functional gastrointesti-
factors on physical symptoms [23, 24]. More nal disorders using the questionnaire on pediatric gas-
recently, features of IBS occurring after an infec- trointestinal symptoms. J Pediatr Gastroenterol Nutr.
2005;41:305–16.
tious episode have been shown in some patients 12. Di Lorenzo C, Rasquin A, Forbes D, et al. Childhood
to overlap with those of inflammatory bowel dis- functional gastrointestinal disorders: child/adolescent.
eases. With these advances, the frontiers between In: Drossman A, editor. The functional gastrointesti-
organic and functional are becoming thinner, nal disorders. Durham, NC: BW&A Books Inc.; 2006.
p. 723–7.
challenging our present dualistic view [25]. How 13. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood
long the Rome criteria will remain a useful clini- functional gastrointestinal disorders: child/adolescent.
cal tool before FGIDs become “organic” is indeed Gastroenterology. 2006;130:1527–37.
a challenging question. Meanwhile, I remain con- 14. Hyman PE. Will the Rome criteria help pediatrics? J
Pediatr Gastroenterol Nutr. 2008;47:700–3.
vinced that these criteria constitute a valuable 15. Baber KF, Anderson J, Puzanovova M, et al. Rome II
tool for both research and clinical approaches to versus Rome III classification of functional gastroin-
FGIDs in children and that their use should be testinal disorders in pediatric chronic abdominal pain.
promoted among physicians [26]. J Pediatr Gastroenterol Nutr. 2008;47:299–302.
16. Chogle A, Dhroove G, Sztainberg M, et al. How reli-
able are the Rome III criteria for the assessment of
functional gastrointestinal disorders in children? Am
J Gastroenterol. 2010;105:2697–701.
References 17. Saps M, Youssef N, Miranda A, et al. Multicenter,
randomized, placebo-controlled trial of amitriptyline
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assessment by a Delphi group opinion technic. N Engl Gastroenterology. 2009;137:1261–9.
J Med. 1973;288:1272–5. 18. Saps M, Pensabene L, Turco R, et al. Rotavirus gastro-
2. Thompson WG. The road to rome. Gastroenterology. enteritis: precursor of functional gastrointestinal disor-
2006;130:1552-6. ders? J Pediatr Gastroenterol Nutr. 2009;49:580–3.
3. Drossman DA, Richter JE, Talley NJ, et al. The func- 19. Saps M, Pensabene L, Di Martino L, et al. Post-
tional gastrointestinal disorders: diagnosis, pathophy- infectious functional gastrointestinal disorders in chil-
siology and treatment: a multinational consensus. dren. J Pediatr. 2008;152:812–6.
Boston; 1994. 370 p. 20. Halac U, Noble A, Faure C. Rectal sensory threshold
4. Wong RK, Tan JS, Drossman DA. Here’s my phone for pain is a diagnostic marker of irritable bowel syn-
number, don’t call me: physician accessibility in the drome and functional abdominal pain in children. J
cell phone and e-mail era. Dig Dis Sci. Pediatr. 2010;156:60–5.
2010;55:662–7. 21. Shulman RJ, Eakin MN, Czyzewski DI, et al. Increased
5. Rasquin-Weber A, Hyman PE, Cucchiara S, et al. gastrointestinal permeability and gut inflammation in
Childhood functional gastrointestinal disorders. Gut. children with functional abdominal pain and irritable
1999;45 Suppl 2:II60–8. bowel syndrome. J Pediatr. 2008;153:646–50.
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22. Youssef NN, Di Lorenzo C. Pediatric gastrointestinal Part II: Clinical applications and implications for
motility—future directions and challenges. Dig Dis. research. Psychosom Med. 2009;71:135–51.
2006;24:308–12. 25. Grover M, Herfarth H, Drossman DA. The functional-
23. Lane RD, Waldstein SR, Chesney MA, et al. The organic dichotomy: postinfectious irritable bowel syn-
rebirth of neuroscience in psychosomatic medicine. drome and inflammatory bowel disease-irritable bowel
Part I: Historical context, methods, and relevant basic syndrome. Clin Gastroenterol Hepatol. 2009;7:48–53.
science. Psychosom Med. 2009;71:117–34. 26. Hyman PE, Monagas J. Rectal perceptual hypersensi-
24. Lane RD, Waldstein SR, Critchley HD, et al. The tivity: a biomarker for pediatric irritable bowel syn-
rebirth of neuroscience in psychosomatic medicine. drome. J Pediatr. 2010;156:5–7.
 Infant Regurgitation and Pediatric
Gastroesophageal Reflux Disease 30
Yvan Vandenplas, Bruno Hauser, Thierry Devreker,
and Silvia Salvatore

nausea, and retching. Vomiting is defined as

Definitions expulsion with force of the refluxed gastric con-
tents from the mouth [2, 3]. Vomiting associated
Determination of the exact prevalence of gastroe- with reflux is likely the result of the stimulation of
sophageal reflux (GER) and GER disease (GERD) pharyngeal sensory afferents by refluxed gastric
at any age is virtually impossible for many rea- contents. Rumination is the consequence of a con-
sons: most reflux episodes are asymptomatic, traction of the abdominal muscles resulting in the
symptoms and signs are nonspecific, and self- habitual regurgitation of recently ingested food
treatment is common. “Physiologic GER” is GER that is subsequently spitted up or reswallowed.
associated with absence of symptoms, or during GERD is a spectrum of a disease that can best
the first months of life accompanied with regurgi- be defined as manifestations causing esophageal
tation, and occasionally with vomiting. Regur- or extraesophageal troublesome symptoms or
gitation, spitting up, possetting, and spilling are esophageal or adjacent organ injury secondary to
synonyms and are defined as the passage of the reflux of gastric contents into the esophagus
refluxed gastric contents into the pharynx and or, beyond, into the oral cavity or airways. To be
sometimes expelled out of the mouth [1]. defined as GERD, reflux symptoms must be trou-
Regurgitation is distinguished from vomiting by blesome to the infant, child, or adolescent and not
the absence of a central nervous system emetic simply troublesome for the caregiver [4].
reflex, retrograde upper intestinal contractions, Environmental and genetic factors are indentified
as predisposing factors [2].
Transient lower esophageal sphincter relax-
Y. Vandenplas, M.D., Ph.D. (*)
ations (TLESRs) are the most frequent and
Pediatrics, Universitair Ziekenhuis Brussel,
Laarbeeklaan 101, 1090, Brussels, Belgium important pathophysiologic mechanism causing
e-mail: [email protected] GER at any age, from prematurity into adulthood
B. Hauser, M.D. [5, 6]. More information on pathophysiology can
Paediatrics Department, Paediatric Gastroenterology be found elsewhere [5].
Hepatology and Nutrition Division, Universitair
Kinderziekenhuis Brussel, Brussels, Belgium
T. Devreker, M.D. Symptoms of GERD
Pediatric Gastroenterology Department, Universitair
Kinderziekenhuis Brussel, Brussels, Belgium
While reflux occurs physiologically at all ages,
S. Salvatore, M.D.
there is also at all ages a continuum between
Pediatric Department, University of Insubria, Ospedale
“F. Del Ponte”, Varese, Italy physiologic GER and GERD [2]. Less than 10%

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 331

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_30, © Springer Science+Business Media New York 2013
332 Y. Vandenplas et al.

Table 30.1 Symptoms and signs that may be associated

with gastroesophageal reflux Uncomplicated Regurgitation
Symptoms
Recurrent regurgitation with/without vomiting Regurgitation is the most common presentation of
Weight loss or poor weight gain infantile GER and is usually but not always effort-
Irritability in infants less. Regurgitation is neither necessary nor
Ruminative behavior sufficient to diagnose GERD, because it is not sen-
Heartburn or chest pain
sitive or specific [4]. Excessive regurgitation is one
Hematemesis
of the symptoms of GERD, but the terms regurgita-
Dysphagia, odynophagia
tion and GERD should not be used as synonyms.
Wheezing
Up to 70% of healthy infants have daily physio-
Stridor
Cough
logic regurgitation, resolving without intervention
Hoarseness from the age of 6 months onward. Frequent regur-
Signs gitation, defined as >4 times per day, occurs in
Esophagitis about 20% of infants during the first months of life.
Esophageal stricture By 12–14 months of age, regurgitation has disap-
Barrett’s esophagus peared in over 95% [9, 10]. A prospective study
Laryngeal/pharyngeal inflammation confirmed disappearance of regurgitation before 12
Recurrent pneumonia months, although the prevalence of feeding refusal,
Anemia duration of meals, parental feeding-related distress,
Dental erosion and impaired quality of life was related to the ear-
Feeding refusal lier frequency of regurgitation and persisted even
Dystonic neck posturing (Sandifer syndrome) after the disappearance of the regurgitation [11].
Apnea spells Regurgitation is frequent in infants because of the
Apparent life-threatening events (ALTE). Adapted from large liquid volume intake, the limited capacity of
Vandenplas, Rudolph CD, Di Lorenzo C, Hassall E., et al.
Pediatric gastroesophageal reflux clinical practice guidelines;
the esophagus (10 ml in newborn infants), and the
joint recommendations of the North American Society for horizontal position of infants. Infants ingest per kg
Pediatric Gastroenterology, Hepatology, and Nutrition bodyweight more than twice the volume that adults
(NASPGHAN) and the European Society Pediatric do (100–150 ml/kg/day compared to 30–50 ml/kg/
Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J
Pediatr Gastroneterol Nutr 2009;49(4):498–547
day), causing more gastric distention, and as a con-
sequence more TLESRs. Feeding frequency is also
higher in infants than in adults, resulting in more
postprandial periods during which TLESRs are
more common. Irritability may accompany regur-
gitation and vomiting; however, in the absence of
other warning symptoms (Table 30.2), it is not an
of infants and children have (acid and trouble- indication for extensive testing [1]. Parental coping
some) GERD [7]. The presenting symptoms of capacity or anxiousness usually determines if a
GERD differ according to age. Possible associa- physician is consulted or not. Infant regurgitation is
tions exist between GERD and hiccups, chronic a benign condition with a good prognosis, needing
cough, chest pain, hoarseness, recurrent otitis no other intervention than parental education and
media, asthma, pneumonia, bronchiectasis, anticipatory guidance, and if necessary, interven-
apparent life-threatening events (ALTE), laryn- tion on feeding volume, frequency, and composi-
gotracheitis, sinusitis, and dental erosions tion will contribute to parental reassurance.
(Table 30.1), but causality or temporal associa- Overfeeding exacerbates recurrent regurgitation.
tion has not been established for many of these Thickened or anti-regurgitation formula decreases
signs and symptoms [8]. overt regurgitation [1].
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 333

Table 30.2 Warning signals requiring investigation in

infants with regurgitation or vomiting GER(D) and Distressed Behavior
Bilious vomiting
GI bleeding The concept that infant irritability and sleep dis-
– Hematemesis turbances are manifestations of GER is largely
– Hematochezia derived from adult data [1]. The same amount of
Consistently forceful vomiting distress and crying may be deemed by some par-
Onset of vomiting after 6 months of life ents as easily acceptable while it may be unbear-
Failure to thrive able for others. Many factors, such as dietary
Diarrhea protein milk allergy and exposure to tobacco
Constipation smoke, may cause infant irritability. There is sub-
Fever stantial interindividual variability and some
Lethargy
healthy infants may cry up to 6 h a day.
Hepatosplenomegaly
In adults, “nonerosive reflux disease”
Bulging fontanelle
(“NERD”) is a widely accepted entity. Again in
Macro-/microcephaly
Seizures
adults, impaired quality of life, notably regarding
Abdominal tenderness or distension pain, mental health, and social function, has been
Documented or suspected genetic/metabolic syndrome demonstrated in patients with GERD, regardless
Adapted from Vandenplas, Rudolph CD, Di Lorenzo C,
of the presence of esophagitis [13]. The develop-
Hassall E., et al. Pediatric gastroesophageal reflux clinical ing nervous system of infants seems susceptible
practice guidelines; joint recommendations of the North to pain (hyper)sensitivity when in contact with
American Society for Pediatric Gastroenterology, acid despite the absence of tissue damage. Some
Hepatology, and Nutrition (NASPGHAN) and the
European Society Pediatric Gastroenterology, Hepatology,
adults “learn to live with their symptoms” (only
and Nutrition (ESPGHAN). J Pediatr Gastroneterol Nutr half of the heartburn complainers seek medical
2009;49(4):498–547 help, although 60% take medications) and
develop tolerance to long-lasting symptoms.
A relation between GER, GERD, and feeding
Recurrent Regurgitation/Vomiting refusal has not been established. Persistent cry-
and Poor Weight Gain ing, irritability, back arching, and feeding and
sleeping difficulties have been proposed as equiv-
Although usually regurgitation causes little more alents of adult heartburn. However, two placebo-
than a nuisance, regurgitation of large amount of controlled studies with proton pump inhibitors
ingested food may result in caloric insufficiency (PPIs) in distressed infants presenting with fre-
and malnutrition. Poor weight gain is a crucial quent regurgitation failed to show an effect on
warning sign that necessitates clinical evaluation crying superior to placebo [14, 15].
and testing. Hospitalization may be needed. Some The Food and Drug Administration (FDA) has
infants have no apparent abnormalities and end up completed its review of four clinical trials evalu-
being diagnosed as suffering from “nonorganic ating the use of PPIs in infants (ages 1 month to
failure to thrive” (“NOFTT”), a “disorder” that <12 months) for the treatment of GERD and con-
sometimes is attributed to social/sensory depriva- cluded that PPIs should not be administered to
tion and socioeconomic or primary maternal-child treat the symptoms of GERD in the otherwise
problems. GERD is only one of the many etiolo- healthy infant without evidence of acid-induced
gies of “feeding problems” during infancy. Poor disease [16].
weight gain, feeding refusal, back arching, irrita- Up to date, there is no evidence that routine
bility, and sleep disturbances have been reported acid suppressive therapy is effective in infants
to be related as well as unrelated to GERD [12]. who present only with inconsolable crying.
334 Y. Vandenplas et al.

Symptoms of GERD and cow’s milk protein Dysphagia is a typical symptom of children
allergy (CMPA) overlap [17]. CMPA and GERD with eosinophilic esophagitis (EoE) or esopha-
may coexist or CMPA may complicate GERD geal strictures but has also been linked to
[17]. Treatment of CMPA implies the use of hydro- esophagitis. The impressive rise in prevalence of
lysates (or amino acid formula). Improvement of EoE is still poorly understood [20], and difficulties
GER(-like) symptoms with hydrolysates is not a in distinguishing EoE from reflux esophagitis are
proof that an underlying immunological disease common. In reflux esophagitis, the eosinophilic
exists, such as CMPA, since hydrolysates have a infiltrate is in theory limited to less than 5/per
more rapid gastric emptying. A thickened hydro- high power field (HPF) with 85% positive
lysate may be helpful in regurgitating babies with response to GER treatment, compared to primary
CMPA (unpublished data). EoE with >20 eosinophils per HPF. Demonstration
of failure of PPI treatment as a condition needed
to diagnose EoE brought reflux esophagitis back
GER(D) and Heartburn in the picture [21]. Patients with allergic esophagi-
tis are typically younger and have atopic features
Heartburn is the predominant GER symptom in (allergic symptoms or positive allergic tests), but
adults, occurring weekly in 15–20% and daily in no specific symptoms. Atopic features are
5–10% of subjects. While the verbal child can reported in more than 90% and peripheral eosino-
communicate pain, descriptions of the intensity, philia in 50% of patients.
location, and severity may be unreliable until the
age of at least 8 years and sometimes later [4].
Diagnosis and management of GERD in older GER(D) and Extraesophageal
children (>12 years) and adolescents follow the Manifestations
recommendations for adults [1].
GER(D) and Reactive Airway Disease

GERD and Esophagitis Although an etiologic role for GER in reactive

airway disease has not been demonstrated, differ-
Esophagitis is defined as visible breaks of the ent pathophysiologic mechanisms have been pro-
esophageal mucosa [1]. Children with GER symp- posed: direct aspiration, vagal-mediated bronchial
toms present esophagitis in 15% up to 62%, and laryngeal spasm, and neurally mediated
Barrett’s esophagus in 0.1–3%, and refractory inflammation. Chronic pulmonary hyperinflation
GERD requiring surgery in 6–13% [1, 18]. Erosive predisposes to GER. An association between
esophagitis in 0–17-year-old children with GERD asthma and reflux measured by pH or impedance
symptoms was reported to occur in 12.4% and to probe has been reported in many studies [8].
increase with age [19]. The median age of the Wheezing appears more related to GERD if it is
group with erosive esophagitis was 12.7 ± 4.9 nocturnal. There are no diagnostic studies that
years versus 10.0 ± 5.1 years in patients without help in selecting patients in whom reflux treat-
[19]. The incidence of erosive esophagitis was ment may result in a reduction of asthma medica-
only 5.5% in those younger than 1 year [19]. tion, if there are such patients at all [1, 8]. In a
Obviously, patient selection and recruitment, dif- series of 46 children with persistent moderate
ferences in definition of esophagitis, and avail- asthma despite use of bronchodilators, inhaled
ability of self-treatment may affect these data. In corticosteroids, and leukotriene antagonists, 59%
nonverbal infants, behaviors suggesting esophagi- (27/46) had an abnormal pH-metry [22]. Reflux
tis include crying, irritability, sleep disturbance, treatment resulted in a significant reduction in
and “colic.” Infants may also appear very hungry asthma medication. Patients with a normal pH-
for the bottle until their first swallows and then metry were randomized to placebo or reflux treat-
become irritable and refuse to drink. ment: 25% (2 of only 8 children) of the treated
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 335

patients could reduce their asthma medication, concentrations than in serum [29]. However,
while this was not possible in any patient on pla- several epidemiologic studies suggest a low
cebo [22]. Another study found omeprazole inef- incidence of reflux symptoms in patients with
fective in improving asthma symptoms and recurrent middle-ear infections. Data from sev-
parameters in children with asthma [23]. In eral placebo-controlled studies and meta-anal-
patients with reactive airway disease, a “negative yses uniformly have shown no effect of
symptom association probability” does not antireflux therapy on upper airway symptoms
exclude a causal role for GER since a threshold or signs [1]. The presence of pepsin and bile in
“amount” of reflux may be necessary to start air- middle-ear fluid might as well be the conse-
way inflammation. quence of reflux (and vomiting) at the moment
of the acute middle-ear infection rather than
proof that chronic GER may be responsible for
GER(D) and Recurrent Pneumonia the chronic middle-ear problem.

GER causing recurrent pneumonia has been

reported with an incidence as low as 6% [24]. GER(D) and Dental Erosions
No test can determine whether reflux is caus-
ing recurrent pneumonia. A new technique to Young children and children with neurologic
record pharyngeal reflux has been developed impairment appear to be at greatest risk to have
(Restech®), with promising results needing dental erosions caused by GER. Juice drinking,
confirmation [25]. However, according to bulimia, and racial and genetic factors that affect
recent data from our unit (yet unpublished), dental enamel and saliva might be confounding
there is no correlation between results of variables that have been insufficiently considered
Restech® and multichannel intraluminal imped- [1]. There have been no long-term (intervention)
ance monitoring (MII). follow-up studies in high-risk populations.
The sensitivity and specificity of lipid-laden
macrophages for GER(D) is poor. The measure-
ment of pepsin in bronchial aspirate seems to be GER(D) and Sandifer Syndrome
more promising, although with substantial over-
lap between patients and controls [26]. One study Sandifer syndrome (spasmodic torsional dysto-
evaluating nuclear scintigraphy with late imaging nia with arching of the back and opisthotonic
reported that 50% of patients with a variety of posturing, mainly involving the neck and back) is
respiratory symptoms had pulmonary aspiration an uncommon but specific manifestation of
after 24 h [27]. But aspiration also occurs in GERD.
healthy subjects, especially during sleep [1].
Moreover, later studies failed to reproduce these
findings [28]. Pathologic acid reflux occurs in the GER(D) and Apnea, ALTE, and SIDS
majority of CF patients, even before respiratory
symptoms develop [1]. The literature can best be summarized as follows:
most series fail to show a temporal association
between GER and pathologic apnea, apparent
GER(D) and ENT Manifestations life-threatening events (ALTE), and bradycardia
[1]. However, a relation between GER and short,
Several studies have detected pepsin in the physiologic apnea has been shown [30, 31]. There
middle-ear fluid, albeit with a huge variation in are well-described cases or small series that dem-
incidence (14–73%) [1]. Bile acids have also onstrate that pathologic apnea can occur as a con-
been detected in middle-ear liquid, in higher sequence of GER.
336 Y. Vandenplas et al.

previously treated with H2-receptor antagonists

GER(D) and Neurologic Impairment (H2RAs) or PPIs, Barrett’s esophagus was
detected in 13%. An esophageal stricture was
The neurologic impaired child is known to be at present in 5 of the 13 patients with Barrett’s
risk for increased GER and GERD. Diagnosis (38%) [33]. Reflux symptoms during childhood
of GERD in these children is often challenging were not found to be different in adults without
due to their underlying conditions. Whether than in adults with Barrett’s [34]. Barrett’s has a
this group of patients has more severe reflux male predominance and increases with age.
disease, has less effective defense mechanisms, Patients with short segments of columnar-lined
or presents with more severe symptoms because esophagus and intestinal metaplasia have been
of the inability to express and/or recognize found to have similar esophageal acid exposure
symptoms remains open for debate. Response but significantly higher frequency of abnormal
to treatment, both medical and surgical, is poor bilirubin exposure and longer median duration of
in the neurological impaired child compared to reflux symptoms than patients without intestinal
the neurologic normal child. metaplasia [35]. There is a genetic predisposition
in families in patients with Barrett’s esophagus
and esophageal carcinoma [1].
GER(D) and Other Risk Groups Peptic ulcer and esophageal and gastric neo-
plastic changes in children are extremely rare. In
Symptomatic GER is estimated to occur in adults, a decreased prevalence of gastric cancer
30–80% of children who have undergone repair and peptic ulcer with an opposite increase of
of esophageal atresia [32]. Children with con- esophageal adenocarcinoma and GERD has been
genital abnormalities, such as hiatal hernia and noted over the last 30 years [36]. This has been
malrotation, or who have had major thoracic or attributed to several independent factors, such as
abdominal surgery are at risk for developing changes in dietary habits such as a higher fat
severe GERD. Although there is abundant litera- intake, an increased incidence of obesity, and a
ture on increased prevalence of GER in over- decreased incidence of Helicobacter pylori infec-
weight and obese adults, data in children are tion [36]. Frequency, severity, and duration of
scarce. There are no data in literature suggesting reflux symptoms are related to the risk of develop-
that preterm babies have more (severe) reflux ing esophageal cancer. Among adults with long-
than term-born babies, although many premature standing and severe reflux, the odds ratios are 43.5
babies are treated for reflux. The role of reflux in for esophageal adenocarcinoma and 4.4 for ade-
patients with bronchopulmonary dysplasia and nocarcinoma at the cardia [37]. It is unknown
other chronic respiratory disorders is not clear. whether mild esophagitis or GER symptoms per-
sisting from childhood are related to an increased
risk for severe complications in adults.
GERD and Complications

Barrett’s esophagus, strictures, and esophageal Diagnosis

adenocarcinoma are complications of chronic
severe GERD. Barrett’s esophagus is a premalig- Diagnostic procedures will not be discussed in
nant condition in which metaplastic specialized detail. History in children is difficult to obtain
columnar epithelium with goblet cells is present and considered poorly reliable up to the age of
in the tubular esophagus. In a series including minimally 8 or even 12 years old [1]. Orenstein
402 children with GERD without neurological or developed the “infant GER questionnaire”
congenital anomalies, no case of Barrett’s esoph- (I-GERQ) [38]. But, the I-GERQ cutoff score
agus was detected [18]. In another series includ- failed to identify 26% of infants with GERD and
ing 103 children with long-lasting GERD and not was positive in 81% of infants with normal
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 337

esophageal histology and normal pH-metry Ambulatory 24-h esophageal pH monitoring

[39]. Barium contrast radiography, nuclear scin- measures the incidence and duration of acid
tiscanning, and ultrasound are techniques evalu- reflux, while impedance measures all reflux epi-
ating postprandial reflux and provide limited sodes, if they are accompanied by a bolus.
information on gastric emptying. Barium stud- Esophageal pH-metry is the best method to mea-
ies are not recommended as first-line investiga- sure acid in the esophagus, but not all reflux caus-
tion to diagnose GERD, but are of importance to ing symptoms is acid and not all acid reflux is
diagnose anatomic abnormalities such as hiatal causing symptoms. Both hardware (electrodes,
hernia, malrotation, duodenal web, and stenosis devices) and software influence the results [41,
and may suggest functional abnormalities such 42]. Although normal ranges have been estab-
as esophageal achalasia. The results of ultra- lished for pH-metry, it should be remembered
sound are investigator dependent, and a relation that they are hard- and software dependent and
between reflux detected on ultrasound and have been established with glass electrodes.
symptoms has not been established [1]. Intraluminal impedance measures electrical
Manometry does not demonstrate reflux, but has potential differences and is becoming of increas-
been instrumental to uncover pathophysiologic ing interest (see below).
mechanisms causing reflux and is indicated in All GER investigation techniques test differ-
the diagnosis of specific conditions such as ent aspects of reflux. Therefore, it is not unex-
achalasia [1]. Experience in children with spec- pected that the correlation among the results of
trophotometric esophageal probes to detect bili- the different techniques is poor. There is no
rubin is still very limited. Orel and coworkers “always-best” investigation technique to diag-
found that some children with esophagitis suffer nose GER(D). “Logic” (but not evidence-based
bile reflux [40]. medicine) suggests that if the question asked is
Modern endoscopes are so miniaturized that “does this patient have esophagitis?” then endos-
endoscoping preterm infants of less than 1,000 g copy with biopsy is the best technique. If it is in
has become technically easy. Macroscopic lesions the interest of the patient to measure acid GER
associated with GERD include erosions, exudate, episodes, 24-h pH-metry is the preferred tech-
ulcers, structures, and hiatal hernia. “Erythema” nique. If it is important to measure “all episodes
of the distal esophagus in young infants is a nor- of reflux,” multichannel intraluminal impedance
mal finding because of the increased number of (MII) seems to be the investigation of choice.
small blood vessels at the cardiac region. However, postprandial reflux is mainly weakly
Endoscopy may also show a “sliding hernia,” acid or alkaline, and postprandial reflux was in
stomach that is protruding in the esophagus dur- general considered to be not clinically relevant,
ing belching, influenced by the amount of and most techniques measuring postprandial
insufflated air during endoscopy. Recent consen- reflux (barium swallow, ultrasound, scintiscan-
sus guidelines define reflux esophagitis as the ning) are often not recommended for this reason.
presence of endoscopically visible breaks in the As long as therapeutic options are mainly limited
esophageal mucosa at or immediately above the to acid-reducing medication, one may question if
GE junction [1, 4]. Endoscopy-negative reflux it is really relevant to measure weakly acid and
disease is common. There is a poor correlation alkaline reflux.
between the severity of symptoms and presence
and absence of esophagitis. There is insufficient
evidence to support the use of histology to diag- Esophageal Impedance Recording
nose or exclude GERD. Biopsies of duodenal,
gastric, and esophageal mucosa are mandatory to The measurement of reflux by MII is not pH
exclude other diseases [1]. More detailed infor- dependent, but in combination with pH-metry, it
mation on pros and cons of histology can be allows detection of acid (pH < 4.0), weakly acid
found in recent consensus papers [1, 4]. (pH 4.0–7.0), and alkaline reflux (pH > 7).
338 Y. Vandenplas et al.

Experience has shown that impedance needs to ods. Conversely, the number of weakly acid
be performed in combination with pH-metry, reflux episodes per hour was significantly higher
since pH-only events occur (mainly during the in feeding than in fasting periods [45]. In 17
night and mainly in young infants). Also gas symptomatic preterm newborns fed naïve and
reflux can be measured, since liquid reflux causes fortified human milk, pH-MII revealed an
a drop in impedance and gas reflux an increase. inverse correlation between naïve human milk
Obviously, “more” reflux episodes are detected protein content and acid reflux index (RIpH:
with impedance pH-metry than with pH-metry P = 0.041, r = −0.501). After fortification, osmo-
alone, but the question remains at this moment lality often exceeded the values recommended
unanswered if “more is always necessary or bet- for infant feeds, and a statistically significant
ter.” Recent (yet unpublished) research showed a (P < 0.05) increase in nonacid reflux indexes
very high intra- and interobserver variability was observed [46].
between “experts.” The major clinical interest of MII-pH was combined with epigastric imped-
impedance seems to be demonstration of symp- ance for 3 h in 30 newborns referred for apparent
tom association, but normal data and validation life-threatening events (ALTE) and signs of
of symptom association parameters in children GERD [47]. An inverse correlation was evident
are missing. Interestingly, pH-only episodes, for reflux frequency and gastric emptying veloc-
reflux episodes detected with pH-metry but not ity (r2 = 0.94; P < 0.001) and between acid refluxes
with impedance (drop in pH without bolus move- and the gastric filling state (r2 = 0.95; P < 0.001),
ment), occur in young children [43]. A major dif- whereas a positive correlation was found between
ference between pH-metry and impedance the reflux level and the gastric filling state
regards the “nature” of the reflux: pH-metry mea- (r2 = 0.52; P < 0.05) [47].
sures the chemical clearance of the esophagus, Other studies analyzed the relation in time
while impedance measure the bolus (volume) between reflux episodes and extraesophageal
clearance. In general, chemical clearance is much manifestations, such as apnea. Corvaglia et al.
slower than bolus clearance. investigated 52 preterm infants and showed that
154 (14%) apneas out of 1,136 were related in
time to GER. The frequency of apnea during the
Impedance Studies in Newborns 1-min time around the onset of GER (within
30 s before and after) was significantly higher
A number of studies have studied the number of than the apnea frequency detected in GER-free
reflux episodes as primary outcome. In 52 symp- periods (P = 0.03). Furthermore, the frequency
tomatic preterm infants, 24-h MII-pH detected of apnea in the 30 s after GER (GER-triggered
2,834 GER episodes: 2162 (76%) nonacid and apneas) was greater than that detected in the
672 (24%) acid. The acid bolus exposure index 30 s before (P = 0.01). This suggests that a num-
was 0.28% (0.02–2.73%), and the nonacid bolus ber of apneas are induced by GER [48]. In a
exposure index was 1.03% (0.06–38.15%). By small group of 6 premature infants with apnea
considering only pH sensor (pH-monitoring or hypoxemia not responsive to caffeine treat-
analysis), an average of 53.2 AR episodes were ment, a total of 405 reflux events [306 (76%)
detected and esophageal exposure to acid was weakly acid and 99 acid refluxes] and 142
11% (or thus more than 30 times higher than apneas were detected. The sub-analysis based
with impedance) [44]. The influence of feeding on chemical composition and duration of
on the number of reflux episodes was analyzed refluxate showed that the frequency of apneas
in a number of reports. In 21 healthy preterm associated with weakly acid reflux events was
newborns, in which the nasogastric feeding tube significantly greater than the one calculated for
was replaced by a feeding-impedance catheter, reflux-free period [0.416/min (0.00–1.30) vs.
the number of acid reflux episodes per hour was 0.016/min (0.003–0.028), respectively; P < 0.05]
higher during fasting than during feeding peri- and that the frequency of apneas occurring dur-
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 339

ing reflux events longer than 30s was significantly (frequency, content, extent, and clearance time)
higher than those occurring during shorter reflux despite significant acid suppression (reduced
events (22 vs. 11%; P < 0.004) [49]. number of episodes and reflux index) and clinical
The relation between body position and reflux improvement (reduced number of symptoms
episodes was evaluated in a number of studies. In recorded) [54].
10 healthy preterm infants, a “crossover position
study” and postprandial evaluation showed more
liquid GER in the right than in the left lateral Studies in Infants
position. Gastric emptying was faster in the right
than in the left lateral position [50]. Similar Several studies report that in infants significantly
findings were reported by another group in 22 more acid reflux is detected with “classic pH-
preterm babies presenting with regurgitation and monitoring analysis” (pH < 4.0) than with
postprandial desaturations: the number of acid “impedance” (bolus detection with a pH < 4.0).
and nonacid reflux episodes was significantly In other words, there is a substantial difference
lower when the subjects were in the prone and between chemical and bolus reflux. Woodley
left-side sleeping position in comparison to the et al. analyzed the tracings of 14 infants.
supine and right-side positions [51]. The left-side Significantly fewer (~ 25%) acid reflux episodes
position showed the lowest esophageal acid expo- were detected using MII-pH when compared to
sure in the early postprandial period, whereas in pH monitoring alone. Estimates of esophageal
the prone position acid reflux was smallest in the acid exposure using pH monitoring alone were
late postprandial period [51]. twofold higher than with impedance criteria:
Using an esophageal impedance-manometry 71.8% of the acid reflux episodes detected by pH
catheter incorporating an intragastric infusion monitoring could not be confirmed by combined
port, it was shown in 8 preterm infants that more MII-pH [55]. Di Fiore and coworkers analyzed
transient lower esophageal sphincter relaxations impedance tracings obtained in 80 preterm and
(TLESRs) were triggered in the right lateral posi- 39 term infants: 59% out of 2,572 events detected
tion compared to the left lateral position. First by pH were not identified by MII. A significant
TLESR occurred at a significantly lower infused higher incidence of these pH-only events
volume and percentage of feed in right compared occurred in preterm versus term infants. The two
with left lateral position. TLESRs and GER were major identified reasons for this discrepancy
triggered at small volumes, unlikely to induce were absence of change in impedance and failure
gastric distension [52]. to meet MII scoring criteria [56]. In 12 symp-
MII-pH was carried out in 13 newborns tomatic infants, MII-pH revealed that total acid
receiving 0.3 mg per kg domperidone and in 13 GER episodes, total acid reflux exposure time,
controls. Each newborn was compared to the and acid episodes lasting 5 min or longer were
control nearest in postconceptional age. GER largely a function of classic 2 phase (acid reflux
episodes per hour increased significantly com- episode with bolus component and bolus clear-
pared to the baseline in the domperidone group, ance time shorter than acid clearance time) and
whereas there were no differences in the maxi- of pH-only acid GER types [57].
mum proximal extent reached by the refluxes. MII-pH tracings from 12 symptomatic infants
The authors speculated that the paradoxical showed that mean duration of volume clearance
increase in the number of GER episodes could was much shorter than chemical clearance [58].
be the expression of a domperidone-induced Volume clearance did not change throughout the
amplification of the motor incoordination of the feeding cycle, but chemical clearance was
neonatal gastroesophageal tract [53]. significantly prolonged during fasting compared
In 26 preterm infants and term neonates, with feeding and first postprandial hour. The
esomeprazole (0.5 mg/kg once daily for 7 days) authors speculated that inefficient chemical clear-
produced no change in bolus reflux characteristics ance during fasting is likely due to reduced
340 Y. Vandenplas et al.

efficiency of acid clearance mechanisms that [64]. Recently, data were published obtained in a
could include salivation, swallowing, peristalsis, large population of 291 children referred for sus-
and/or intraluminal secretion [58]. pected GERD, and sensitivity and diagnostic
In 9 infants with chronic lung disease, a total accuracy of MII-pH versus pH monitoring and
of 511 AR events were temporally (2-min win- symptom association were determined [65].
dow) associated with symptoms in only 1 patient MII-pH detected 13,631 reflux episodes, 6,260
in 3, and an SSI of 77% was noted when AR (46%) of which were nonacid. The prevalence of
reached the pharynx (11% respiratory, 17% sen- weakly acid reflux during 24 h and during post-
sory, and 12% movements associated). A 3.5-fold prandial periods as well as the proximal exten-
higher correlation between reflux episodes and sion of the refluxates was significantly greater in
symptoms was found if acid clearance time was infants than in children. The diagnostic accuracy
prolonged [59]. of combined MII-pH in revealing reflux episodes,
In 16 infants with a diagnosis of ALTE (mean and specifically AR, was significantly higher in
of age 3 months), 23.4 reflux episodes were infants than in children. The authors concluded
recorded with pH monitoring, whereas the num- that the addition of MII to conventional pH moni-
ber of reflux episodes obtained with impedance toring significantly increased the diagnostic yield
was 70.9, with 36.2% acid and 63.8% weakly of symptom association analysis in revealing an
acid reflux episodes. In only one patient, 4 apneas association between extraesophageal symptoms
were associated with GER (3 nonacid and one and reflux, irrespective of age, whereas in study-
acid) resulting in a statistically positive relation ing typical symptoms this was true only for
(SI > or = 50%; SSI > or = 10%) [60]. infants [65].
However, recent information showed that
baseline impedance is lower in the presence of
Studies in Children esophagitis than in patients with normal esopha-
geal mucosa. As a consequence, baseline imped-
In 75 infants and children, aged from 9 days to 12 ance (BImp) reflects esophageal mucosal integrity
years, 2,247 reflux events were detected by MII, [66–68]. In rabbits, esophagitis was shown to
while only 967 reflux events were detected by decrease BImp with about 1/3rd compared to the
pH-metry. Nonacid reflux was more predominant BImp in healthy controls [66]. The measurement
during postprandial periods (P < 0.001). The of BImp may increase the information obtained
symptom index was higher if reflux was mea- from a MII-pH recording and thus bring possible
sured with MII-pH (31.1%) than with pH probe clinical advantage [68].
(8.2%) [61]. In a 12-h MII-pH study, Del Buono In 50 children undergoing both MII-pH and
confirmed an increased number of reflux episodes bronchoscopy, there was no significant correla-
(both acid and nonacid) and median height of tion between the lipid-laden macrophage index
reflux events in 9/16 neurological impaired chil- and the number of reflux episodes. In the sub-
dren fed through a nasogastric tube, in compari- group of patients who underwent fundoplication
son to the orally fed subgroup [62]. In 50 patients for intractable respiratory disease, there was no
(29 infants and 21 children) MII detection of all significant difference in any of the reflux param-
bolus GER yielded a significantly greater number eters between patients who did and did not
of patients that were symptom positive: 36 (72%) experience clinical improvement after fundopli-
compared with 25 (50%) with standard pH moni- cation [69].
toring. Symptoms of cough, pain irritability/cry- In a more recent study, 21 children with a
ing, sneeze, nausea, choking, back arching, diagnosis of bronchial asthma, recurrent lung
heartburn, hiccups, stridor, and bad breath were consolidations, and recurrent laryngotracheitis
included for analysis [63]. underwent MII-pH, fiber-optic bronchoscopy,
The presence or absence of esophagitis does and bronchoalveolar lavage. The number of non-
not seem to be related to the results of MII-pH acid reflux episodes and the number of those
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 341

reaching the proximal esophagus were followed longitudinally for 1 year without
significantly higher in patients with recurrent pharmacotherapy, histology remained abnor-
lung consolidations than in those with bronchial mal in all [71]. It is not known if treatment of
asthma and laryngotracheitis. Bronchoalveolar GER during infancy changes the long-term
lavage studies showed a significantly higher lip- outcome and GERD in adults.
id-laden macrophage content in children with
recurrent lung consolidations than in those with
bronchial asthma and laryngotracheitis. The Non-pharmacologic and Nonsurgical
lipid-laden macrophage content correlated Therapies for GER
significantly with the total number of reflux epi-
sodes (r = 0.73) and with those reaching the prox- The most common reason to seek medical help
imal esophagus (r = 0.67). Finally, the lipid-laden for parents of young infants with suspected
macrophage content correlated with the number GERD is frequent regurgitation and infant dis-
of nonacid reflux episodes (r = 0.61), with those tress. Because infants with physiologic regurgita-
reaching the proximal esophagus (r = 0.64) and tion are difficult to distinguish from infants with
with the percentage of bronchoalveolar neutro- mild to moderate GERD symptoms, non-phar-
phils (r = 0.7) [70]. macologic treatment (reassurance, dietary and
positional treatment) is considered the appropri-
ate first approach. Observation of feeding and
Treatment Options handling of the child during and after feedings is
essential. Many infants are overfed or fed with an
Because symptoms of GER and GERD are fre- inappropriate technique [1]. Reassurance while
quent and nonspecific, especially during infancy, showing compassion for the impaired quality of
and because there is no “golden-standard” diag- life is of importance [1].
nostic technique, many infants and children are Many infants presenting with frequent regurgi-
exposed to empiric antireflux treatment. tation have a distressed behavior and are irritable.
Therapeutic options vary from reassurance, nutri- A thickened or commercialized anti-regurgitation
tional and positional treatment, and administra- formula (not antireflux formula!) decreases visual
tion of prokinetic and acid-reducing medications regurgitation, but does not systematically decrease
to surgery (Table 30.3). Physiologic GER does (acid) reflux [72]. However, data from three inde-
not need medical treatment. Therapeutic inter- pendent studies suggest acid reflux is actually
vention should always be a balance between reduced with cornstarch thickened formula [73].
intended improvement of symptoms and risk for Commercialized thickened formula is preferred to
side effects. thickening agents added to formula at home; the
nutritional content of the thickening agent and its
effect on osmolality have been taken in account in
Complications of Nonintervention the commercialized formula [1]. Dietary protein
allergy may be a cause of reflux, regurgitation,
Although data on the natural evolution of and vomiting, often accompanied by distressed
regurgitation are now available, there are only behavior [1, 2]. Ongoing studies suggest promis-
limited data on the natural history of GERD in ing results with thickened extensive hydrolysates
infants and children because most patients (unpublished data).
receive treatment. Recent data suggest a Sleeping positions that have been suggested to
decreased quality of life in a number of parents reduce GER include prone, left side after feed-
of infants presenting with frequent regurgita- ing, and supine 40° anti-Trendelenburg. Prone
tion, even if the regurgitation has disappeared position is considered obsolete in infants because
[11]. Although symptoms improved in more of the increased risk of sudden infant death (SID).
than half of the infants with reflux esophagitis Van Wijk et al. concluded that biggest benefit
342 Y. Vandenplas et al.

Table 30.3 Schematic therapeutic approach in 2011

Phase 1 Parental reassurance. Observation. Lifestyle changes. Exclude overfeeding
Phase 2 Dietary treatment (decrease regurgitation). Thickened formula, thickening agents, extensive
hydrolysates, or amino acid-based formula in cow’s milk allergy. Positional treatment (°)
Phase 3 For immediate symptom relief: alginates (some efficacy in moderate GERD), antacids only in
older children
Phase 4 Proton pump inhibitors (drug of choice in severe GERD; more safety data needed). H2-receptor
antagonists less effective than PPIs
Phase 5 Prokinetics (but not one product available on the market in 2010 has been shown to be
effective) would treat pathophysiologic mechanism of GERD
Phase 6 Laparoscopic surgery
Efficacy and safety data in infants and children for most anti-GER medication is limited (°): data on 40 ° supine sleep-
ing position in infants are limited Adapted from Vandenplas, Rudolph CD, Di Lorenzo C, Hassall E., et al. Pediatric
gastroesophageal reflux clinical practice guidelines; joint recommendations of the North American Society for
Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society Pediatric
Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroneterol Nutr 2009;49(4):498–547

was achieved with a strategy of right lateral posi- receptor agonist used to reduce spasticity in neuro-
tioning for the first postprandial hour with a posi- logically impaired patients. Baclofen was shown
tion change to the left thereafter to promote to reduce the number of TLSERs and acid GER
gastric emptying and reduce liquid GER in the during a 2-h test period and to accelerate gastric
late postprandial period [50]. However, at least emptying [75]. The data on baclofen are still very
two independent studies reported a significantly limited and the number of adverse events does not
increased risk of SID in the side compared to the justify yet its widespread use. A baclofen was
supine sleeping position. The results of a pilot originally considered as possibly more promising,
study with the “Multicare-AR Bed®” suggest that but results are disappointing as well. M0003
a specially made bed that nurses the infant at 40° (Movetis) is a “next generation gastrokinetic.”
supine body position reduces regurgitation, acid M0003 is a specific and high-affinity 5-HT4 ago-
reflux (measured with pH monitoring), and nist for the treatment of upper GI disorders, focus-
reflux-associated symptoms (evaluated with the ing initially on severe gastroparesis and pediatric
I-GERQ) [74]. reflux in children. Today, the drug is still in the
phase of development, and clinical trials in chil-
dren have not yet started.
Prokinetics and Other Nonacid-
Reducing/Blocking Medication
(Alginate-)Antacids
From the pathophysiologic point of view, proki- and Mucosaprotectors
netics seem the most logic therapeutic approach to
treating GERD. Unfortunately, according to the The key therapeutic advantage of antacids is their
NASPGHAN-ESPGHAN guidelines, the adverse rapid onset of action, within minutes from inges-
events of currently available prokinetics, including tion. These products have mainly been validated in
metoclopramide, domperidone, and cisapride, out- adults. Results showed a marginal but significant
weigh their potential benefit, since the latter was difference between Gaviscon infant and placebo in
never clearly demonstrated [1]. Bethanechol, a average reflux height (being better for placebo!) and
direct cholinergic agonist, studied in a few con- raise questions regarding any perceived clinical
trolled trials has uncertain efficacy and a high inci- benefit of its use [76]. Data on compliance in infants
dence of side effects in children with GERD. and children (these products have a poor taste) and
Baclofen is a gamma-aminobutyric acid (GABA)-B side effects (many antacids have a high aluminum
30 Infant Regurgitation and Pediatric Gastroesophageal Reflux Disease 343

content) are missing. Extrapolating from adult data, gastrointestinal flora and bacterial overgrowth
one may conclude that it is unlikely that mucosap- [1]. As a consequence, the prevalence of infec-
rotectors would be effective in children. tious respiratory and gastrointestinal tract infec-
tions is increased [1].

H²-Receptor Antagonists (H2RAs) and

Proton Pump Inhibitors (PPI) Surgery and Therapeutic Endoscopic
Procedures
Since PPIs are more effective acid suppressing
agents than H2RAs, PPIs are often considered the Therapeutic endoscopic procedures are rarely
preferred option for treatment of GERD in chil- indicated and should only be performed where
dren and adults. PPIs are prodrugs since protona- there is evidence of experience. Most of the lit-
tion of the molecule in highly acidic environments erature on surgical therapy in children with
is necessary for their action. PPIs must be taken GERD consists of retrospective case series in
once a day, before breakfast, and must be pro- which documentation of the diagnosis of GERD
tected from gastric acid by enteric coating. The and details of previous medical therapy are
achievement of “maximal acid suppressant deficient, making it difficult to assess the indica-
effect” can take up to 4 days. The granules and tions for and responses to surgery [1]. Adult
tablets should not be crushed, chewed, or dis- series report that between 37% and 62% of
solved as gastric acid secretion may alter the patients are taking PPI a few years after the sur-
drugs. If the microgranules are enteric coated, the gery [77, 78]. Different antireflux surgical
capsules can be opened and administered orally approaches do exist. In general, experience
or via a feeding tube, in suspension in an acidic seems to be the best guidance for choosing the
medium such as fruit juice, yogurt, or apple preferred technique. While antireflux surgery in
sauce. A “homemade” liquid formulation, pro- certain groups of children may be of consider-
duced by dissolving the granula, not the micro- able benefit, a failure rate of up to 22% has been
granula, in 8.4% bicarbonate solution has been reported [1]. Children with underlying condi-
used in some reports [1]. Omeprazole and esome- tions predisposing to the most severe GERD
prazole are approved in the USA and Europe for comprise a large percentage of many surgical
use in children older than 1 year of age; in the series. Total esophagogastric dissociation is an
USA, lansoprazole is approved as well. In uncon- operative procedure that is useful in selected
trolled trials and case reports, omeprazole was children with neurologic impairment or other
used in dosage between 0.2 and 3.5 mg/kg/day conditions causing life-threatening aspiration
for periods ranging from 14 days to 36 months. during oral feedings.
Lansoprazole, omeprazole, and pantoprazole are
metabolized by a genetically polymorphic
enzyme, CYP2C19, absent in approximately 3% References
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 Infant Colic
31
David R. Fleisher

other time in their lives. Crying increases during

Definition the first month, peaks during the second month,
and tends to decline thereafter. It tends to be greater
There is no universally accepted definition of infant in late afternoons and evenings [8, 9]. This tempo-
colic [1] because there is no agreement on its nature ral pattern of crying by infants generally is similar
or pathogenesis. The definition used in the present to the usual course of crying by colicky infants.
discussion is crying during the first 3 months of life The question remains as follows: is colicky crying
for 3 or more hours per day on 3 or more days per etiologically different from the crying of noncol-
week in infants who do not suffer other conditions icky infants, or is it the same but at the upper end
that may cause prolonged crying, e.g., organic dis- of the normal crying curve? Surprisingly, the fre-
eases, hunger, or neglect [2–4]. This definition is quency of onset of crying bouts in colicky infants
heuristic, with elements chosen for the purpose of is similar to that of infants in general [10], but the
defining a population to be studied. duration of their crying bouts is longer and they
Although there is no proof that colicky crying are less consolable [11]. Typical colicky crying is
is caused by pain in the abdomen or any other part high pitched. Bouts may begin suddenly, without
of the infant’s body [5], nevertheless, it is widely warning, and have a rapid crescendo toward peak
believed that the cause of colicky crying is abdom- intensity, accompanied by clinched fists, drawn-up
inal pain of intestinal origin [6]. As a result, infants knees, and generally increased muscle tone [12].
with seemingly refractory colic are referred to
pediatric gastroenterologists often enough to jus-
tify including infant colic on the list of pediatric Epidemiology
functional gastrointestinal disorders [7].
Colicky crying is best considered within the Colic is virtually unknown in some primitive and
context of “normal” infant crying during the first traditional societies in which an infant’s cry is
year. All infants cry. Brazelton’s data [8], confirmed treated as an emergency signal and responded to
28 years later by Barr [9], demonstrated what is immediately [10]. Western societies provide less
referred to as “the crying curve.” During the first 3 cultural reinforcement of rapid, intuitive parental
months, infants generally cry more than at any responses to the crying of young infants, and
their crying is more likely to be viewed as a med-
D.R. Fleisher, M.D. (*) ical problem [13, 14]. Although estimates of the
Pediatric Gastroenterology Division, Department of Child prevalence of colic vary between 9 and 40% [15,
Health, University of Missouri School of Medicine, 16], it is generally reported to occur in about 20%
705 Centennial Court, Columbia, MO 65203-2993, USA
e-mail: [email protected] of infants [12, 17]. Colic affects infants of all

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 347

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_31, © Springer Science+Business Media New York 2013
348 D.R. Fleisher

socioeconomic classes equally, boys as often as Research on infant colic has taken two main
girls and breast-fed as often as bottle-fed infants paths: one is based on the presumption that infant
[16–18]. It is unrelated to a family history of colic is (a) caused by pain, (b) that the pain is intra-
allergy [16, 17]. There is conflicting evidence abdominal, and (c) that it originates in the gastroin-
regarding the effects of prolonged labor, forceps testinal tract. The other path is based on the
delivery, and epidural anesthesia as predisposing presumption that colicky crying has a neurodevel-
factors to colic [19, 20]. These events may have opmental basis, not caused by pain or organic dis-
transient or persistent noxious effects on the cen- ease of any kind—that “colic is something that
tral nervous system which may cause intractable infants do, rather than a condition they have” [31].
crying of organic etiology, different (by definition Research based on the presumption that colic
[2]) from the colicky crying of well babies. is due to abdominal pain has shown statistically
Some infants with intrauterine growth retarda- significant physiologic differences between pop-
tion are born with diminished muscle tone, activ- ulations of colicky infants and infants who do not
ity, and social responsiveness; they are unusually cry excessively. Whether these physiologic char-
quiet and prefer to be left alone during the first acteristics of colicky infants cause their crying,
two weeks. Thereafter, they may have long bouts result from crying, or are produced concurrently
of inconsolable crying which have been attrib- by whatever causes the crying is an unsolved
uted to “neurophysiologic hypersensitivity” [21]. question [5, 12, 22, 23, 32–38]. Suffice to say that
The relevance of this syndrome to ordinary “3 none of these abnormalities explain the temporal
months colic” is unknown. pattern or the effectiveness of soothing measures
that would not be expected to relieve abdominal
pain. And none have thus far led to an etiologic
Differential Diagnosis of Prolonged cure for colic [23, 24, 37].
Crying in Young Infants The neurodevelopmental hypothesis is onto-
logical. The fetus is in an almost constant steady
Persistent and recurrent crying in early infancy state. Once out of the womb, however, the neo-
may be a sign of cow’s milk protein intolerance nate loses its unchanging environment and is
[22–25], reflux esophagitis [26], fructose intoler- accosted by new experiences, such as hunger,
ance, infant abuse, congenital central nervous thirst, visual stimulation, environmental excite-
system abnormalities, infant migraine, urinary ment, temperature changes, and tactile experi-
tract infection, anomalous left coronary artery, ences, to name a few. Once out of the womb,
intestinal volvulus, and other illnesses [27]. The when the neonate experiences a state of feeling
diseases that may be misdiagnosed as infant colic hungry, it reacts by making the transition to the
usually lack its typical temporal pattern and tem- feeding state. It is hypothesized that “colic” is the
porary responses to effective soothing maneuvers behavior of infants who have difficulty making
[28, 29]. Whereas the diagnosis of organic causes transitions from one state to another [14].
of persistent crying may be confirmed by techno- Difficulty in state transitions might cause a baby,
logic tests, there is no test by which infant colic who is crying because it is hungry, to suck a few
can be ruled in or ruled out. times when put to the breast, then pull away, arch
Is colicky crying essentially different from backward, and fuss. The fussing rapidly intensifies
that of the 25% of “normal” babies who cry more into “colicky” crying which makes feeding tem-
than 2 and 3 h per day [8, 12]? Or is it simply porarily impossible and can persist, even though
crying of the highest intensity, acoustically indis- the infant is still hungry. Similarly, a sleepy baby
tinguishable from crying caused by acute pain, might be unable to make a smooth transition from
hunger, or loneliness [28, 29]? Are the activities being awake but sleepy to falling asleep.
that accompany the crying of colic specific to Colicky infants tend to be more reactive to sen-
colic or are they nonspecific motor accompani- sory stimuli as well as more difficult to soothe
ments of intense crying of any cause [30]? [39]. Therefore, removing distracting stimuli from
31 Infant Colic 349

the environment may make state transitions easier. prevalence of colic [20, 44–46]. Excessive crying
This is exemplified by the infant whose nighttime may exacerbate maternal depression or anxiety
feedings were made easier while being gently car- and distort the mother’s perception of what might
ried about in a dark, quiet room. be ordinary crying behavior [3, 45, 47].
Although the duration and intensity of an
infant’s crying can be modified by soothing tech-
niques, the pattern of crying during the first 3 Management
months, referred to as “the normal crying curve,”
cannot be modified [1, 9]. As stated by Miller and Parents who view their infant’s colic as a tempo-
Barr, “…crying—including that which is said to rary, benign pattern of behavior don’t seek medi-
be typical of colic—may be better understood as cal attention or, if they do, need only be effectively
a behavioral state that is non-specific to any one reassured that their baby is well [48]. However,
of a number of causes. Rather, those infants colic can present as a crisis when the crying
whose crying is labeled as colic may represent seems uncontrollable, when all attempts at “cur-
individual irritability and difficulty with state ing” the infant have failed, and when parents feel
regulation, in which the cry state is more readily overwhelmed, angry, and guilty [43, 49].
provoked and intractable once established [1].” The goal of management should not be to
abolish the crying; nothing of what is known
about the physiology of colicky infants has led to
How Does Colic Subside? a “cure.” Antispasmodics, sedatives, simethicone,
formula changes, fiber supplements, and other
At about 2–3 months of age, infants become more measures based on the assumption that the crying
attentive and socially responsive. This develop- is due to gut pain have produced little or no
mental shift accompanies their acquisition of an benefit beyond their placebo affects in most
awareness of the distinction between “self” and infants [38, 50–53]. A more realistic goal is help-
“other” [40]. They become better able to sooth ing parents through the difficult early months of
themselves, more adaptive, and able to interact their infant’s development [50, 54].
and give pleasure to their caregivers [1, 41]. Less effective management strategies involve
These developmental shifts occur at about the trying a succession of harmless formulas and
age that colic subsides. One hypothesis for the medications of little or no efficacy [5, 55]. Colic
disappearance of colic is that the developmental is a time-limited condition, highly responsive to
advances that occur at 2–3 months enhance their placebo [56]. Sooner or later, one of the trial
ability to manage state transitions and enable the measures will “work.” Sequential prescriptions
infant to more effectively self-sooth and evoke give parents “something to do” in the meantime.
desired behaviors from caregivers. These new The advantage of this approach is that it requires
abilities provide the infant with options for ten- little of the clinician’s time. One of its disadvan-
sion resolution other than crying. Developmental tages is that treatments carry with them the impli-
advances are smoother and accompanied by less cation that something “wrong” is being treated,
crying if the infant’s temperament is easy and the and this iatrogenic stigma is reinforced when
mother is caring, intuitive, and self-confident and whatever is “wrong” is “cured” by a medical pre-
when the dyadic relationship between them pro- scription [57]. Another disadvantage is its impact
ceeds with smooth reciprocity [42, 43]. on parents whose hopes may turn to anxious
Parents may bring to the colic syndrome despair each time a treatment fails.
difficulties of their own which may present the cli- The following elements of management are
nician with therapeutic opportunities. Emotional derived from frequently encountered themes dur-
tension and depression during pregnancy, adverse ing my experience with about 350 infants referred
experiences during labor and delivery, and post- for symptoms of infant colic that were refractory
partum depression are associated with a greater to previous management.
350 D.R. Fleisher

Acknowledge the Difficulty paradigm believable. Parents would probably feel

and Importance of Their Problem better if they believe that their infants’ crying is
part of normal development rather than an abnor-
Previous clinicians may have told them that their mal affliction [60]. Satisfying their need to feel
infant has colic, that it is not serious, that it will go better about their infant helps them shift to a less
away, and that all that they need to do is be patient. troubling explanation of why their infant cries.
If the parents had been able to accept such state-
ments, they would not have come for another opin-
ion. They need to hear that, regardless of what the Affirm the Baby’s Excellent Health
term “colic” implies, it can cause great suffering and Great Promise
and disruption of family life [43, 49, 58].
The crying is due not to a sickness or defect, but to
the fact that he or she may be the kind of a normal
Finding and Modeling Calming baby that is more receptive and intensely reactive
Methods to what goes on in the environment [39]. Although
such temperament characteristics make the infant
A crying bout is an opportunity for the clinician more challenging and less pleasurable during the
to model comforting procedures, e.g., rocking first 2–4 months, these same characteristics may
and patting and responding quickly before the make his or her personality and developmental
bout gains momentum. Successful modeling of progress more exciting and pleasurable once they
soothing procedures should be done as a diagnos- get through this difficult period [61].
tic procedure to discover what is effective, being
careful to avoid the false implication that the cli-
nician is a more competent caregiver [59]. Affirm the Excellent Prognosis

Infant colic subsides by or before 3–4 months of

Dismantling the Pain Theory Is Essential age in most cases. Give the parents “light at the
to Management end of their tunnel.” Coping is much more difficult
without it. Carey has stated that “Optimism
If the parents cannot see their child’s crying as makes a big difference. Any treatment of colic
anything other than pain behavior, then, regard- that is accompanied by indifference or pessimism
less of how much we tell them that colic is safe will almost certainly fail. The enthusiasm of the
and will soon subside, they won’t be satisfied. clinician matters enormously” [62].
Competent parents cannot put up with watching
their infant suffer pain they feel powerless to
relieve. They want relief and they insist that it be Teaching Techniques for Controlling
given immediately. Demerol has been recom- Colicky Crying
mended for otherwise intractable colic, and the
use of a narcotic analgesic is humane and appro- None of the above concepts will do much good if
priate if one accepts that “colic is pain” [55]. the parents don’t have practical methods for con-
The possibility that colicky crying might not trolling crying bouts. Tolerance for their baby’s
be due to abdominal pain is counterintuitive. crying wanes rapidly. Review the list of common
Parents may have difficulty relinquishing the pain techniques: rocking, secure swaddling, rhythmic
paradigm [54]. Up to this point, they may have rolling back and forth in a pram, car rides, monot-
had no other explanation for the crying, and to onous noise, windup swings, and many more.
experience it without any explanation is to suffer Bouts of crying gain momentum rapidly but are
existential anxiety. Good communication skills easier to stop if soothing measures are applied
enable the clinician to make the developmental promptly [10, 54, 63].
31 Infant Colic 351

Making Caregiving Easier their well-being and the overriding importance of

recognizing it before it becomes disabling.
Advice should be individualized; find out what Three practices can help prevent depletion of
has worked in the past. Avoid stock recommen- their emotional and physical strength: free time
dations regarding feeding, burping, or holding [14, 49, 66], a rescue mechanism [49], and, for
techniques, especially if they increased the parents of infants who cry during the night, guar-
baby’s or the mother’s discomfort [59]. For anteed sleep.
example, burping after every ounce of feed is a Free time is defined as scheduled windows of
recommendation based on the unsubstantiated time during which the mother can withdraw from
notion that swallowed air causes colic. In prac- caring for her infant, leave the caregiving milieu,
tice, these repeated interruptions make feedings and engage in recreational activities she enjoys
frustrating for both infant and mother [64]. so that, when the interval of time-off is over, she
When infants accumulate air in their stomachs may return to her infant refreshed. Several condi-
sufficient to cause a feeling of fullness, they tions are necessary for free time to work: (a) their
spontaneously stop sucking. These pauses are duration and frequency aren’t as important as
ideal times to burp the baby; otherwise, he or whether or not they are scheduled. Coping with
she will experience sudden deprivations of feed- demanding tasks is made easier if one knows
ing satisfaction as the mother tries to get the when a break will come. (b) The surrogate care-
baby to eructate small amounts of swallowed giver must be someone the parents feel is experi-
air. Colicky babies tend to show more frequent enced, caring, and able to cope with a severe bout
dissatisfaction during feedings than noncolicky of crying. Strangers or immature babysitters
babies [32]. The imposition of frequent, arbi- won’t do because the mother won’t be able to
trary interruptions which ignore the infant’s focus on herself if she has to worry about her
cues invites trouble. Should parents be advised baby while she is out. (c) The surrogate caregiver
to feed on demand or according to a schedule? needs to know that the mother will return at the
Should they be told to let their baby cry or never promised time in order for him or her to do their
let it cry? These questions have no “correct” job well. (d) The clinician must admonish the
answers [5]. The best way is usually the easiest mother to do something that may be difficult for
way. What might be easiest for one mother her, namely, to put the baby out of her thoughts;
might be impossibly difficult for another. Find forget, as much as possible, that she is a parent;
out what is easiest for each individual infant– and enjoy the time for herself so that she can
mother couple and support them in doing it their return from her brief absence with renewed feel-
easy way. Recognize the distinction between ings of being in love with her baby. The greatest
pediatric judgment and parental judgment; obstacle to implementation of free time is the
respect and support the parents’ judgment. mother’s feeling that “forgetting about” her baby
Infants cannot be spoiled by being held or fed and focusing on her own pleasure is unconscio-
liberally [54]. However, caregiving can be nable. The clinician must help her overcome her
“spoiled” if parents ignore their own sense of potential guilt by emphasizing that, when prop-
what creates distress and comfort in their infant erly done, her free time is necessary and beneficial
or themselves [65]. to her baby and to the entire family as well.
A rescue mechanism is defined as having a
prearranged contingency plan for her husband, a
Address the Parents’ Needs trusted relative, or a friend who will come to her
assistance immediately should she begin to feel
Parents may minimize or deny their stress and overwhelmed by the demands of her infant. Like
fatigue. They invariably provide ample evidence panic, feelings of becoming overwhelmed are
of it during the clinical interview. Notice it, reflect unpredictable and may develop quite rapidly.
upon it, and emphasize its corrosive effect on They should be viewed as a genuine emergency.
352 D.R. Fleisher

The more confidence the mother has that help tion into sleep and thereby stop crying; the
will come should she need it, the less vulnerable colicky baby is not yet able to make this tran-
she will feel and the less likely she would use the sition and therefore continues to cry to an
rescue mechanism [41]. extent that may result in a self-perpetuated
Guaranteed sleep is useful for parents of col- state of sleepless crying.
icky infants who cry during the night. Either one Recognition of such state-transition-associ-
parent (usually the mother) is designated as care- ated crying patterns is important because colicky
giver during the night or both parents respond infants improve with time in their ability to go to
simultaneously, all night long, whenever the baby sleep. As they master this skill, their requirement
needs comforting. The former arrangement may for comforting changes from needing prolonged
be unfair and lead to feelings of resentment. The soothing, in order to prevent crying from interfer-
latter practice deprives both parents of sleep. ing with falling asleep, to being permitted a
They should consider dividing the night into two period of uninterrupted crying during which they
4-h shifts. The parent who is “off” can go on successfully get themselves to sleep. If the
sleeping, while the parent who is “on” knows that recently colicky infant continues to receive
when his or her 4-h shift is over, it is their turn to prompt comforting with each bout of state-transi-
sleep. Four hours of guaranteed sleep is probably tion-associated crying, it may interfere with its
more restful than 8 h of apprehensive dozing in acquisition of improved self-regulation and self-
anticipation of the infant’s next bout of crying. soothing [49, 67]. As the colicky baby approaches
the age of 3 months, it is advisable for the parents
to experiment with letting their baby “cry itself to
Understanding the Infant’s Needs sleep.” The end of colic is near when the baby
succeeds in this.
Many babies cry for several minutes or more
prior to falling asleep. Wolff described a noncol-
icky infant who routinely needed to cry for awhile The Supportive Role of the Clinician
in order to fall asleep [30]. When he experimen-
tally interrupted this necessary period of crying Every infant–parent system is unique. Therefore,
by applying soothing maneuvers, the infant any set of recommendations for management can
stopped crying only to begin the obligatory cry- be no more than a point of departure from which
ing period again as soon as the soothing maneu- each family develops their own ways of coping
ver was discontinued. The sequence (resumed [49]. Parents need 24-h accessibility to a physi-
crying interrupted by promptly applied soothing) cian or nurse who knows them and their baby [5]
could be repeated in an “on–off–on–off” pattern so that he or she can open mindedly reassess the
for half an hour or more. However, when the infant when concerns about its health arise. The
infant was allowed to cry without interruption, physician’s promise to remain accessible enables
the crying subsided spontaneously within a few the parents to continue on task without turning to
minutes as the infant lapsed into deep sleep. unnecessary medical diagnostic procedures or
By contrast, colicky babies don’t stop cry- false “cures.” Parents’ support groups may pro-
ing. Their crying increases in intensity and vide an invaluable resource for deepening par-
may persist for hours. Both types of babies— ents’ understanding of themselves and the
those with ordinary crying and those with col- nurturing process [68].
icky crying—are similar in that they may The etiology of infant colic remains elusive.
respond to repeated applications of comfort- Nevertheless, it is almost never refractory to
ing maneuvers with an “on–off–on–off” management, no matter how severe. If approached
response pattern. They differ, however, in comprehensively, it provides clinicians with
their ability to get themselves to sleep; the opportunities for enormous therapeutic success
noncolicky baby is able to make this transi- and satisfaction.
31 Infant Colic 353

20. Thomas DB. Aetiological associations in infantile colic:

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 Functional Diarrhea in Toddlers
(Chronic Nonspecific Diarrhea) 32
Ernesto Guiraldes and José Luis Roessler

longed dehydration, malabsorption, and wasting,

Definition and Epidemiology is still an important cause of secondary malnutri-
tion and diarrheal mortality in the developing
Functional diarrhea in toddlers or chronic world [7, 8].
nonspecific diarrhea (CNSD) is a frequent rea-
son for consultation to ambulatory pediatrics
and pediatric gastroenterology, being the lead- Clinical Presentation
ing cause of chronic diarrhea in otherwise well
children, 1–3 years of age, from an industrial- The consensus committee Rome III has classified
ized country [1–6]. It seems to predominate in CNSD within the functional digestive disorders
middle and upper socioeconomic strata although of infancy and childhood and defined it as fol-
its exact prevalence in different regions of the lows: “… CNSD is defined by daily painless
world is not known. By definition, CNSD occurs recurrent passage of three or more large unformed
without underlying, preexistent nutrient malab- stools for four or more weeks with onset in
sorption [6]. infancy or preschool years. There is no evidence
This chapter focuses on CNSD in toddlers and for failure-to-thrive if the diet has adequate calo-
older infants and excludes the protracted (“intrac- ries. The child appears unperturbed by the loose
table”) and deteriorating diarrheal syndrome, stools, and the symptom resolves spontaneously
evolving from an acute diarrheal episode, and by school age” [6]. The Rome III diagnostic cri-
whose incidence in Western countries has sharply teria proper [6] are described below, in the sec-
declined in more recent decades. This latter tion “Diagnosis.”
entity, pathophysiologically related to malnutrition The diagnosis of CNSD should come immedi-
and to protracted or overlapping (and often mul- ately to mind in all patients 12–36 months of age,
tiple) gastrointestinal infections leading to pro- who look healthy, well nourished, and active and
have a pattern of intermittent or nearly constant
runny stools containing recognizable undigested
E. Guiraldes, M.D. (*) vegetable matter [5]. As Hoekstra perceptively
Pontificia Universidad Católica de Chile adds: “Every pediatrician knows the tableau
and Universidad Mayor, El Bosque Sur 827, vivant of extremely worried parents around a
Providencia, 7510328, Santiago, Chile sparkling, healthy looking child who appears to
e-mail: [email protected]
be unaware of all the commotion” [5]. Often
J.L. Roessler, M.D. CNSD has begun following a viral gastroenteri-
Pediatric Gastroenterology Division, Pediatrics
Department, Hospital Félix Bulnes, Santiago, Chile tis. When instructed, rather vaguely, to use

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 355

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_32, © Springer Science+Business Media New York 2013
356 E. Guiraldes and J.L. Roessler

“plenty of clear fluids,” in order to prevent dehy- infants given formulae containing modified food
dration, parents offer recreational clear liquids starch (acetylated distarch phosphate) and found
time and again with the misguided belief that that this regime increased breath hydrogen and pro-
these constitute a physiological therapy and thus duced loose stools and, if given together with sorbi-
start a vicious cycle of ongoing diarrhea. Periods tol and fructose, manifest diarrhea developed.
of improvement in stool characteristics seem to The limited research that has been carried out
occur rather randomly while relapses may also on motility and CNSD suggests that intestinal
coincide with infections (mostly upper respira- motility is disturbed in children with CNSD [14]
tory) and other causes of biopsychosocial stress. although the available evidence does not actually
prove that this is the primary mechanism of “dis-
ease.” Most clinicians agree that in CNSD there
Pathophysiology is a significantly shortened time in mouth-to-anus
transit [5], which would be one of the explana-
Given the obvious difficulty in performing pro- tions for the characteristic presence of noticeable
spective intervention studies on CNSD and the undigested vegetable material in feces. Most
ethical constraints to such research, most data likely this results from a reduced colonic transit
pertaining to this entity is retrospective (and cir- time. In children with CNSD, food may fail to
cumstantial) and basically points to the patho- interrupt the migratory motor complex (MMC:
genic mechanisms discussed below. the “intestinal housekeeper,” a periodic series of
In most cases, the mechanism of diarrhea physiologically excitatory myoelectric and
appears, convincingly, to be related to excessive related contractile activity) [14], perhaps owing
intake of fluids, particularly those with a high osmo- to an immature gut motor development.
larity, such as soft drinks and fruit juices, as well as It is not generally well recognized that the
products (and supplements) that contain fructose or water content of normally looking stools is
sorbitol [3–5, 9]. The latter is a nonabsorbable alco- 70–75 %, while in watery stools this will be 90 %.
hol sweetener which, when taken in certain amounts, This small increase in water content can thus
can induce osmotic diarrhea in like fashion an make all the difference in the parental perception
excess of fructose does. Several authors have of health and disease [5]. In CNSD, this increase
reported positive (abnormal) breath hydrogen tests in stool water content does not entail a true mal-
after intake of fruit juices rich in fructose content, absorptive mechanism and can be rightfully con-
by children [10–12]. It has been suggested that in sidered a “cosmetic” disorder of the stools. When
patients with CNSD, the aforementioned products the anomalous dietary patterns are corrected and
generate hypermotility, a concept that is in accor- the child’s diet is normalized, the typical result is
dance with experimental studies. A pathogenic rela- a sustained return to normal stools [2–6, 9].
tionship exists, too, between CNSD and the
ingestion of a diet low in fat [2, 4, 5, 9], which is
plausible, as fat in the diet induces a physiological Diagnosis
slowing of intestinal transit.
Hoekstra et al. [12] have suggested that, in apple The diagnostic criteria according to the Rome III
juices, in addition to fructose, the increased pres- consensus [6] are as follows.
ence of nonabsorbable sugars resulting from the For more than 4 weeks, daily painless, recur-
enzymatic processing of apple pulp is an important rent passage of three or more large, unformed
etiological factor in CNSD. The same group has stools, in addition to all of these characteristics:
discouraged the use of fructose breath tests in chil- 1. Onset of symptoms begins between 6 and
dren suspected of CNSD because of the significant 36 months of age.
overlapping distribution of results in the control 2. Passage of stools occurs during waking
group, which would preclude any meaningful hours.
classification of abnormal vs. normal groups [12]. 3. There is no failure to thrive if caloric intake is
Lebenthal-Bendor et al. [13] studied toddlers and adequate.
32 Functional Diarrhea in Toddlers (Chronic Nonspecific Diarrhea) 357

Although CNSD was described several [6]. It is suggested that some alternative condi-
decades ago and has recently been validated tions, such as giardiasis, cryptosporidiosis,
by committees of experts [6, 9], the fact is that Clostridium difficile infection, and celiac disease
in general pediatric practice, this is a diagno- (CD), be ruled out [6]. The latter does often
sis that often is mislabeled. Yet, the typical cause a visible deterioration of the patient’s
clinical and dietary history of toddler diarrhea, nutritional status so it is not usually a differential
when properly elicited, should allow the prac- diagnosis that comes to the clinician’s mind
titioner to make a prompt diagnosis with mini- faced to CNSD. However, it should be kept in
mal inconveniences and costs for the patient mind that the nutritional and anthropometric
and family and ideally with a minimum of consequences of CD may not be fully evident in
laboratory tests. However, the relative ease of the short term and that in some cases, this entity
diagnosis and simplicity of treatment of this does not behave “typically” in the pediatric age
condition are suspicious and not convincing range and presents in a mild fashion.
enough to some physicians seeking a more
complex pathophysiological rationale or a
more “organically” based explanation. Treatment
Therefore, it is not uncommon that CNSD is
omitted in the differential diagnosis of chil- In the absence of warning signs, the sound manage-
dren with chronic or intermittent diarrhea, and ment of chronic nonspecific diarrhea should be
the typical symptom complex is often labeled based on the immediate prescription of a normal
as lactose intolerance or other enzymatic mal- dietary regime, with a drastic reduction in the
function, intestinal “immaturity,” food allergy, excessive fluid intake and the suppression of hyper-
enteroparasitosis, small bowel bacterial over- osmolar and carbonated drinks and industrial juices
growth syndrome, or other diagnosis—popu- mentioned above [5, 6]. It has also been suggested
lar or trendy for each geographical region or that frequent intake of cold fluids and ingestion of
historical period [15]. These tentative diagno- food between meals be avoided, in order to prevent
ses are characteristically followed by the pre- a disruption on the MMC and intestinal hypermo-
scription of prolonged and equally tility. A normal proportion of fat should be restored
unsubstantiated dietary regimes [15] that are in the diet. The use of antibiotics, antidiarrheal
sometimes highly costly as well as by trials of medications, and elimination diets has no rational
a panoply of medications, including antibiot- basis or therapeutic advantages and should thus be
ics, antispasmodics, or whichever product is discouraged. Parents should be given advice and
in vogue. support in what regards the mechanisms and prog-
While it is common in certain places that nosis of CNSD [6] since they are typically confused
every child with chronic diarrhea is referred to a and concerned at the persistence of symptoms and
pediatric gastroenterologist, CNSD can be the lack of apparent improvement on the child’s
promptly diagnosed and treated by a proactive stool patterns. It is particularly important to avoid
general practitioner or general pediatrician. The iatrogenic consequences, manifested mainly in the
evaluation of children with chronic diarrhea abuse of highly restrictive diets, which may cause
requires a complete clinical history and a sound nutritional deficiencies in the child and domestic
physical examination [6]. Factors that may cause disruption within the family.
or exacerbate diarrhea, such as diet, antibiotics,
products with laxative effects, and past enteric
infections, should be investigated. Dietary fac- References
tors (already commented) are the mainstay of the
history and the subsequent diagnostic rationale. 1. Davidson M, Wasserman R. The irritable colon of
childhood (chronic nonspecific diarrhea syndrome).
When laboratory tests are performed, these
J Pediatr. 1966;69:1027–38.
should reveal no abnormalities and be consistent 2. Cohen SA, Hendricks KM, Eastham EJ, Mathis RK,
with a normal nutritional and absorptive status Walker WA. Chronic nonspecific diarrhea. A compli-
358 E. Guiraldes and J.L. Roessler

cation of dietary fat restriction. Am J Dis Child. First World Congress of Pediatric Gastroenterology,
1979;133:490–2. Hepatology, and Nutrition. J Pediatr Gastroenterol
3. Greene HL, Ghishan FK. Excessive fluid intake as a Nutr. 2002;35 Suppl 2:S110–7.
cause of chronic diarrhea in young children. J Pediatr. 10. Hyams JS, Etienne NL, Leichtner AM, Theuer RC.
1983;102:836–40. Carbohydrate malabsorption following fruit juice
4. Kneepkens CMF, Hoekstra JH. Chronic nonspecific ingestion in young children. Pediatrics. 1988; 82:
diarrhea of childhood: pathophysiology and manage- 64–8.
ment. Pediatr Clin N Am. 1996;43:375–90. 11. Hoekstra JH, Van den Aker JHL, Hartemink R,
5. Hoekstra JH. Toddler diarrhoea: more a nutritional Kneepkens CMF. Fruit juice malabsorption: not only
disorder than a disease. Arch Dis Child. 1998; 79: fructose. Acta Paediatr. 1995;84:1241–4.
2–5. 12. Hoekstra JH, Van den Aker JHL, Ghoos YF, Hartemink
6. Hyman PE, Milla PJ, Benninga MA, Davidson GP, R, Kneepkens CMF. Fluid intake and industrial pro-
Fleisher DF, Taminiau J. Childhood functional gastro- cessing in apple juice induced chronic non-specific
intestinal disorders: neonate/toddler. Gastroenterology. diarrhoea. Arch Dis Child. 1995;73:126–30.
2006;130:1519–26. 13. Lebenthal-Bendor Y, Theuer RC, Lebenthal A, Tabi I,
7. Ochoa TJ, Salazar-Lindo E, Cleary TG. Management Lebenthal E. Malabsorption of modified food starch
of children with infection-associated persistent diar- (acetylated distarch phosphate) in normal infants and
rhea. Semin Pediatr Infect Dis. 2004;15:229–36. in 8–24-month-old toddlers with non-specific diar-
8. Fang GD, Lima AA, Martins CV, Nataro JP, Guerrant rhea, as influenced by sorbitol and fructose. Acta
RL. Etiology and epidemiology of persistent diarrhea Paediatr. 2001;90:1368–72.
in northeastern Brazil: a hospital-based, prospective, 14. Fenton TR, Harries JT, Milla PJ. Disordered small
case–control study. J Pediatr Gastroenterol Nutr. intestinal motility: a rational basis for toddlers’ diar-
1995;21:137–44. rhoea. Gut. 1983;24:897–903.
9. Hyams J, Colletti R, Faure C, et al. Functional gastro- 15. Lloyd-Still JD. Chronic diarrhea of childhood and the
intestinal disorders: Working Group Report of the misuse of elimination diets. J Pediatr. 1979;95:10–3.
 Functional Dyspepsia
33
Alycia Leiby and Denesh K. Chitkara

category or the other and there have been no

Introduction studies in pediatrics validating the existence of
these two entities. Essential features of FD do
The term “dyspepsia,” originating from the Greek include persistent pain or discomfort above the
meaning “bad to digest,” is defined as chronic or umbilicus, not associated or relieved by a change
recurrent pain or discomfort centered in the upper of stool frequency or form, as well as a lack of
abdomen that is characterized by symptoms of evidence for inflammatory, anatomic, metabolic,
nausea, vomiting, bloating, and early satiety, all of or neoplastic conditions [1]. In order to satisfy the
which are usually exacerbated by food intake. Rome criteria for FD, the pain should be present at
Dyspepsia can also overlap with heartburn; how- one or more times per week for at least 2 months.
ever, heartburn alone is usually characterized
as gastroesophageal reflux disease (GERD).
Dyspepsia has recently been subdivided into pre- Epidemiology
dominant symptoms of pain in the upper abdomen,
known as epigastric pain syndrome, versus pre- Upper gastrointestinal (GI) symptoms are com-
dominant symptoms of discomfort, such as nau- mon in children and adults. In a community-
sea, vomiting, and bloating, known as postprandial based study, 5–10% of otherwise healthy
distress syndrome. The 2006 pediatric Rome crite- adolescents reported typical dyspeptic symp-
ria for functional dyspepsia (FD) do not distin- toms of nausea, heartburn, and acid brash within
guish between these two types though, as many the past year [2]. In addition, 20% of adoles-
young children do not fit precisely into one cents have noted upper abdominal pain at some
point during the previous year [2]. In pediatric
A. Leiby, M.D. patients who ultimately undergo an esophago-
Pediatric Gastroenterology and Nutrition, Goryeb gastroduodenoscopy for their symptoms, two-
Children’s Hospital, Atlantic Health, Morristown, NJ, USA thirds have no evidence of mucosal inflammation
D.K. Chitkara, M.D. (*) and are diagnosed with FD [3]. De Giacomo
Pediatric Gastroenterology and Nutrition, et al. described a prevalence of dyspepsia of as
Goryeb Children’s Hospital, Atlantic Health, much as 45% in a school-age population of chil-
Morristown, NJ, USA
dren in Italy [4]. The annual prevalence of dys-
Assistant Professor, Department of Pediatrics Mount pepsia in adults in Western countries is
Sinai School of Medicine, NY, USA
approximately 25%, and the condition accounts
Morristown Memorial Hospital, for 2–5% of all primary care consultation [5].
100 Madison Avenue, Morristown, NJ 07962, USA
e-mail: [email protected] Only approximately half of adult dyspepsia

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 359

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_33, © Springer Science+Business Media New York 2013
360 A. Leiby and D.K. Chitkara

sufferers in Europe and the USA seek medical Table 33.1 Differential diagnosis for dyspepsia
help for their symptoms, and yet FD remains a Functional disorders
major source of morbidity and economic burden Functional dyspepsia
[5]. More importantly, dyspepsia can have a GERD predominant symptoms
significant impact on quality of life for both Rumination syndrome
children and their parents and families [6]. Post-viral gastroparesis
Abdominal migraine
Inflammatory/mucosal
Pathogenesis Gastroesophageal reflux disease
Helicobacter pylori gastritis
Peptic ulcer
Dyspeptic symptoms are associated with a vari-
NSAID ulcer
ety of underlying disorders, such as reflux
Eosinophilic gastroenteritis
esophagitis, peptic ulcer disease, and anatomical
Infection: Giardia, Blastocystis hominis, Dientamoeba
abnormalities. A list of the differential underly- fragilis
ing diagnoses for dyspepsia is in Table 33.1. In a Bacterial overgrowth
prospective audit of their patient practice, Hyams Inflammatory bowel disease
et al. characterized the underlying causes of chil- Menetrier’s disease
dren who presented with dyspepsia in their prac- Varioliform gastritis
tice. Of the subjects who underwent evaluation Celiac disease
with upper endoscopy, 38% had the presence of Lactose/carbohydrate malabsorption or intolerance
mucosal inflammation either in the esophagus, Henoch–Schonlein purpura
stomach, or duodenum [3]. Nine percent had Anatomic disorders
Helicobacter pylori (H. pylori) with gastric Malrotation with/without volvulus
inflammation [3]. The remaining 62% of children Duodenal web
Psychiatric disorders
had no underlying organic, metabolic, or gastro-
Psychogenic vomiting
intestinal mucosal causes identified to explain
Depression
their symptoms and were characterized as having
Somatization
FD [3]. Similarly, in adults, the majority of indi-
Anxiety
viduals with symptoms of dyspepsia have FD. Panic disorders
The etiology of FD is best understood within Conversion reactions
the biopsychosocial model of illness. The Anorexia nervosa
pathophysiology of symptoms of functional dys- Others
pepsia is related to abnormalities of function in Chronic pancreatitis
the upper gastrointestinal motor function in about Chronic hepatitis
50% of adults and greater than 70% of children Ureteropelvic junction obstruction
[7, 8]. Specifically, delayed gastric and small Biliary dyskinesia
intestinal transit, decreased gastric accommoda- Intestinal pseudo-obstruction
tion, and gastric dysrhythmia [8] have been found Lymphoma, carcinoma
in dyspeptic patients. In a retrospective chart
review, 40% of pediatric patients with FD had
slow small bowel transit as measured by radioac-
tive egg meal and increased likelihood of bloat- meal bolus, and visceral hypersensitivity may
ing and abdominal pain complaints [9]. Abnormal contribute to many postprandial symptoms, par-
gastric emptying has also been found by both ticularly bloating, nausea, and early satiety [11].
scintigraphy and 13C breath testing in multiple Compared to healthy adults, adolescents with FD
studies [8–10]. In addition, impaired gastric had significantly higher fasting gastric volume
accommodation, as measured by a decreased and lower postprandial volume change when
ability of the stomach to relax in response to a measured by 99mTc-SPECT [10].
33 Functional Dyspepsia 361

Despite the lack of mucosal inflammation in

the majority of children with dyspepsia, a subset Clinical Presentation
of patients has a grossly normal but microscopi-
cally inflamed duodenum and stomach. A retro- Dyspepsia-associated abdominal pain is often
spective analysis of adults with postprandial localized to the epigastrium, in the right or left
distress syndrome revealed that 47% had duode- upper quadrants. In younger children, however,
nal eosinophilia and a significant association with pain is more likely to be periumbilical. Severe epi-
allergy [12]. Friesen et al. found 71% of children gastric pain and ulcer-like dyspepsia were
undergoing endoscopy for dyspepsia had duode- significantly associated with H. pylori infection in
nal eosinophilia (>10 eosinophils/hpf), and 90% children, while dysmotility-like dyspepsia was not
of these patients responded to either a combina- [4]. Pain usually develops immediately after eat-
tion of H1/H2 blockade or cromolyn [13]. When ing and persists for 3–4 h. 80% of dyspeptic
compared to non-atopic children, atopic children patients will report more than five symptoms [19].
were shown to have higher mast cell and eosino- Nausea, pyrosis, oral regurgitation, early satiety,
phil counts within the gastric mucosa, with mast postprandial abdominal bloating and/or distention,
cell activation upon cows’ milk challenge [14]. excess gas with or without increased belching or
Gastric dysfunction was also found in the atopic flatulence, queasiness, fullness, and retching are
group by electrogastrography after antigen chal- common complaints. A history of vomiting is not
lenge. Mast cell–nerve interactions are recog- uncommon. However, if vomiting is persistent and
nized in irritable bowel syndrome and may play a associated with “red flag” symptoms such as
role in FD [15]. significant abdominal pain, hematemesis, bilious
An altered threshold of gut-wall receptors, emesis, recurrent fevers, persistent weight loss, or
an abnormal modulation in the conduction of blood in the stool, a more extensive and expedited
the sensory input, or a decreased threshold for clinical work-up is indicated [1].
pain perception at the central level may all
contribute to visceral hypersensitivity, with
increased sensitivity to gastric balloon disten- Diagnosis and Evaluation
tion being specific for FD [7]. Altered motor
response or altered visceral sensation to gut The optimal diagnostic evaluation of a child who
distention caused by substances such as lac- presents with dyspepsia remains controversial.
tose, fructose, fatty acids, and bile acids may Since most patients will have functional dyspep-
explain why some patients respond clinically sia, approaching the diagnosis positively facili-
to dietary restrictions [16]. A wide variety of tates optimal care. Diagnostic evaluation should
physical and psychological stress factors exter- be driven by an index of clinical suspicion based
nal to the GI tract may trigger abdominal symp- on pertinent alarm signs in the history and physi-
toms, suggesting that dysfunction of the cal examination. A well-structured history, physi-
extrinsic innervation of the gut may also con- cal exam, and growth curve review is essential in
tribute to the pathogenesis of the condition. patients with uninvestigated dyspepsia in order to
Depression and anxiety are two common identify those with gastroesophageal reflux dis-
comorbid conditions associated with functional ease (GERD) and exclude other structural dis-
GI disorders. Anxiety, particularly in hyper- eases such as abdominal wall and biliary pain. It
sensitive patients, is associated with a decreased is also important to explore psychosocial factors
pain and discomfort threshold and decreased as this can have a major impact on the success of
gastric compliance [17]. Recent evidence based management [1]. A reasonable initial laboratory
on PET functional brain imaging suggests that work-up includes a full blood count, measure-
this may be related to decreased activation of ment of the erythrocyte sedimentation rate, chem-
the pregenual anterior cingulate during gastric istry profile (including liver and renal function
distention [18]. tests), stool ova and parasite analysis, and uri-
362 A. Leiby and D.K. Chitkara

nalysis. Presence of H. pylori should be investi- However, these tests are invasive and should be
gated for the child with severe ulcer-like dyspepsia considered as secondary or tertiary investigations
and risk factors such as a family history of H. in the child with atypical complaints.
pylori and crowded or institutional living condi-
tions [20]. The test for H. pylori should be a
monoclonal stool antigen test, as the sensitivity Course of Illness and Prognosis
and specificity may approach 100% [21], or a 13C
urea breath test. An upper GI series with small Hyams et al. described the clinical constellation
bowel follow-through may be indicated in chil- and natural history of dyspepsia in children and
dren with severe abdominal pain and recurrent adolescents in pediatric gastroenterology prac-
vomiting to rule out an anatomic disorder and/or tice. A standardized questionnaire was adminis-
mechanical obstruction. Serum amylase, lipase, tered by a pediatric gastroenterologist to all
and ultrasonography are indicated for discrete subjects older than 5 years of age (and their par-
acute episodes of pain, triggered by a meal or ents) treated in a referral pediatric gastroenterol-
localized to the right upper quadrants. Esophageal ogy practice for 1 month or more for abdominal
pH/multichannel intraluminal impedance moni- pain or discomfort, nausea, or vomiting. Duration
toring may be useful to detect extra-esophageal of symptoms of less than 1 year and vomiting
manifestations of GERD and unrecognized were risk factors for mucosal inflammation.
GERD. Hydrogen breath tests may be a useful Follow-up at 6 months to 2 years revealed 70% of
diagnostic adjunctive tool for evaluation of clini- subjects were either asymptomatic or much
cally suspected bacterial overgrowth and lactose/ improved regardless of the cause of dyspepsia
carbohydrate malabsorption. [3]. However, the remainder had mild to no
In most children with dyspeptic symptoms, improvement or worsening of symptoms despite
the likelihood of finding a mucosal abnormality medical management. More recently, Miele et al.
is low, but patients with alarm symptoms such as supported these findings in a prospective study of
weight loss, recurrent vomiting, bleeding, ane- children with functional gastrointestinal disor-
mia, dysphagia, and jaundice, as well as patients ders and found most patients improved at 3 and
frequently taking nonsteroidal anti-inflammatory 12 months. Patients with FD only comprised 13%
drugs (NSAIDs), should be considered appropri- of this group, however [22].
ate candidates for upper endoscopy. Endoscopy
is ultimately necessary to exclude peptic ulcers,
erosive esophagitis, H. pylori infection, gastritis, Management
and eosinophilic esophagitis, all of which may
mimic symptoms of GERD. Microscopic upper A thorough history and clinical evaluation is
GI inflammation is common in children and essential to guide management decisions and to
adults with symptoms of dyspepsia, but its clini- exclude GERD and irritable bowel disease in
cal significance is still unclear. These findings patients with untreated dyspepsia. Historically,
have been described in asymptomatic adults and the initial therapy for patients with uninvestigated
patients with irritable bowel syndrome, and there- dyspepsia has been empirical treatment with ant-
fore, mild histologic gastritis or duodenitis with a acids, proton pump inhibitors, and prokinetic
macroscopically normal upper endoscopy in the agents, depending on symptoms. A more compre-
absence of chronic ingestion of NSAIDs may hensive approach uses the biopsychosocial model
also be consistent with a diagnosis of FD. Further in formulating a treatment plan that involves a
evaluation of gastric and small bowel motility by combination of educational, pharmacological,
scintigraphy, barostat to investigate gastric psychological, as well as complementary thera-
accommodation and visceral sensitivity, or pies (Table 33.2). Using the Rome criteria to pro-
manometry may be helpful to better delineate the vide a positive and expeditious diagnosis of FD
pathophysiology of the individual’s symptoms. helps the patient and family shift their focus away
33 Functional Dyspepsia 363

Table 33.2 Management options for dyspepsia Considering that abnormal gastric emptying is
1. General principles often present in patients with FD, prokinetic agents
(a) Anti-reflux measures are an appealing option for those with dysmotility-
(b) Trigger avoidance like symptoms, such as fullness, bloating, or early
2. Diet satiety. In a meta-analysis, Van Zanten et al. illus-
(a) Timing of meals trated that both cisapride (a 5HT4 agonist) and
(b) Small, frequent meals domperidone (a dopamine antagonist) were
(c) Solid versus liquid diet efficacious in FD [25]. However, cisapride is no
(d) Minimize high fat and excessively spicy foods longer available through general prescription in
3. Pharmacology
most countries, and domperidone is currently not
(a) H2 blockers—cimetidine, famotidine,
ranitidine
generally available in the USA. Metoclopramide
(b) Proton pump inhibitors—omeprazole, (central and peripheral dopamine-2 antagonist) is
esomeprazole, lansoprazole, pantoprazole thought to be helpful for symptoms of nausea, full-
(c) Prokinetic agents—metoclopramide, domperi- ness, and bloating, but its use is limited by the neu-
done, cisapride, erythromycin rologic side effects [26]. Low-dose erythromycin (a
(d) Impaired gastric accommodation—sumatrip- motilin agonist) has been shown to accelerate gas-
tan, buspirone
tric emptying, but it also decreases gastric accom-
(e) Duodenal eosinophilia—montelukast
modation and may increase dyspeptic symptoms.
(f) Visceral hypersensitivity—amitriptyline
Erythromycin also has a high occurrence of tachy-
4. Surgical
(a) Nutritional supplementation—gastrostomy/
phalaxis after 3–4 weeks of therapy. Medications
gastrojejunostomy/jejunostomy such as sumatriptan and buspirone (5HT1 agonists)
5. Alternative therapy that improve gastric accommodation reflex are
(a) Hypnotherapy beginning to be evaluated for FD, but their efficacy
(b) Cognitive behavioral therapy in pediatrics has not been established [27].
(c) Psychotherapy Low-dose tricylic antidepressants have also
(d) Acupuncture been used particularly to decrease hyperalgesia
(e) Herbal therapy—Iberogast, ginger and improve sleep, although the evidence for
their use is stronger in irritable bowel syndrome
from continued testing and investigations to than FD. A small study of seven adults with FD
improvement of symptoms and quality of life. showed that all improved after 4 weeks of ami-
Determining the patient’s most distressing symp- triptyline versus placebo and concluded that the
tom may also help to target particular treatment increased tolerance to aversive visceral sensation
options and individualize therapy. was the likely mechanism [28]. Bouras et al. fol-
Several large studies have now shown that lowed gastric sensorimotor function and post-
proton pump inhibitors (PPI) (omeprazole and prandial symptoms in a group of 41 healthy adult
lansoprazole) are more effective than H2 antago- volunteers given with either 25 or 50-mg amitrip-
nists in relieving symptoms of uninvestigated tyline or placebo for 2 weeks. Gastric emptying
dyspepsia [23]. The data for omeprazole in dys- was found to be delayed in both treatment groups,
pepsia indicate that patients in whom ulcer-like without effect on gastric volume or satiation but
pain is described as the most bothersome symp- with a significant reduction in nausea 30 min
tom are most likely to respond to PPI therapy after the nutrient drink test [29]. A recent pediat-
[24]. In these patients, full-dose omeprazole ric study compared amitriptyline to placebo in a
1–2 mg/kg/day up to 40 mg daily is recommended mixed population of irritable bowel syndrome,
for treatment. An empirical trial of high-dose PPI FD, and functional abdominal pain in 83 chil-
is useful to confirm the acid-related nature of dren. Those that were <35 kg received 10 mg/day
dyspeptic symptoms, as patients with functional and those >35 kg received 20 mg/day. No differ-
dyspepsia have been shown to have duodenal ence was found between groups, but almost two-
hypersensitivity to acid. third in both groups improved, underscoring the
364 A. Leiby and D.K. Chitkara

power of placebo. Of note, anxiety scores showed Although the evidence is not overwhelming,
significant improvement in the active treatment some patients may benefit from minimizing fatty,
arm of the study. gaseous, and spicy foods as well as NSAID use
In the subset of patients with evidence of duo- [44] and, for those with more symptoms of dys-
denal eosinophilia [12], there is preliminary evi- motility, attempting smaller, more frequent meals.
dence to suggest that the use of montelukast, a Depending on the clinical setting, therapies
leukotriene inhibitor, may provide benefit. Forty should be considered in a systematic manner, and
children with duodenal eosinophilia (>10 eosino- failure of multiple therapies should result in a
phils/hpf) were randomized to receive 10 mg of referral for endoscopy.
montelukast or placebo for 2 weeks, with 62% of
the treatment group showing a positive response,
as measured by a rating of “improved to excel- References
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 Irritable Bowel Syndrome
34
Bella Zeisler and Jeffrey S. Hyams

largely derived from adult data, which likely have

Introduction pediatric applicability.

Chronic abdominal pain is one of the most com-

mon presenting complaints both to primary care Pathophysiology of IBS
pediatric providers and pediatric gastroenterolo-
gists. The past two decades have witnessed a dra- Given widely varying clinical presentations (con-
matic change in the way chronic abdominal pain stipation predominant (IBS-C), diarrhea predom-
is considered, evolving from a largely pejorative inant (IBS-D), mixed defecation pattern (IBS-M))
psychosocial diagnosis of nonorganic pain to one as well as a history of post-infectious versus not
in which there is increasing evidence of abnor- post-infectious symptom development, it is likely
malities in motor, sensory, autonomic, immuno- that multiple mechanisms contribute to the devel-
logic, genetic, and psychological factors resulting opment of IBS. Whether these pathogenetic path-
in disordered brain-gut communication. During ways are similar in children and adults is not
this time the Rome criteria for functional gastro- known; though with the exception of much
intestinal disorders have been developed to pro- greater female predominance in adults, the clini-
vide a common language describing the clinical cal picture is quite similar. It has been suggested
manifestations of brain-gut disorders [1]. One that noxious stimulation by gastric suction at
such disorder, irritable bowel syndrome (IBS), birth may lead to long-term visceral hypersensi-
commonly affects children and is the subject of tivity and cognitive hypervigilance resulting in a
this chapter. In this chapter, we will provide an greater likelihood of developing functional intes-
overview of IBS in children while describing tinal disorders [2]. Physical and/or sexual trauma
pathophysiological mechanisms and treatments, is a well-known risk factor for IBS in adults.

Altered Motility

Systematic studies of large numbers of children

with IBS are not available. Data from adults have
B. Zeisler, M.D. • J.S. Hyams, M.D. (*) shown delayed colonic transit in IBS-C and
Division of Digestive Diseases, Hepatology, and accelerated colonic transit in IBS-D [3]. One
Nutrition, Connecticut Children’s Medical Center,
study showed a disturbed rectal contractile
282 Washington Street, Hartford, CT 06106, USA
e-mail: [email protected] response to meals in children with IBS [4].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 367

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_34, © Springer Science+Business Media New York 2013
368 B. Zeisler and J.S. Hyams

Genetic Determination Gastrointestinal Microbiota

and Mucosal Immune Activation
The concordance rate for IBS in monozygotic
twins has generally been found to be higher Evidence suggests that low-grade inflammation
than in dizygotic twins. However, data suggest with increased CD3+ cells, T cells, macrophages,
having a parent with IBS has a greater influence and mast cells may play a role in IBS [14, 15]. Post-
than having a twin sibling and that the heredit- infectious IBS is well described in adults and chil-
ability of anxiety and depression may play dren [16, 17]. Most published data concern IBS
large roles. It has also been proposed that gene following bacterial infection, whereas the literature
polymorphisms involving the serotonergic, does not similarly support IBS following viral infec-
adrenergic, and opioidergic systems, as well as tion [18] despite anecdotal evidence to the contrary.
genes encoding proteins with neuromodulatory Fecal microbiota of adults with IBS differs from
and immunomodulatory properties, may be healthy controls with reduced numbers of lactoba-
important [5]. Polymorphisms in the promoter cilli and Collinsella [19]. Controversy exists as to
region of the serotonin reuptake transporter whether small intestinal bacterial overgrowth
(SERT) protein have been associated with dif- (SIBO) may play a role in IBS [20]; these data are
ferent forms of IBS in adults [6]. In addition, largely based on lactulose breath testing rather than
decreased measured SERT mRNA in colonic quantitative culture of small bowel fluid. Increased
biopsy specimens has been reported in pediat- intestinal methane production has been associated
ric patients with IBS compared to pediatric with IBS-C [21]. Both oral antibiotics [22] and pro-
controls, thus supporting the role of 5-HT sig- biotics [23] have been shown to reduce symptoms
naling in IBS [7]. Lastly, a low prevalence of in IBS (see below on treatment).
the high-producer genotype for IL-10 (an anti-
inflammatory cytokine) has been noted in
patients with IBS [8]. Epidemiology of IBS

IBS has been observed worldwide; in the United

Visceral Hypersensitivity States, one study found a prevalence of 8% in
middle school and 14% in high-school-aged
Barostat studies have convincingly demonstrated children [24]. Up to 45% of children presenting
rectal hyperalgesia in children with IBS with with chronic abdominal pain in whom evalua-
lowered thresholds for pain as well as abnormal tion fails to find structural, inflammatory, or
pain referral after rectal distention [9, 10]. neoplastic disease have symptoms consistent
Autonomic dysfunction with increased sympa- with IBS [1]. Obesity has been suggested as a
thetic activity has been suggested [11]. risk factor [25].

Psychiatric Disorders and Cerebral Clinical Manifestations

Activation
IBS is a chronic, recurring disorder involving a
Psychiatric disorders such as anxiety, depres- range of symptoms including abdominal pain or
sion, and somatization have been associated discomfort and disturbances in stool form and/or
with IBS. Using advanced brain imaging tech- frequency. Symptoms may be severe and disabling
niques, differences have been shown in activa- leading to significant concern for patients, families,
tion within the insula, prefrontal cortex, and practitioners. Due to extensive medical testing
thalamus, and cingulate cortex in adults with in patients with significant gastrointestinal com-
IBS compared to healthy controls in response to plaints, monetary costs, both direct and indirect, as
visceral stimulation [12, 13]. well as quality of life costs can be high [26, 27].
34 Irritable Bowel Syndrome 369

Several clinical guides have been proposed to aid Table 34.1 Rome III diagnostic criterion for IBS in chil-
practitioners in making a positive, timely diagnosis dren ages 4–18 [1]
of IBS, while avoiding exhaustive medical testing Both of the following must include:
that may be time consuming, expensive, and anxi- 1. Abdominal discomfort ( as defined by an
ety provoking. The Manning criteria published in uncomfortable sensation not described as pain) or
pain associated with 2 or more of the following at
1978 were the first widely used validated clinical least 25% of the time:
diagnostic tool for IBS [28]. Over the last decades, • Improvement with defecation
IBS diagnostic criteria have been refined by a suc- • Onset associated with a change is frequency of
cession of working teams through the Rome pro- stool
cess, culminating in the Rome III criteria for IBS • Onset associated with a change in form
published in 2006, as a subsection of diagnostic cri- (appearance) of stool
2. No evidence of an inflammatory, anatomic, meta-
teria for the spectrum of functional gastrointestinal
bolic, or neoplastic process that explains symptoms
disorders. To better reflect clinical experience in
Criteria must be fulfilled at least once per week for at least
pediatrics and to expedite diagnosis and treatment, 2 months prior to diagnosis
there are distinct Rome III criteria for pediatrics that
are more inclusive than adult criteria [29] with
respect to duration of symptoms (Table 34.1). Table 34.2 Alarm features in children and adolescents
In addition to clinical criteria for the diagnosis of with abdominal pain and abnormal stool pattern [1]
IBS, the Rome III working groups have furthermore • Gastrointestinal bleeding
delineated 4 IBS subtypes based on stool form: IBS • Perirectal disease
with constipation (IBS-C), IBS with diarrhea (IBS- • Fever
D), mixed IBS (IBS-M), and un-subtyped IBS • Arthritis
(IBS-U). Subclassification may help practitioners • Persistent vomiting
select more targeted therapies in clinical practice, • Persistent right upper or right lower quadrant pain
with the caveat that symptoms may change over • Dysphagia
time and classification may not be firm. • Involuntary weight loss
Additional supporting symptoms not required • Nocturnal symptoms
to make the diagnosis of IBS but commonly • Family history of inflammatory bowel disease,
celiac disease, and peptic ulcer disease
observed include abnormal stool frequency,
• Pubertal delay
straining, urgency, gas bloat, passage of mucus,
and sensation of incomplete evacuation. IBS has
also been associated with other gastrointestinal, for celiac disease in patients presenting with IBS
somatic, and psychological symptoms including symptoms may be worthwhile from a cost point
upper gastrointestinal complaints (e.g., dyspep- of view [31, 32]. A differential diagnosis for con-
sia), fibromyalgia, headache, backache, genito- ditions that may present similarly to IBS is pro-
urinary symptoms, anxiety, depression, and poor vided in Table 34.3. If any red flags are raised,
school performance [30]. initial laboratory tests to consider that are rela-
tively inexpensive and readily available include a
complete blood count, erythrocyte sedimentation
Clinical Evaluation rate, serum aminotransferases, urinalysis, and
celiac serology. The need for other diagnostic
If the practitioner highly suspects IBS based on testing such as abdominal imaging, breath tests,
gastrointestinal complaints that meet Rome III and endoscopy will depend on the clinical judg-
criteria, and the patient exhibits no alarm signs as ment of the practitioner. More recently, serologic-
listed in Table 34.2, specificity for IBS is high, based proprietary blood tests have been marketed
the diagnostic yield of further testing is generally to aid practitioners in the diagnosis IBS. Since
low, and no further testing is necessary. There are there are no published data on the accuracy of
limited data however, suggesting that screening these tests, their diagnostic role is not clear.
370 B. Zeisler and J.S. Hyams

Table 34.3 Differential diagnosis of chronic abdominal Table 34.4 Therapeutic approaches to irritable bowel
pain and abnormal stool pattern syndrome
Celiac disease Medications
Carbohydrate intolerance • Antispasmodics
Inflammatory bowel disease • Antidepressants
Small intestinal bacterial overgrowth • Probiotics
Infection • Antibiotics
Gastrointestinal polyps • Melatonin
• Chloride channel agonists
• 5-HT targets (largely investigational)
• Guanylate cyclase receptor agonists
(investigational)
Therapy Dietary
• Limiting possible “triggers”
There are many approaches to the treatment • Increased fiber
of IBS involving medications, dietary manip- Behavioral approaches
ulations, and behavioral and physical thera- • Cognitive behavioral therapy
pies. An effective treatment plan is often – Psychotherapy
multifaceted and should be individually tai- – Hypnotherapy
lored and symptom directed. It must be noted – Guided imagery
that data in the pediatric literature to support Physical therapies
the evidence-based use of any particular treat- • Massage
• Acupuncture
ment strategy for IBS are sparse. Most thera-
• Reflexology
peutic strategies are empiric and/or are
extrapolated from adult studies or from stud-
ies of recurrent abdominal pain rather than
irritable bowel syndrome speci fi cally as Drugs
de fi ned by Rome criteria.
The cornerstone of successful treatment of Antispasmodics
IBS is an effective physician-patient-family Anticholinergic medications such as dicyclomine
relationship based on validation of pain com- and hyoscyamine may produce symptom relief
plaints, education, and ongoing support and through inhibition of smooth muscle contraction.
reassurance for the patient and family mem- Despite their common use in clinical practice,
bers. Realistic goals of therapy are not neces- pediatric studies are lacking and adult studies
sarily to eliminate symptoms, but rather to have not found clear efficacy [33, 34].
optimize patient function, quality of life, school Anticholinergic side effects may include consti-
attendance, and extracurricular participation pation, dry mouth, and urinary retention. Evidence
through a biopsychosocial approach. These has also been conflicting for the use of pepper-
goals may be achieved by alleviating symp- mint oil whose active ingredient, menthol, is
toms using appropriately selected pharmaco- thought to produce smooth muscle relaxation in
logic and non-pharmacologic approaches, the ileum and colon via calcium channel blocker
while at the same time identifying and address- properties. While less rigorous and/or smaller
ing psychological comorbidities and social studies have yielded positive results for its use in
factors that contribute to illness behavior. In the treatment of IBS [35–38], including one
order to set realistic expectations, goals of pediatric-specific study [39], other larger studies
treatment should be made clear with the patient do not show efficacy [40]. However, despite a
and family from the start. Pharmaceutical and dearth of convincing evidence, peppermint oil is
non-pharmaceutical approaches for the treat- becoming more commonplace for the treatment
ment of IBS are shown in Table 34.4. of IBS likely secondary to its relatively favorable
34 Irritable Bowel Syndrome 371

side effect profile and role as a “natural” remedy. in adults with IBS yielding mixed results. Some
Possible side effects of peppermint oil include trials have shown benefit for the use of certain
rectal and esophageal burning. Bifidobacterium and Lactobacillus strains and
VSL #3 and mixed strains of probiotics in
Antidepressants IBS-D [23, 51–54], while other studies report
The mechanism of action of antidepressant medica- negative results [55–57]. High-quality
tions for the treatment of IBS is not fully under- pediatric-specific studies are limited and also
stood; it is likely complex, involving multiple targets conflicting. While some studies of children
on the brain-gut axis. Studies have suggested that with IBS found a modest benefit for the use of
benefit in IBS may be due to a combination of their Lactobacillus GG in IBS [58, 59], a different
psychotropic, neuromodulatory, and analgesic prop- pediatric study found that Lactobacillus GG
erties [41–44]. In the adult literature, there is solid was not superior to placebo [60]. Thus, the role
evidence showing the benefit of tricyclic antidepres- of probiotics for the treatment of IBS, particu-
sants (TCA) on IBS symptoms, particularly for larly in pediatrics, remains uncertain. In addi-
IBS-D [45, 46]. In pediatrics, the data are limited tion, the lack of quality control/quality
and somewhat conflicting. One recent trial of ami- assurance with respect to the type and number
triptyline for the treatment of IBS in teenagers of live organisms found in the myriad probiotic
showed overall improvement [47], whereas another products sold over the counter poses an addi-
recent study in a pediatric population demonstrated tional challenge for their therapeutic use.
that amitriptyline and placebo offer similar benefit
[48]. In the adult literature, there is a limited body of Antibiotics
evidence for the use of selective serotonin reuptake With some evidence suggesting that small intesti-
inhibitors (SSRIs) in the treatment of IBS particu- nal bacterial overgrowth (SIBO) may play a role
larly for IBS-C [41, 49, 50]. However, there are no in IBS [20], the use of antibiotics for the treat-
large studies for the use of SSRIs in children with ment has been investigated. Several small, short-
IBS. In neither adult nor pediatric literature are there term studies have demonstrated symptomatic
head-to-head trials comparing SSRIs and TCAs for improvement in adult patients with IBS treated
use in IBS. Side effects for TCAs and SSRIs include with a course of metronidazole or the nonabsorb-
fatigue, dizziness, headaches, cardiac dysrhythmias, able antibiotic rifaximin [22, 61–63]. Large,
and worsening depression. Constipation may be a well-designed trials that include pediatric partici-
side effect of TCAs, and diarrhea may be a side pants are necessary to establish a definitive role
effect of SSRIs. Due to the potential side effect of for antibiotics in the treatment of IBS.
cardiac dysrhythmias with TCAs and SSRIs, a base-
line EKG should be considered prior to initiating Melatonin
therapy. Patients on antidepressant medications must Melatonin is a sleep-promoting hormone primar-
be monitored carefully for signs of depression. ily secreted by the brain. It has more recently
been shown to be produced in the gastrointestinal
Probiotics tract as well, and although the mechanism remains
Evidence suggests that enteric flora is a regula- unclear, recent investigation suggests that mela-
tor of mucosal inflammation and immunity, tonin secretion and metabolism may be involved
and derangements of enteric flora may contrib- in the pathogenesis of IBS [64–66]. Preliminary
ute to IBS symptoms [14, 15]. Probiotics, studies have shown that administration of exoge-
which are live microorganisms capable of nous melatonin may have a beneficial role in IBS
inducing a beneficial effect in the host, are pos- independent of its effect on sleep [67–69].
tulated to alleviate IBS symptoms via restora-
tion of the normal enteric flora and Chloride Channel Agonists
downregulation of mucosal inflammation. Lubiprostone, a bicyclic fatty acid prostaglandin
Various strains of probiotics have been studied E2 derivative, stimulates type 2 chloride channels
372 B. Zeisler and J.S. Hyams

in the intestine to increase fluid secretion and Miscellaneous

transit thereby improving symptoms of constipa- Other symptom-targeted agents that are often used
tion. Lubiprostone has been US FDA approved in patients with IBS include loperamide for the
for the treatment of adults with chronic idiopathic treatment of associated diarrhea and various laxa-
constipation since January 2006 and for the treat- tives (e.g., polyethylene glycol 3350) for the treat-
ment of IBS-C in adult females since April 2008. ment of constipation. Antacids, promotility agents
A 2009 combined analysis of 2 phase 3, random- (e.g., metoclopramide, erythromycin), and antie-
ized, placebo-controlled studies demonstrated a metics are used to target nausea and dyspepsia.
higher response rate for lubiprostone compared
with placebo in predominantly adult females with
IBS-C [70]. Reported side effects of lubiprostone Dietary Approaches
are nausea, headache, and diarrhea. Overall, the
data for lubiprostone are limited and mostly Fiber
available in abstract form. Dietary supplementation with fiber is often used as
a first-line approach in patients with IBS-C, par-
5-Hydroxytryptamine (5-HT) Targets ticularly in the primary care setting [79]. Fiber is
5-HT (serotonin) is a neurotransmitter found in the postulated to shorten intestinal transit time thereby
gut thought to mediate gastrointestinal sensorimo- alleviating constipation and decreasing intraco-
tor function. Recent research investigating the role lonic pressure. Adult studies have shown that fiber
of 5-HT in the pathophysiology of IBS has shown may improve constipation but not pain associated
altered 5-HT signaling in the digestive mucosa [7]. with IBS [80–83]. In fact, the evidence suggests
As such, alosetron, a 5-HT3 receptor antagonist, and that insoluble fiber, in particular, may actually
tegaserod, a 5-HT4 partial agonist, have been shown worsen pain in IBS due to increased gas bloat [82].
to be effective in the treatment of adults with IBS-D There are no pediatric-specific studies published
and IBS-C, respectively [71–73]. Alosetron appears on the use of fiber in IBS, and the limited data on
to decrease visceral sensation, prolong and reduce the use of fiber in recurrent abdominal pain in chil-
postprandial motility, increase colonic compliance, dren do not suggest clear benefit [84, 85].
and enhance small bowel water and salt absorption
slowing down transit time [74]. Tegaserod may Elimination Diet
increase gastrointestinal motility and alter visceral Many patients perceive their IBS to be triggered
sensitivity. Alosetron, released in 2000, and tegase- by food [86, 87] and often want to discuss the role
rod, released in 2002, were subsequently withdrawn of food in their condition. In a systematic review
from the market shortly thereafter secondary to an of the literature including 7 studies that examined
association with ischemic colitis and serious adverse the severity of IBS symptoms after dietary exclu-
cardiovascular events, respectively. In the United sion followed by food challenge, a positive
States currently, alosetron is available for the treat- response to an elimination diet ranged from 15 to
ment of IBS-D through restricted marketing. 71% [88]. Milk, wheat, eggs, and coffee were the
most frequently identified offenders. As the authors
Guanylate Cyclase Receptor Agonists of this systematic review point out, each study
Linaclotide is a peptide agonist of guanylate cycla- included had major methodological flaws, and
se-C. It is a first-in-class investigational drug cur- therefore, given the difficulty for patients in main-
rently in clinical development for the treatment of taining elimination diets and the risk of imbal-
IBS-C. In animal studies, linaclotide has been found anced nutrition particularly in the pediatric
to stimulate intestinal fluid secretion and transit and population, further studies are needed to validate
decrease visceral hypersensitivity [75]. Human dietary elimination as a treatment for IBS.
studies have shown potential benefit for constipa- There have been several recent studies linking
tion and IBS-C [76–78] and linaclotide recently was IBS with higher food-specific IgG levels [89, 90]
approved by the FDA for these indications. and positive skin prick testing [91], implicating a
34 Irritable Bowel Syndrome 373

role for directed food elimination in the treatment guidelines, IBS was considered a diagnosis of
of IBS. This association is currently weak, and exclusion obliging extensive, often times low-yield
further investigation is therefore needed. medical testing in many patients. With clinical
guidelines in place, the diagnosis of IBS can be
usually made in a timely and efficient manner.
Psychological Therapies There are myriad therapeutic options for the treat-
ment of IBS involving medications, dietary manip-
Cognitive behavioral therapy has been studied as a ulations, and behavioral and physical therapies.
treatment for IBS. Techniques used by therapists However, there is little strong evidence to support
may include psychotherapy, guided imagery, pro- any one particular approach. An effective strategy
gressive muscle relaxation, and gut-directed hyp- is often multifaceted and should be individually
notherapy. A meta-analysis of psychological tailored and symptom directed. Previous studies
therapies in the treatment of adults with IBS have demonstrated a particularly high placebo rate
showed a robust positive effect on symptoms [92]. for the treatment of IBS [94], suggesting that with
However, as pointed out by the authors, the studies a strong physician-patient-family relationship,
included in the analysis were highly subject to bias patients will improve regardless of the treatment
as none were well blinded, and true placebo groups approach. Future research in IBS will be focused
were not incorporated into the study designs. A on the pathophysiology of this disorder in the
pediatric-focused Cochrane systematic review of hopes of discovering more targeted therapies.
psychosocial interventions (based on cognitive
behavioral therapy) for recurrent abdominal pain
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 Functional Abdominal Pain
35
Manu R. Sood

be used to describe children with FAP. In this

Introduction chapter, FAP implies children who fulfill the Rome
criteria for FAP and, as per definition, have no
Functional gastrointestinal disorders (FGIDs) identifiable cause for the pain. The term includes
encompass a cluster of symptoms resulting from subjects and studies which have referred to this
disorders of gastrointestinal (GI) function or cen- disorder as recurrent abdominal pain in the past.
tral processing of information originating from the
GI tract. Abdominal pain is one of the most com-
mon symptoms associated with FGIDs in children Definition
such as functional dyspepsia, irritable bowel syn-
drome, abdominal migraine, and functional The Rome diagnostic criteria are widely used in
abdominal pain (FAP). Although Rome criteria research studies and are now being adapted for
have differentiated pain-associated FGIDs into use in clinical practice. According to the Rome III
distinct categories, a degree of overlap exists. It is criteria, childhood FAP is classified as abdominal
therefore not unusual for patients to fulfill symp- pain which occurs at least once per week for at
tom-based criteria for two or more FGIDs. Further least 2 months, it can be episodic or continuous,
confusion can occur when we label these disorders and there are insufficient criteria for other FGIDs.
“functional,” as some people may not understand There should be no evidence of an inflammatory,
what “functional” means. In the past, poorly anatomic, metabolic, or neoplastic process that
descriptive terms such as idiopathic, chronic, and can explain the subject’s symptoms [1]. Children
recurrent abdominal pain have been used to with abdominal pain at least 25% of the time with
describe children with FAP. Since “recurrent loss of daily functioning or somatic symptoms
abdominal pain” can be caused by many disparate such as headaches, limb pain, and/or difficulty
conditions and does not necessarily reflect the sleeping should be classified under childhood
functional nature of abdominal pain, experts in the functional abdominal pain syndrome [1]. This
field have recommended that this term should not definition is a description of symptoms, and crit-
ics think it is too general, and there are very few
M.R. Sood, M.D., F.R.C.P.C.H. (*) studies which have attempted to validate the accu-
Chief Pediatric Gastroenterology Division, racy of the Rome criteria in clinical settings.
Medical College of Wisconsin, Medical Since, the Rome criteria require the clinician
Director of Pediatric Gastroenterology, to exclude inflammatory, anatomical, and meta-
Children’s Hospital of Wisconsin,
Milwaukee, WI 53226, USA bolic disease process before diagnosing FAP,
e-mail: [email protected] some diagnostic testing is inevitable. Alarm

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 377

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_35, © Springer Science+Business Media New York 2013
378 M.R. Sood

Table 35.1 Alarm symptoms suggestive of an organic due to different definitions and diagnostic criteria
disease in children with chronic abdominal pain used to define FAP in these studies. Functional
Symptoms abdominal pain accounts for approximately 2–4%
Involuntary weight loss of pediatric clinic visits and almost 25% of the
Vomiting especially bile or blood referrals to tertiary gastroenterology clinics [7].
GI blood loss Most studies evaluating symptoms in groups of
Unexplained fever children suggest there are two peaks in preva-
Persistent right upper or lower quadrant pain
lence of FAP: one between 4 and 6 years of age
Delayed puberty
and the second between 7 and 12 years of age [8,
Family history of IBD
9]. In contrast, Perquin et al. demonstrated a pro-
Nocturnal symptoms waking the child from sleep
gressive rise in symptoms of RAP in children
Dysuria, hematuria, or flank pain
Examination
below 12–15 years of age [10].
Scleral icterus, pale conjunctivae The original study by Apley reported a slight
Rebound, guarding, or organomegaly female predominance with a female-to-male ratio
Perianal disease (skin tags, fissure, fistulae) of 1.3:1 [5]. Subsequent studies which included
Occult or gross blood in the stool children and adolescents reported a female-
to-male prevalence ratio of 1.4:1 [6]. Gender dif-
ferences in the prevalence of FAP are not obvious
symptoms which are more likely to occur in the in children younger than 8 years of age. In boys
presence of an organic disease have been pro- the prevalence in 5–10-year-olds is 10–12%, after
posed to circumvent this issue, but there is little which there is a slight decline followed by a later
clinical data regarding their accuracy (Table 35.1). peak around 14 years of age. In girls there appears
Proponents of the biopsychosocial model recom- to be a sharp increase in reported incidence of
mend that in the absence of alarm symptoms, a abdominal pain after the age of 8 years [6, 10].
presumptive diagnosis based on symptoms can One study of adolescents in a suburban town in
be made and help avoid a diagnostic workup USA reported no significant difference in preva-
which is invariably negative in FAP. Recent stud- lence rates among males and females, although
ies suggest that the introduction of the Rome cri- strict criteria for FAP were not applied [11].
teria has not altered physician practice behavior
and diagnostic testing is still common in children
with FAP [2, 3]. There are no evidence-based Pathophysiology
guidelines regarding which organic disease must
be excluded or which tests are helpful before Functional abdominal pain is thought to be a
diagnosing FAP. A recent survey study suggested multifactorial disorder resulting from a complex
that the vast majority of gastroenterologists do interaction between psychosocial factors, famil-
not feel that the Rome criteria are very useful in ial genetic vulnerability, environmental factors,
clinical practice, and further work to refine and and earlier life experiences through the brain-gut
validate the Rome criteria is needed [4]. axis (Fig. 35.1). The bidirectional brain-gut inter-
action in functional GI illness is well recognized.
The brain receives a constant stream of input
Epidemiology from the GI tract and integrates this with other
interoceptive information from the body and the
In Apley’s original survey of 1,000 primary and environment. It then sends an integrated response
secondary school children, 10.8% of the children back to various target cells within the GI tract
were found to have recurrent abdominal pain [5]. [12]. In healthy subjects, the majority of the
Subsequent studies have reported a prevalence of interoceptive information reaching the brain is
0.3–25% in school-aged children [6]. The wide not consciously perceived but serves primarily as
variability in estimated prevalence is likely to be input to autonomic reflex pathways (see Fig. 35.1).
35 Functional Abdominal Pain 379

Stressors

Higher cortical centers

Pituitary Subcortical centers &

CRH hypothalamus

ACTH Brain stem nuclei

Glucocorticoids Autonomic
Epinephrine Nervous
Norepinephrine System
Adrenal gland

+/–

ENS

Fig. 35.1 Schematic representation of interaction the adrenal glands. In response to ANS activation, cells of
between the sensory neuronal pathways and stress-related the adrenal medulla produce catecholamines such as
activation of the hypothalamic-pituitary-adrenal axis. The adrenaline and noradrenaline. These have potential to
GI afferent stimulus perception is modulated by these modulate activity of the sensory neuronal pathways and
interactions. Following activation of cortical and subcorti- cause visceral hypersensitivity. The cortical and subcorti-
cal brain regions, increased quantities of corticotropin- cal brain centers can facilitate or inhibit the activation of
releasing hormone (CRH) induces the release of second-order spinal neurons in response to visceral affer-
adrenocorticotropin (ACTH) from the anterior pituitary. ent stimulus (adapted from Knowles and Aziz [20])
This in turn stimulates the release of glucocorticoids from

In children with FAP, the conscious perception of changes in emotion and behavior, the latter trans-
the interceptive information or recall of intero- mits conscious sensation by its projections to the
ceptive memories of such an input can result in somatosensory cortex, anterior cingulate cortex,
constant or recurrent pain. The model which and the insula. The spinothalamic pathway is
incorporates peripheral and central abnormalities mainly responsible for pain localization and
in patients with FAP is plausible, but the majority assessment of pain intensity, and the other three
of the data this model is based upon are extrapo- pathways modulate affective pain behavior with
lated from animal and adult human studies. stimulation of important autonomic and descend-
An afferent signal originating in the GI tract ing inhibitory pathways (see Fig. 35.1). In animal
activates the nerve endings in the bowel wall and models, the anterior cingulate cortex and its pro-
travels along the first-order spinal afferents which jections to the amygdala and periaqueductal gray
synapse with the second-order neurons in the matter of the midbrain and the rostral ventrome-
dorsal horn of the spinal cord. The second-order dial medulla and the dorsolateral pontine tegmen-
neurons project to the brain through the spinore- tum can selectively modulate nociceptive
ticular, spinomesencephalic, spinohypothalamic, transmission. Stimulation of these sites inhibits
and spinothalamic tracts. While the first three responses of spinal neurons to noxious stimuli
tracts mainly activate unconscious and autonomic and can have an analgesic effect [13]. Therefore,
responses to visceral sensory input including second-order spinal neurons are activated by
380 M.R. Sood

afferent input from the first-order neurons con- Upregulation of central stress and arousal
veying messages from the bowel and inhibitory circuits through the hypothalamic-pituitary-
input from the brain. Disruption in this balance adrenal axis can induce visceral hyperalgesia.
can result in hypersensitivity. Anxiety and depressive symptoms have been
Peripheral sensitization represents a form of associated with FAP [22–25]. Children with
stimulus-evoked nociceptor plasticity in which FAP appear to be temperamentally anxious and
more prolonged stimulation, especially in the suffer from emotional difficulties. Such temper-
context of inflammation or injury, leads to amental traits have been associated with pessi-
change in the chemical milieu that permits noci- mistic worry, fear of uncertainty, harm avoidance,
ceptor firing at a lower level. The main sensitiz- and a lowered response threshold to environ-
ers implicated in primary sensitization include mental challenges [23, 26]. Children with FAP
bradykinin, histamine, serotonin, proteases, and also demonstrate a subliminal attention bias
cytokines [14]. Persistent abdominal pain fol- toward pain-related and social threat-related
lowing a gastrointestinal infection, surgery dur- words, suggesting a heightened sensitivity to
ing infancy [15], or an inflammatory disorder both internal and external threats [27]. Functional
such as gastroenteritis, Henoch-Schonlein pur- brain imaging studies in adults have shown that
pura, and cow’s milk intolerance can alter pain selectively focusing attention on visceral stimu-
perception, and visceral hypersensitivity is lus results in amplification of innocuous sensory
thought to be one of the mechanisms responsi- events and increased activation of brain regions
ble for this change [16–18]. associated with sensory perception, attention,
Under physiological states, spinal afferents and motivation [13, 22]. These emotional
respond only to noxious stimuli, but under con- responses are thought to play a role in the per-
ditions of injury and inflammation of peripheral sistence and amplification of pain [22].
nerve endings or repetitive noxious stimulation, Early life stress can also influence illness
they can respond to lower-intensity afferent sig- behavior and emotional response to pain [28].
nal, a phenomenon called central sensitization Work in animal models suggests that severe, pro-
[12]. Central sensitization can also affect adja- longed, or repetitive pain can trigger neurobiologi-
cent neurons, leading to the recruitment of pre- cal changes that can permanently modify pain
viously “silent” nociceptors and hyperalgesia in pathways [29]. These changes are likely to be
regions (somatic and visceral) remote to the site mediated through the hypothalamic-pituitary-
of peripheral sensitization. This is also termed adrenal axis [30–32]. A higher incidence of FGIDs
secondary hyperalgesia. In animal models, this and psychiatric comorbidities has been reported in
facilitation is triggered by presynaptic release of adults who were abused as children [33, 34]. What
neurotransmitters and increased intracellular constitutes a painful or a potential sensitizing event
calcium which lead to phosphorylation of is not clear. Painful experiences in neonatal life
N-methyl-d-aspartate (NMDA) receptors and have been related to altered pain processing and
resultant changes in receptor kinetics. Substance hypersensitivity in later life [35, 36]. A stressful
P and other tachykinins play a crucial role in life event such as marital turmoil in the family,
central sensitization [14]. Descending projec- school bullying, and being involved in an accident
tions from the brain stem nuclei to the spinal can predate the onset of FAP. Therefore, stressful
cord enhance or reduce the excitability of dorsal life events both in early and later on in life seem to
horn neurons, which receive afferent input from be a common in children with FAP. Corticotropin-
the viscera, in part through the opioidergic and releasing factor is an important hormone involved
adrenergic descending pain inhibitory pathways. in stress response and can alter GI motility and vis-
Using the water-drinking test and barostat stud- ceral sensitivity [37].
ies, altered sensory gastric perception and vis- Parenting style can influence a child’s ability
ceral hypersensitivity have been reported in to cope with pain [38]. Children of parents who
children with FAP [19–21]. have IBS report more bothersome gastrointesti-
35 Functional Abdominal Pain 381

nal symptoms compare to control children [38]. Table 35.2 Differential diagnosis of functional abdomi-
They also have more school absences and physi- nal pain
cian visits for gastrointestinal symptoms [39]. GI tract
Twin studies have shown that the presence of IBS Gastroesophageal reflux disease
in the respondent’s parents made a larger contri- Peptic ulcer disease
bution to the risk of having IBS than did the pres- Esophagitis (peptic, eosinophilic, or infectious)
ence of IBS in one’s twin, suggesting social Celiac disease
learning is more important than the environmen- Carbohydrate intolerance
Parasitic infestation
tal factors in determining illness behavior [40].
Inflammatory bowel disease
Further support for social learning in determining
Malrotation and volvulus
illness behavior comes from research showing a
Intussusception
relationship between parental responses and chil- Meckel diverticulum
dren’s behavior [6]. Higher levels of parental Chronic appendicitis
solicitousness in response to their child illness Epiploic appendagitis
behaviors are related to higher levels of children’s Gall bladder, liver, and pancreas
symptoms and disability as measured by school Cholelithiasis
absences. Factors associated with solicitous Choledochal cyst
behavior include non-Caucasian race, lower edu- Hepatitis
cational status, single mother or no partner, and Liver abscess
parental perception of severity of their child’s Recurrent pancreatitis
condition [6, 8]. Genitourinary
Urinary tract infection
Hydronephrosis
Clinical Presentation and Evaluation Urolithiasis
Dysmenorrhea
Pelvic inflammatory disease
Functional abdominal pain is typically periumbil-
Endometriosis
ical and usually not associated with vomiting,
Other
weight loss, diarrhea, nocturnal symptoms, or
Gilbert’s disease
growth deceleration. Organic abnormalities have Familial Mediterranean fever
been reported in 25–88% of children with recur- Malignancies
rent abdominal pain [41–43]. However, the causal Porphyria
relationship of some of the reported abnormali- Hereditary angioedema
ties with abdominal pain is not clear. A good Sickle-cell crisis
example is the relationship of H. pylori infection Lead poisoning
with abdominal pain; four studies assessed this Vasculitis (e.g., Henoch-Schonlein purpura)
and none found a positive association [38, 44–
46]. Therefore, studies reporting positive yield of
upper endoscopy in children with abdominal pain lates gallbladder contractions and pancreatic
may overestimate the positive yield of upper secretions. These physiological events can induce
endoscopy if they include H. pylori infection as pain in subjects with biliary tract obstruction and
an association with abdominal pain. pancreatitis. Children with constipation and rec-
The majority of the GI disease which presents tal fecal impaction can also present with post-
with abdominal pain as a symptom can be dif- prandial pain [43]. The gastrocolonic reflex after
ferentiated from FAP by a careful history and the meal can result in cramping pain in the pres-
clinical examination (Table 35.2). Prandial or ence of hard stool in the rectum producing outlet
postprandial pain may be associated with pancre- obstruction. Intolerance to lactose or sucrose or
atobiliary disease and carbohydrate intolerance. from excess fructose or sorbitol ingestion in fruit
Postprandial release of cholecystokinin stimu- juice can also cause pain, bloating, and diarrhea
382 M.R. Sood

[47–49]. A detailed dietary history can help to compared to children in the other groups. The sec-
identify dietary triggers and food intolerance ond trajectory classified as the short-term risk group
which can present with abdominal pain. The “rit- had highest level of symptoms and functional
ual” of this process provides important informa- impairment, but less severe depressive and anxiety
tion and further assures the patient that the symptoms. Symptoms in most of these patients
physician takes their complaints seriously and is improved in a few months, and they had no relapse
seeking a cause. in symptoms at 5-year follow-up. The third trajec-
Identification of troublesome symptoms, pos- tory, classified as the long-term risk group, included
sible triggers, environmental stressors, social or children (14%) with high levels of symptoms and
emotional disturbances, impaired daily function- functional impairment. All had high levels of anxi-
ing, and underlying psychiatric conditions is ety and depressive symptoms, more negative life
helpful in excluding other diagnosis and comor- events, and lower perceived self-worth. Children in
bid conditions. It also helps to develop a patient- this group had persistent symptoms during the
specific management plan. Older children and 5-year study period. It appears that children in the
adolescent should be interviewed without their short-term and long-term group would benefit from
parents and assured of complete confidentiality. referral to a specialist center which has access to a
Physical and sexually abused children often pres- multidisciplinary team, which includes a gastroen-
ent with functional GI symptoms. terologist with an interest in pain-associated FGIDs
Children with periumbilical abdominal pain and and a pain psychologist.
no alarm features usually do not require investiga-
tions. If the symptoms do not improve with empiric
therapy or there is a high suspicion of an organic Management
disease process investigations including a complete
blood count, erythrocyte sedimentation rate, When evaluating children with FAP, it is impor-
C-reactive protein, urine analysis, and culture are tant to allocate sufficient time for the consult in
justified [1, 3, 50]. Other investigations such as bio- order to allow the child and family to share their
chemical profiles (liver and kidney), stool culture concerns. This assures them that the physician is
and examination for ova and parasites, and breath listening and their complaints are being taken
hydrogen testing for sugar malabsorption can be seriously. It is important to explain the pathophys-
performed at the discretion of the clinician. The iology of visceral hypersensitivity in a simple
decision to perform these investigations is based on and child-friendly language. Establishing reason-
the child’s predominant symptoms, degree of func- able goals for improvement enables the physician
tional impairment, and parental anxiety. Plain to provide positive feedback and helps to main-
abdominal X-ray is not a reliable investigation to tain trust in the physician-patient relationship.
diagnose constipation, except when a rectal fecal Patients with prolonged or severe symptoms and
mass is suspected. Repeated negative laboratory a complex behavioral overlay that interfere with
and imaging studies can provoke anxiety, and the participation in a treatment plan may require
child may start thinking that the physician is unable early referral to a specialist center.
to find a cause for the symptoms and a rare and
unusual disease process is being missed.
In one prospective study, three trajectories based Psychological Therapy
on symptom severity, psychological evaluation,
functioning, and self-worth evaluation were Cognitive behavioral therapy (CBT) is based on
identified [51]. Almost 70% of the subjects with the belief that our thoughts, behaviors, and feel-
low levels of symptoms and functional impairment ings interact and aims to reduce or eliminate
improved within 2 months and had no recurrence at physical symptoms through cognitive and behav-
1- and 5-year follow-up. All had low levels of anxi- ioral changes. Cognitive behavioral therapy
ety and depression and scored better on self-worth guides patients to modify or change cognitive
35 Functional Abdominal Pain 383

distortions or irrational, negative thinking to ation and deepening phases, which may incorporate
improve mood and functioning. Parental response the deep breathing, visualization, and muscle relax-
to pain reports and beliefs about the significance ation strategies. Once a state of deep relaxation is
of pain and levels of psychological distress in the achieved, hypnotic suggestions are made, such as
child can affect the severity of GI symptoms and the pain is leaving your body. Most of the studies
disability. Cognitive behavioral therapy would evaluating the role of relaxation therapy in FAP
guide a patient who believes that his or her pain is have reported beneficial effects [58–62]. Cognitive
a symptom of undiagnosed terminal illness to behavioral and relaxation therapies are emerging as
challenge this belief and consider substituting a the first-line treatment for children with FAP; larger
more realistic thought, such as that the pain is and better designed studies in the future will help to
likely to subside and does not represent a termi- confirm their beneficial effect in FAP.
nal illness. Several randomized controlled trials
to test the effectiveness of pain interventions in
children, using a self-management approach that Diet
includes components of CBT and involvement of
parents in treatment, yielded encouraging results Food triggers such as caffeine, fatty or large
(Table 35.3) [52–55]. However, methodological meals, carbonated soft drinks, and lactose, which
limitations in some of these studies have made exacerbate pain or gastrointestinal symptoms,
interpretation of results difficult. A recent should be identified, with an attempt to modify
Cochrane review thought CBT is worth consider- them. Lactose and fructose elimination may be
ing for some children with functional abdominal useful in a small subset of patients [48, 49].
pain, but better quality studies to show the efficacy Dietary fibers may be helpful in some patients
of CBT are needed [56]. The American Academy [63, 64]. Supplementing fiber can cause bloating,
of Pediatrics also rates CBT as efficacious in the which may be distressing for some patients.
treatment of FAP [57]. A Cochrane review reported that there is a lack of
Relaxation treatments guide patients to reduce high-quality evidence on the effectiveness of
psychological distress by achieving a physiological dietary interventions in children with recurrent
state that is the opposite of how the body reacts abdominal pain. The authors also recommended
under stress. Common relaxation techniques include that there was no evidence that fiber supplements,
abdominal breathing, progressive muscle relax- lactose-free diets, or Lactobacillus supplementa-
ation, guided imagery, hypnotherapy, and biofeed- tion are effective in the management of children
back. Guided imagery directs patients to imagine with RAP [65].
themselves in a peaceful scene to create an experi-
ence that is incompatible with stress and anxiety.
The peaceful scene is individualized for each patient Pharmacotherapy
and is visualized with sufficient sensory detail to
absorb the patient’s attention. Biofeedback is an Antisecretory drugs are commonly used to treat
approach that uses instruments to detect and amplify children with abdominal pain, but their efficacy
specific physical states in the body and help bring has not been evaluated. A double-blind placebo
them under one’s voluntary control. The mecha- crossover trial evaluated the improvement in pain
nism of pain relief is based on specific physiological and global assessment scores in 25 children with
changes caused by the biofeedback. Selected physi- abdominal pain. There was improvement in
ological functions are measured such as heart rate, global assessment scores, but not in abdominal
skin temperature, galvanic skin response, or electro- pain scores in children treated with famotidine
myogram. Hypnotherapy includes three sequential compared to placebo [66].
elements: hypnotic induction, deep relaxation, and Tricyclic antidepressants act primarily through
suggestion. Hypnotic induction is produced usually noradrenergic and serotonergic pathways. They
by eye fixation, and this sets the stage for the relax- also have antimuscarinic and antihistaminic
Table 35.3 Studies using psychological therapy to treat FAP in children since 1990s. We have only included studies evaluating 10 or more children
384

Article Population and study design Intervention/control Outcome

Levy et al. (2010) n = 200, 7–17 years CBT: Greater decrease in pain and GI symptoms in CBT
RCS • Relaxation training group
• Modify family response to illness Less parental solicitous responses in CBT group
• Cognitive restructuring
Control group:
• Educational support
• 3 sessions each group
• FU: 6-month posttreatment
Duarte et al. (2006) n = 32, 5–13 years CBT: CBT had higher reduction in pain scores compared
RCS • Psycho-education to controls (86.6 vs. 33.3%)
• Cognitive and behavioral strategies No significant difference in pressure pain
• Self-monitoring threshold
Control group: SMC
4 monthly sessions
FU: 4 months
Hicks et al. (2006) n = 47, 9–16 years CBT: CBT group had significant improvement in pain
RCS • Relaxation scores compared to controls (72 vs. 14%) at
Recurrent headaches and • Cognitive strategies (self-talk) 3-month follow-up
abdominal pain Control: SMC
Online and telephone sessions
FU: 3 months
Robins et al. (2005) n = 69, 6–16 years CBT: Significantly less abdominal pain in the CBT
RCS • Psycho-education group compared to controls. Benefit maintained at
• Relaxation 1-year FU
• Coping strategies No significant difference in functional disability
Control : SMC
Five 50-min sessions
FU: 1 year
Sanders et al. (1994) n = 44, 6–12years CBT: Both groups reported significant decrease in pain
RCS • Parent contingency management CBT group had lower relapse rate and higher rate
• Relaxation training of complete pain relief
• Cognitive (self-talk)
Control: wait list
Six 50-min sessions
M.R. Sood
 35

van Tilburg et al. (2009) n = 34, 6–15 years Home-based guided imagery Treatment responders more in GI group compared
RCS SMC to SMC (63.1 vs. 26.7%)
2 months treatment 61.5% of SMC patients responded to GI
FU: 6 months Treatment benefit was maintained for 6 months
Vlieger et al. (2007) n = 53, 8–18 years Relaxation/hypnotherapy Both groups had significant decrease in pain
RCS • General relaxation intensity and frequency
• Gut-directed hypnotherapy Decrease was more marked in hypnotherapy group
• Ego-strengthening suggestions compared to controls (85 vs. 25%)
Control: SMC
Six 50-min sessions for 3 months
Functional Abdominal Pain

FU: 1 year
Weydert et al. (2006) N = 22, 5–18 years Guided imagery with progressive muscle Significantly greater decrease in pain frequency
RCS relaxation and missed activities in GI group compare to
Control: breathing exercises controls (82 vs. 45%) at 2-month follow-up
Four weekly 60-min sessions
FU: 3 months
Ball et al. (2003) n = 11, 5–18 years Relaxation Significant decrease in pain episodes. All patients
• Abdominal breathing randomized to wait list withdrew from the study
• Progressive muscle relaxation
• Visualization
Control: wait list
Four sessions
Humphreys and Gervitz (2000) n = 64, 4–18 years Comparison between 4 randomized conditions: All groups reported reduction in pain. Fiber alone
RCS Fiber alone has 79% reduction in pain reports, and fiber and
Fiber and relaxation relaxation have 100% reduction in pain reports
Fiber, relaxation, and CBT Addition of CBT and parent training has no
Fiber, relaxation, CBT, and parent training additional benefit
Eight-session duration not stated Three psychological treatments had greater benefit
compared to fiber alone (70.6 vs. 38.1%)
385
386 M.R. Sood

properties. Tricyclic antidepressants with sedative GG group compared to 9.6% in the placebo group
properties can help children with sleep disruption had improvement in abdominal pain. In this study,
and FAP. But their role in treatment of FAP is children with irritable bowel syndrome were more
controversial. A multicenter placebo-controlled likely to respond to Lactobacillus GG therapy com-
study of 90 children with FAP, irritable bowel pared to children with FAP. Another study com-
syndrome, and functional dyspepsia compared pared 8-week Lactobacillus rhamnosus GG therapy
the effect of 4-week amitriptyline therapy with in 141 children with irritable bowel syndrome and
placebo [67]. A total of 63% of patients reported FAP with placebo [70]. At week 12, improvement
feeling better in the amitriptyline group com- in abdominal pain was achieved in 72% subjects in
pared with 57.5% in the placebo group. None of the probiotics group compared to 53% in the pla-
the outcome variables were significantly different cebo group. Probiotics may be helpful in treating
between the two groups. A fixed dose for a rela- children with pain-associated FGIDs, but their
tively short period of time was used in this trial. mechanisms of action are not well understood.
Future studies evaluating the effect of an escalat- Modulation of gastrointestinal lumen toward an
ing dosage schedule for a relatively longer period anti-inflammatory state and conversion of undi-
of time would help to clarify the role of tricyclic gested carbohydrates into short-chain fatty acids
antidepressants in the treatment of FAP. may help to improve gut function.
Another study evaluated citalopram, a selective
serotonin reuptake inhibitor, in 25 children with
FAP aged 7–18 years. In this flexible-dose, open- Outcome
label trial, the initial daily dose of citalopram was
10 mg for a week, increasing to 20 mg at week 2 The relationship between FAP and FGIDs in adult
and then 40 mg at week 4 if there was no clinical life is controversial. A weak association between
response and the medication was well tolerated. FAP in childhood and headaches and IBS in adult
Total duration of treatment was 12 weeks [68]. life has been suggested [71]. A recent meta-analysis
The primary outcome measure was Clinical Global of 18 studies that included 1,331 children with FAP
Impression Scale-Improvement. Secondary out- who were followed for a median of 5 years, 29.1%
come measures included self- and parental reports continued to report abdominal pain at follow-up
of abdominal pain, anxiety, depression, somatic [72]. Chitkara et al. reported that 18–61% of chil-
symptoms, and functional impairment. Eighty- dren with FAP continue to report symptom of
four percent of patients were classified as respond- abdominal pain 5–30 years later [6]. The risk fac-
ers in whom the abdominal pain rating, anxiety, tors associated with poor prognosis include onset of
depression, and functional impairment all improved symptoms before 6 years of age, duration of symp-
significantly. It is not clear if the primary beneficial toms more than 6 months, family history of pain-
effect of selective serotonin reuptake inhibitor related FGIDs, multiple surgical procedures, low
therapy in FAP is through modulation of brain educational level, and socioeconomic status [73,
regions involved in visceral sensation or due to 74]. Mulvaney et al. identified higher levels of anxi-
their effect on psychiatric comorbid symptoms. ety, depression, lower self-worth perception, and
Low-grade bowel inflammation and immune more negative life events in subjects who had poor
alteration have been reported in adults with IBS and outcome at 5-year follow-up [51].
are associated with changes in the gut flora. In post-
infectious IBS patients, probiotics can help to
restore the qualitative and quantitative changes in Summary
indigenous gut flora and improve symptoms [9].
Lactobacillus GG therapy for 4 weeks was com- Functional abdominal pain is one of the most com-
pared to placebo in 104 children with FAP, func- mon FGIDs of childhood. Since there are no
tional dyspepsia, or irritable bowel syndrome [69]. identifiable structural abnormalities of the GI tract
Twenty-five percent of children in the Lactobacillus and no diagnostic tests to evaluate alterations in GI
35 Functional Abdominal Pain 387

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 Cyclic Vomiting Syndrome:
Comorbidities and Treatment 36
Bhanu Sunku and B.U.K. Li

Despite improved characterization, recognition, There is common confusion over the nomenclature
and understanding of cyclic vomiting syndrome as the older classification is “abdominal migraine”
(CVS) in the past two decades, without a delin- and the newer term since the 1990s is “cyclic vomit-
eated pathophysiologic cascade, it remains ing syndrome” or “cyclical vomiting syndrome”
classified as a functional gastrointestinal disorder (UK). Today, from an operational standpoint, the
(Table 36.1). Although originally perceived to be predominant and most consistent symptom during
a pediatric disorder, the past decade has been wit- episodes defines the illness, i.e., abdominal pain is
ness to a dramatic rise in diagnosed adults. In termed abdominal migraine, and conversely vomit-
both children and adults, the hallmark symptoms ing is denoted CVS. However, there is considerable
described by Samuel Gee in 1882 remain appli- clinical overlap because ~50% of those diagnosed
cable today and include stereotypical, severe epi- with abdominal migraine also vomit, and 80% of
sodes of vomiting punctuating symptom-free those with CVS also have abdominal pain.
periods, or baseline health [1]. Recent work has The continuum between CVS and migraine
begun to expand the list of comorbidities and was suggested by Whitney in 1898 and corrobo-
clinical subphenotypes and identify pathophysi- rated by other authors including us in 1998 [3, 4].
ologic pathways and new therapeutic avenues. In a cross-sectional school survey in Scotland,
Abu-Arafeh described a developmental progres-
sion from CVS to abdominal migraine and
Definition migraine headaches, median ages 5, 9, and 11
years with prevalences of 1.9%, 4%, and 11%,
Earlier clinical diagnosis has been facilitated by the respectively [5]. This suggests a natural history
recently defined consensus diagnostic criteria by that begins with CVS and ends with migraines.
NASPGHAN (2008) and Rome III (2006) criteria, Although some experience all three phases, the
the former being quantitatively more rigorous, i.e., largest group trades CVS for migraines by age 10.
requiring 3–5 vs. 2 total episodes [2] (Table 36.2). We estimate 75% will develop migraine headaches
by age 18 years (Li, unpublished data).
B. Sunku, M.D. (*) The lack of a specific ICD 9 code and the use
Mount Kisco Medical Group, of persistent vomiting (536.2) render it difficult
110 South Bedford Rd Mount, Kisco, NY 10549, USA to establish the true prevalence of CVS. Typical
e-mail: [email protected]
misdiagnoses, including gastroenteritis, gastroe-
B.U.K. Li, M.D. sophageal reflux, food poisoning, and eating
Division of Gastroenterology, Hepatology & Nutrition,
Pediatrics Department, Medical College of Wisconsin, disorders, often delay accurate diagnosis by a
Milwaukee, WI, USA median 2.5 years. At our GI clinic, CVS was

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 391

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_36, © Springer Science+Business Media New York 2013
392 B. Sunku and B.U.K. Li

Table 36.1 Functional nausea and vomiting Table 36.3 Epidemiology and demographics
disorders [8]
Functional dyspepsia Features
Chronic idiopathic nausea (adult Rome III criteria) Age of onset 4.8 years
Functional vomiting Delay in diagnosis 2.5 years
Cyclic vomiting syndrome Prevalence 2%
Rumination syndrome Incidence 3.15/100,000
Aerophagia Female/male 57:43
Migraine association 39–87%
Table 36.2 NASPGHAN and Rome III diagnostic Adapted from Li BUK, Balint J. Cyclic vomiting
criteria syndrome: evolution in our understanding of a
brain–gut disorder. In: Advances in Pediatrics.
NASPGHAN
Mosby, 2000: 117–160
1. At least five attacks in any interval or a minimum of
three attacks during a 6-month period
2. Episodic attacks of intense nausea and vomiting lasting
morbidity is reflected by the high average annual-
1 h to 10 days and occurring at least 1 week apart ized cost of management of $17,000 in 1998 that
3. Stereotypical pattern and symptoms in the individual includes doctor visits, emergency department visits,
patient inpatient hospitalizations, missed work by parents,
4. Vomiting during attacks occurs at least 4 times/h for and biochemical, radiographic, and endoscopic test-
at least 1 h ing [10]. A growing number of comorbid conditions
5. Return to baseline health between episodes
such as anxiety and postural orthostatic tachycardia
6. Not attributed to another disorder
syndrome also contribute to functional disability.
Rome III
We have begun to document lower global quality of
1. Two or more periods of intense nausea and unremit-
ting vomiting or retching lasting hours to days life scores than in healthy controls and those with
2. Return to usual state of health lasting weeks to functional GI disorders (irritable bowel syndrome)
months equivalent to organic GI diseases (e.g., inflammatory
All respective criteria must be met to meet consensus bowel disease, gastritis, fatty liver disease) (Tarbell
definitions for both NASPGHAN and Rome III S., unpublished data).

second only to gastroesophageal reflux as a cause

of recurrent vomiting [6]. Two school-based sur- Pathophysiology
veys (not clinical exam) estimated the frequency
to be 2% in Scottish and Turkish children In the absence of a defined etiopathogenesis,
(Table 36.3) [5, 7], and the incidence of new cases CVS remains classified as an idiopathic disorder.
of CVS was reported to be 3.15 per 100,000 chil- Recent investigations support the contributory
dren per year in Irish children. In our series, the roles of mitochondrial DNA (mtDNA) mutations
average age of onset of CVS is 4.8 years with a and dysfunction, heightened hypothalamic–pitu-
predominance in girls over boys (57:43). itary–adrenal (HPA) axis activation, and auto-
nomic nervous system (ANS) dysfunction. CVS
is a functional brain–gut disorder perhaps medi-
Impact on QOL ated through altered brainstem modulation of
effector signals.
CVS has a significant deleterious impact on the
quality of life in affected children. Although well in
between episodes approximately 90% of the time, Mitochondrial Dysfunction
58% of affected children require intravenous fluids
during episodes and average ten visits to the emer- In two series, a striking maternal inheritance pat-
gency department. School-age children miss an tern was recognized for migraines in 64% and
average of 24 days of school per year [8, 9]. Medical 54% of probands with CVS [11, 12]. Evidence of
36 Cyclic Vomiting Syndrome: Comorbidities and Treatment 393

mitochondrial dysfunction was first provided mals, like humans, psychological (water avoid-
using NMR to establish decreased ATP produc- ance) and physical (cytokine IL-1b(beta))
tion in peripheral muscle in migraineurs [13]. stressors can impair foregut motility. Ongoing
This mitochondrial pathogenesis gained substan- investigation of the pathophysiologic role of CRF
tial support following the recent identification of in CVS may open a potential therapeutic avenue
two tandem mtDNA polymorphisms, 16519T, using CRF antagonists. Tricyclic antidepressants,
and 3010A with impressive odds ratios of 17 and which inhibit the promoter activity of the CRF
15 in CVS and migraine in haplotype H, respec- gene, are the most efficacious agents in treating
tively [14]. Because the mutations are found in CVS.
the control region rather than the enzyme
sequence, the structure to function relationship is
unclear. However, elevated lactates, ketones, and Autonomic Dysfunction
Krebs cycle intermediates during attacks are con-
sistent with mitochondrial dysfunction. In addi- Most of the prominent symptoms of CVS are
tion, therapeutic trials show promising effects of expressed through the ANS. The peripheral vaso-
mitochondrial supplements coenzyme Q10, constriction, hypersalivation, diaphoresis, tachy-
l-carnitine, and riboflavin in the treatment of cardia, and listlessness are in fact prominent
migraines and CVS [15, 16]. manifestations of nausea that persist throughout
These two mtDNA mutations are also found in the episode typically unrelieved by evacuation of
depression, chronic fatigue, and irritable bowel the stomach. Autonomic dysfunction in the form
syndrome and may link these clinical comorbidi- of postural orthostatic tachycardia syndrome
ties together to a common mitochondrial suscep- (POTS) in children with CVS was recently
tibility factor. reported by Chelimsky [21]. They noted that
treatment of the POTS appeared to help reduce
the frequency of CVS episodes. We found an
HPA Axis Activation overall prevalence of 19% in our CVS patients,
and when we limited the cohort to adolescents
Stressors, both psychological (excitement, panic) >11 years in whom POTS is known to be more
and physical (fever, lack of sleep), are common common, the rate was 31%. Formal investigation
triggers of attacks of CVS. Activation of the HPA of the ANS function in children and adults with
axis during episodes of CVS was first described CVS reveals a consistent pattern of heightened
by Wolfe, Adler, and later Sato, and they docu- sympathetic tone and normal parasympathetic
mented elevated levels of adrenocorticotropic tone [21]. This imbalance is also described in
hormone (ACTH), antidiuretic hormone, cortisol, migraines and other functional gastrointestinal
catecholamines, and prostaglandin E2 and hyper- disorders [22].
tension [17, 18]. Attenuation of CVS symptoms
occurred after use of high-dose dexamethasone
by Wolfe and Adler and indomethacin and cloni- A Model
dine by Sato et al. [19].
The role of corticotropin-releasing factor How these pathophysiologic pathways fit
(CRF) as a brain–gut neuroendocrine mediator of together in a comprehensive model remains to
foregut motility has been extensively described be delineated. mtDNA mutations impair cellular
in animals by Taché et al. [20]. In response to energy production when needs are increased
stressors, released CRF from the hypothalamus during psychological or physical stress condi-
stimulates inhibitory motor neurons in the dorsal tions. If the production cannot meet the height-
motor nucleus of the vagus and causes delayed ened demands, autonomic neurons may be the
gastric emptying, independent of downstream target because of their high intrinsic energy
effects of ACTH and cortisol secretion. In ani- demands. CRF may be the initiating signal trig-
394 B. Sunku and B.U.K. Li

gered by psychological or physical stressors that The vomiting in CVS is uniquely rapid fire
inhibits the upper GI tract motility. The penulti- and peaks at a median frequency of six times an
mate defect in CVS that allows the emetic motor hour and 15 times per episode (Table 36.3). The
program to feed forward and continue for hours vomiting is typically projectile and contains bile,
even despite evacuation of all gastric contents mucus, and occasionally blood, the latter usually
has been hypothesized to be in the periaqueduc- the result of prolapse gastropathy. The intense
tal gray area [23]. This area modulates brain-to- nausea differs from that in gastroenteritis in that
peripheral ANS signals such as the emetic motor it persists even after complete evacuation of gas-
program mediated by the vagus. tric contents as if independent of gastric feed-
back. In fact, many adolescents describe it as the
Clinical Patterns most distressing symptom, only relieved during
CVS has a distinctive on–off temporal pattern of sleep. Due to the unrelenting nausea, during epi-
vomiting that serves as an essential criterion for sodes, these children appear much more debili-
diagnosis. CVS is distinguished by the “on” pat- tated when compared to those with gastroenteritis,
tern of discrete, recurrent, and singularly severe often curled into a fetal position, listless, and
episodes of vomiting that are stereotypical within withdrawn to the point of being unable to walk or
the individual as to time of onset (usually early interact. Anorexia, nausea, midline abdominal
morning), duration (hours or days), and symptom- pain, and retching are the most common gastroin-
atology (pallor, listlessness). The “off” pattern is testinal symptoms.
week- or month-long intervals when the child Certain unusual behaviors can be observed
resumes completely normal or baseline health during CVS episodes that can raise questions
(e.g., if there is other chronic disease), although about an underlying psychiatric disorder. There
5% may have interepisodic symptoms of nausea are children who drink compulsively and then
and mild vomiting [8]. During the episodes, the vomit and describe that that maneuver dilutes the
most common symptoms are listlessness (93%) bitter bile and aids in evacuating it. Others take
and pallor (91%), and others include low grade prolonged, scalding hot showers or baths until
fever or hypothermia, intermittent flushing, dia- the hot water supply is exhausted. Nearly all turn
phoresis, drooling, diarrhea, and hypertension in their rooms into a darkened cave in order to avoid
the Sato variant. Although found in significantly lights and sounds that trigger more nausea. Many
higher frequency than in patients with GI disor- are hyperesthetic to motion, odor, taste, and even
ders, fewer than half have migraine features of parental touch and attempt to shut out the exter-
headache, photophobia, and phonophobia. nal environment.
The duration of episodes generally ranges Various recurring stressors are recognized to
from hours to days with a median duration of precipitate CVS episodes in 76% of patients.
27 h. They can last as long as 10 days but are These include psychological (44%), infectious
always self-limited. Half of patients have “cyclic” (31%), and physical triggers. The psychological
intervals most commonly 4 weeks, predictable stress is more often of an excitatory nature such
within a week, and half have “sporadic,” unpre- as holidays, birthdays, outings, and vacations
dictable attacks. The most common time of onset such as at Disney World. Episodes may be trig-
is early morning (2–4 a.m.) or upon awakening gered by various infections including upper
(6–8 a.m.) in 42%. Many have a remarkably rapid respiratory infections, sinusitis, strep throat, and
onset (1.5 h) and denouement (8 h) from the last flu. Dietary factors include aged-cheese, choco-
emesis to the point of being able to eat and be late, monosodium glutamate, and fluctuating caf-
playful. The 67% with a prodrome have the pre- feine intake (23%). Lack of sleep from excess
emesis pallor, diaphoresis, abdominal pain, and physical exhaustion from travel, sports, slee-
headache but rarely visual disturbances of a clas- povers or a sleep disorder (24%), and menses
sical migraine aura. (catamenial CVS—22%) are also common incit-
ing events. Environmental triggers include
36 Cyclic Vomiting Syndrome: Comorbidities and Treatment 395

changes in barometric pressures in weather fronts. The Sato variant is associated with hypertension
One subgroup with a precisely timed interval during episodes and an endocrine profile of
every 60 days (predictable within a week) with heightened HPA axis activation. Those with long-
no identifiable triggers is especially refractory to interval calendar-timed episodes every 60+ days
therapy. apart appear particularly difficult to treat. Boles
has described a group with neurodevelopmental
deficits in whom CVS begins early in life [24].
Comorbidities There are post-menarcheal girls with catamenial
CVS who respond to low-estrogen birth control
The evolving clinical picture of CVS has included pills or ablation of menses.
an increasing number of associated comorbidi- There is a group of adolescents and adults
ties. In Boles’ series, 25% had coexisting neuro- with CVS who use marijuana to alleviate nausea
logical findings of developmental delay, seizures, and vomiting that instead may aggravate CVS
hypotonia, and skeletal myopathy as well as cog- symptoms and has been labeled as cannabis-
nitive and cranial nerve dysfunction [24]. These induced hyperemesis. It is more likely cannabis-
children classified as CVS+ were found to have triggered CVS [29]. One series of nine patients
an earlier age of onset for CVS and a three- to reports termination of bouts of emesis after ces-
eightfold higher prevalence of dysautonomic sation of chronic use of marijuana. Another case
(neurovascular dystrophy) and constitutional series noted 7 out of 13 marijuana users experi-
(growth retardation) manifestations than CVS enced improvement of nausea and anxiety raising
patients without neurological findings. Other the possibility that marijuana may be aggravate
comorbidities in non-neurologically impaired in some and mitigate in others [30].
children include anxiety (47%) and depression
(14%) [25], irritable bowel syndrome in (67%) Evaluation
[26], GERD (39%), colonic dysmotility (20%) At present, there are no specific tests to diagnose
[24], postural orthostatic tachycardia syndrome CVS, and the diagnosis rests primarily upon
(19%) (Li, unpublished), and chronic fatigue and fulfilling clinical criteria. The first step requires
complex regional pain syndrome (12%) [27]. differentiating a cyclic pattern (high intensity, low
Often, these contribute to the poor quality of life frequency) of vomiting in which extraintestinal
and have to be treated concomitantly to help disorders including CVS are most common from a
restore the child to functionality. chronic vomiting (low intensity, high frequency)
one in which upper GI tract disorders predominate
[6]. Approximately 90% of children who fulfill the
Subgroups NASPGHAN consensus criteria (Table 36.2) are
ultimately found to have CVS [2, 6]. Most of the
There appear to be subphenotypes of CVS, some testing in undiagnosed children who present with
of which overlap and may be present in the same recurrent vomiting is directed toward identifying
patient. The 83% that are migraine related (posi- underlying gastrointestinal, neurologic, renal,
tive family or self history) tend to have metabolic, and endocrine causes that can be uncov-
significantly less severe episodes that are more ered in the remaining 10%. The challenge to the
responsive to antimigraine therapy [28]. It now clinician is to determine which and how much test-
appears that the majority has a matrilineal inheri- ing should be performed, as the traditional “shot-
tance pattern (for migraine and other functional gun” approach is costly, time-consuming, and
disorders) and may have mtDNA mutations and invasive.
mitochondrial dysfunction [12]. Many appear to The recent NASPGHAN Consensus Statement
have predominantly sympathetic overtone and (2008) guidelines recommend against the tradi-
comorbid POTS in whom treatment of POTS tional shotgun approach and only for initial an
helps reduce frequency of vomiting episodes. upper gastrointestinal series to exclude malrota-
396 B. Sunku and B.U.K. Li

Table 36.4 Evaluation of cyclic vomiting dehydration during acute episodes requires a pro-
• Patient meets consensus criteria for CVS UGI series to tocol for use at home, emergency departments,
evaluate for malrotation + serum electrolytes, BUN, and hospital wards. Lifestyle modifications, simi-
creatinine and no warning signs or findings to suggest lar to those in migraines, during the well phase
an organic disorder trial of empiric therapy to treat CVS
can help prevent episodes and are discussed
If warning signs are present:
below. For those with more frequent or severe
• Severe abdominal pain, bilious, and/or hematem-
esis liver and pancreatic serum chemistries, episodes (e.g., more than once a month), prophy-
abdominal ultrasound (or CT or MRI), lactic therapy taken daily to prevent the next epi-
esophagogastroduodenoscopy sode is best. In some with less frequent or severe
• Fasting, high-protein meal, intercurrent illness episodes, abortive therapy taken only during the
precipitating episodes of vomiting serum and urine
metabolic evaluation (lactate, ammonia, carnitine
prodrome or at the onset of the episode is suc-
profile, amino acids, and organic acids) prior to cessful. The use of mitochondrial supplements to
treatment during episode and metabolic consult treat suspected underlying mitochondrial dys-
• Abnormal neurological findings (altered mental function is gaining evidence and acceptance.
status, papilledema) brain MRI, neurology consult At present, there are no controlled therapeutic tri-
als. One formal randomized controlled trial on IV
ondansetron was attempted by the authors and
tion and anatomic obstructions and a basic meta- thwarted by an impressive 90% reduction in rate of
bolic profile (electrolytes, glucose, BUN, episodes upon enrollment even without prophylactic
creatinine) [2]. Further testing beyond that should therapy (Li, unpublished data). The NASPGHAN
be based upon specific warning signs (Table 36.4). Consensus Statement recommendations on treatment
In those who present with bilious vomiting and are based upon therapeutic responses from case series
abdominal tenderness, abdominal imaging should and expert opinion of the task force [2]. The main
be performed to exclude hydronephrosis, pan- recommendations include first-line prophylactic use
creatitis, and cholecystitis. In those in whom epi- of cyproheptadine and amitriptyline in children under
sodes are triggered by intercurrent illnesses, age 5 years and 5 years or older, respectively, with
fasting, or high-protein meals, screening should propranolol as the second line. Sumatriptan was rec-
be performed for urea cycle, fatty acid oxidation, ommended as an abortive agent for those >12 years.
disorders of organic and amino acid metabolism, For rescue therapy during acute episodes, IV rehy-
and mitochondrial disorders. This screening has a dration with high-dose antiemetic ondansetron (0.3–
better diagnostic yield in the early part of an epi- 0.4 mg/kg/dose) and sedation from diphenhydramine
sode of CVS before intravenous glucose and or lorazepam was recommended.
fluids are administered. Those presenting with
abnormal neurological findings including altered
mental status, papilledema, ataxia, or seizure Rescue Approach
should have a neurological evaluation and brain
MRI considered. Presentation of CVS under the The rescue therapies are used when the vomiting is
age of 2 should also prompt further metabolic or well established in an episode and fails to respond
neurological testing [2]. to abortive strategies. The goal is to correct fluid
and electrolyte deficits and render the child more
Treatment comfortable through antiemetic therapy, analge-
Management of CVS is multifaceted and chal- sics, and sedation for relief from intractable nau-
lenging. The goals of treatment are to reduce the sea and pain. The recommendation is for an IV
frequency and severity of episodes, reduce school bolus of saline for rapid correction of fluid deficits
absenteeism and enhance functionality, improve and 10% dextrose 0.45 normal saline at 1.5× main-
quality of life, and establish a protocol for rescue tenance rates to provide sufficient cellular energy
therapy in home and hospital settings. Treatment to terminate ketosis. One may have to reduce IV
of nausea and vomiting, abdominal pain, and rates and increase Na + content when hyponatremia
36 Cyclic Vomiting Syndrome: Comorbidities and Treatment 397

Table 36.5 Abortive and rescue pharmacotherapy sleepovers, or travel sports tournaments are often
Antimigraine cited as triggers of episodes. Good sleep hygiene
Sumatriptan 20 mg intranasal at episode onset and may (e.g., turning off all phones, computers, music,
repeat once or 25 mg po once. SE: chest and neck TV) with a regimented sleep time can help reduce
burning, coronary vasospasm, headache the frequency of episodes. Providing at least
Alternatives: frovatriptan, rizatriptan, zolmitriptan
maintenance volumes of fluids is widely used to
Antiemetic
treat migraines and postural orthostatic tachycar-
Ondansetron 0.3–0.4 mg/kg per dose q 4–6 h iv/po/
rectal/topical. SE: headache, drowsiness, dry mouth
dia syndrome. Providing energy sources before
Alternatives: granisetron strenuous activity, preferably of low glycemic
Aprepitant 125, 80, 80 mg one q.d. prior to anticipated index and high-protein sources, may prevent an
episode energy deficit. Routine exercise can help reverse
Sedative the deconditioned state. Finally, avoiding
Lorazepam 0.05–0.1 mg/kg per dose q 6 h iv/po: useful identified triggers specific to the individual (e.g.,
adjunct to ondansetron. SE: sedation, respiratory lack of sleep) or generally found in migraines
depression
(monosodium glutamate and fluctuations in caf-
Chlorpromazine 0.5–1 mg/kg per dose q 6 h iv/po. SE:
drowsiness, hypotension, seizures feine intake) may help reduce the frequency of
Diphenhydramine 1.25 mg/kg per dose q 6 h iv/po: episodes. Although there is limited evidence of
useful adjunct to chlorpromazine. SE: hypotension, efficacy, Fleisher reported that consultation and
sedation, dizziness lifestyle modifications alone reduced the fre-
Analgesic quency of episode in 70% of patients without
Ketorolac 0.5–1 mg/kg per dose q 6 h iv/po. SE: beginning prophylactic therapy [26].
gastrointestinal bleeding, dyspepsia
Alternatives: opioids (hydromorphone)
From Sunku B. Cyclic vomiting syndrome, a disorder of
all ages. Gastroenterol Hepatol (NY). 2009 July; 5(7):507–
Prophylactic therapy
515. Reprinted with permission
Prophylactic therapy is administered during the
and diminished urine output from elevated antidi- interictal period in order to prevent future episodes.
uretic hormone release is present in Sato-variant The NASPGHAN consensus recommendations
CVS. Ondansetron has been the most widely used for the initial treatment were for cyproheptadine
5HT3 antagonist given safely at higher than stan- for the younger (<5 years) and amitriptyline for
dard doses (0.3–0.4 mg/kg/dose) [11]. the older children and adolescents (³5 years) [2]
Diphenhydramine, lorazepam, or chlorpromazine (Table 36.6). Despite its pharmacokinetics,
combined with diphenhydramine are used for cyproheptadine (0.25–0.5 mg/kg) appears to be
sedation because for some sedation is the only effective given as a single nighttime dose, rather
means of providing relief from the unrelenting than in two or three divided doses [31].
nausea and pain (Table 36.5). When the first-line Amitriptyline causes side effects in 50%, the
analgesic ketorolac fails to alleviate pain, hydro- most common being morning sedation (like a
morphone can be used and is occasionally required hangover), and is stopped in 21% [32]. Beginning
as a continuous patient-controlled analgesia. at a low dosage of 0.2–0.3 mg/kg at bedtime and
titrating in 10 mg increments every week (unless
too sedated) to the target dose of 1.0–1.5 mg/kg
Lifestyle Modifications allows the child to adapt to the side effects.
Switching to other tricyclic antidepressants such
Lifestyle modifications are used during the inter- as nortriptyline and desipramine may circumvent
ictal phase of CVS when the child is not in an intolerable side effects. An EKG for QTc interval
episode in order to avoid exposure to known and is recommended before starting amitriptyline and
potential precipitants of episodes. The lack of after reaching the target dose to monitor for pro-
sleep resulting from disturbed sleep patterns, longed QTc interval [33]. Propranolol is second
398 B. Sunku and B.U.K. Li

Table 36.6 Prophylactic pharmacotherapy more likely to respond to antimigraine agents such as
Antimigraine cyproheptadine, amitriptyline, and propranolol (79%
Amitriptyline start and 0.2–0.3 mg/kg and advance to vs. 36%) than those children without a migraine con-
1–1.5 mg/kg/day q.h.s.: monitor EKG QTc interval nection [28]. Post-menarcheal girls with catamenial
prior to starting. First choice ³ 5 yrs old. Side effects:
CVS often respond to low-estrogen birth control pills
sedation, anticholinergic
Propranolol 0.25–1 mg/kg/day divided b.i.d or t.i.d:
(Loestrin, Lo/Ovral, Alesse, Seasonale) or Depo-
monitor resting heart rate. SE: hypotension, bradycar- Provera. Sato-variant CVS associated with intraepi-
dia, fatigue sode hypertension have been treated with tricyclic
Cyproheptadine 0.25–0.5 mg/kg/day divided b.i.d. or antidepressants in the USA and Depakote (divalproex
q.h.s.: First choice <5 years old. SE: sedation, weight sodium) in Japan [19].
gain, anticholinergic
Alternatives: nortriptyline, imipramine, desipramine
Anticonvulsants
Topiramate increase to 1.5–2.0 mg/kg/day divided b.i.d.
Abortive Therapy
Phenobarbital 2–3 mg/kg/day q.h.s. SE: sedation,
cognitive impairment Abortive therapy is given during the prodrome or
Alternatives: gabapentin, levetiracetam, zonisamide, at the beginning of the vomiting episode in the
valproate, carbamazepine hope of stopping it. The most specific abortive
Mitochondrial supplements therapy includes antimigraine triptans. The nasal
l-Carnitine 50–100 mg/kg £ 2 g/day divided b.i.d. SE: (sumatriptan or zolmitriptan) or subcutaneous
diarrhea, fishy body odor.
(sumatriptan) forms appear more effective than
Coenzyme Q10 10 mg/kg/ divided b.i.d. £400 mg/day
oral forms that cannot effectively reach the duo-
Riboflavin 10 mg/kg/day divided b.i.d. £400 mg/day
denum due to repeated vomiting (Table 36.5) [2,
From Sunku B. Cyclic vomiting syndrome, a disorder of
37]. The triptans appear to be either fully effec-
all ages. Gastroenterol Hepatol (NY). 2009 July; 5(7):507–
515. Reprinted with permission tive or not at all and more effective if adminis-
tered early in episode and if the duration of
episodes is less than 24 h (Li, unpublished data).
line and can be monitored for efficacy and toxic- In a few children, ondansetron given alone
ity by a drop in pulse rate of 15–20 beats per min- aborts episodes in progress. Although the oral
ute and below 55 bpm, respectively. forms may not reach to duodenum, ondansetron
If standard prophylactic therapy fails, anticon- can be reformulated by individual pharmacies into
vulsants and Ca2+-channel antagonists have been a rectal suppository or topical forms. Although not
used. Phenobarbital at low (2–3 mg/kg) night- established, we use the same dose as the oral form.
time doses has been reported to be effective [34]. In a few adolescents with severe, disabling abdom-
In children, cognitive dysfunction is a well- inal pain accompanying the vomiting, use of opi-
known side effect and one that occurs with other oids such as hydromorphone can quickly abolish
anticonvulsants as well. Others used topiramate, the pain and vomiting. The NK1 antagonist aprep-
zonisamide, and levetiracetam, with positive evi- itant may be given orally prior to the anticipated
dence in adults with migraine headaches and vomiting in a calendar-timed CVS episode.
cyclic vomiting syndrome [35, 36]. Another
group of agents includes Ca2+-channel antago-
nists with the main side effect of hypotension. Mitochondrial Supplements

The use of mitochondrial supplements as adjunc-

Treatment by Subgroup tive prophylactic therapy in CVS is being used
more and more based upon evidence in migraines.
Treatment may be selected by clinical subgroup. Their use in suspected mitochondrial dysfunction
Children with so-called migraine related with a posi- has been bolstered by the recent finding of two
tive family history or migraines themselves are much mitochondrial DNA mutations by Boles [15]. In
36 Cyclic Vomiting Syndrome: Comorbidities and Treatment 399

some children, the accompanying chronic fatigue fact, 72% of the children in our series report sleep
may respond to these supplements. These supple- as the harbinger of the end of the episode. We
ments have demonstrated efficacy in prevention have observed that induced sleep will sometimes
of migraine headaches in adults (randomized end the episode, seemingly as if the “vomiting
controlled trial) and preliminary evidence of center” in the brainstem has “rebooted” back to
efficacy in pediatric migraine and CVS in chil- baseline in the off position. The consensus rec-
dren [38–40]. The doses used include riboflavin ommendation is either intravenous lorazepam or
at 10 mg/kg divided b.i.d. to 400 mg/day, l-carni- chlorpromazine with diphenhydramine [2].
tine at 50–100 mg/kg up to 2 g/day divided b.i.d., However, if both fail to sedate and ameliorate the
and CoQ10 10 mg/kg up to 400 mg/day divided unrelenting nausea and vomiting, general anes-
b.i.d. The dose and duration of therapy has not thesia may be the last resort. In one case series,
been established in children with CVS. 18 h of dexmedetomidine-induced general anes-
Acupuncture using P6 point has also been used thesia terminated prolonged, intractable episodes
with variable efficacy [41]. in three children [42]. Although this protocol
required continuous monitoring in the PICU, it
did not require intubation because of its lack of
Approach to the Refractory Patient respiratory depression. We have also used this
approach successfully in extreme cases.
In tertiary and quaternary referral settings, a size-
able number of children with CVS do not respond
to the therapies outlined above. There are several References
approaches we have used in such patients. The first
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Hosp Rev. 1882;18:1–6.
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2. Li BUK, Lefevre F, Chelminsky GG, et al. North
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tumors (e.g., Chiari malformation). Pediatrics. 1996;97:364–8.
If no specific trigger or cause can be identified 7. Ertekin V, Selimoglu MA, Altnkaynak S. Prevalence
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 Aerophagia
37
Oren Koslowe and Denesh K. Chitkara

terms based on the Rome criteria which include

Introduction air swallowing and belching [5], though some
studies use more inclusive criteria [6, 7]. The
Aerophagia is a functional gastrointestinal dis- Rome III committee defined aerophagia in chil-
order recognized with relative frequency in the dren as including two or more of the following
pediatric and adult population. The term symptoms at least once per week for a minimum
“aerophagia” was applied in the late nineteenth 2 months before diagnosis: (1) air swallowing,
century by Bouveret and quickly adopted by (2) abdominal distention because of intralumi-
others [1, 2], although reports of the symptoms nal air, and (3) repetitive belching and/or
associated with aerophagia predate that descrip- increased flatus (Table 37.1) [5]. These criteria
tion, perhaps by centuries. There is a report of a modified slightly the criteria established by the
conscript who swallowed large quantities of air Rome II committee by decreasing the required
in order to develop tympany and escape military duration of symptoms [8]. The symptom-based
service in 1814 [3], but one could even imagine diagnostic criteria frequently overlap with other
that those with morbus ructuosus (a term applied functional gastrointestinal disorders such as
to sufferers of “wind”-related conditions) and functional dyspepsia and irritable bowel syn-
the “pneumatists” (practitioners of such disor- drome. However, there are clinical clues and
ders), who often cared for them dating to the diagnostic techniques to help in the differentia-
time of Hippocrates, were also exhibiting simi- tion [9]. Although not required to make a diag-
lar features of aerophagia [4]. Differentiating nosis of aerophagia, an esophageal air sign (an
aerophagia as a unique functional and patho- abnormal air shadow over the proximal esopha-
logic entity has been a challenge. It is character- gus) on chest radiograph has been suggested as
ized primarily in descriptive and symptomatic a specific diagnostic criterion for pathologic
aerophagia [7]. The Rome III committee short-
ened the required presence of symptoms for
O. Koslowe, M.D.
diagnosis from 12 weeks over the preceding
Department of Pediatrics Gastroenterology and Nutrition,
Goryeb Children’s Hospital/Atlantic Health System, 12 months to once per week over the preceding
Morristown Memorial Hospital, 100 Madison Avenue, 2 months to more closely approximate the clini-
Morristown, NJ 07962, USA cal presentation and be more inclusive. While
D.K. Chitkara, M.D. (*) several reports have associated aerophagia with
Department of Pediatrics Gastroenterology and Nutrition, developmentally delayed children, many chil-
Goryeb Children’s Hospital, Atlantic Health,
dren with aerophagia are developmentally
Morristown, NJ, USA
e-mail: [email protected] appropriate for age [6].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 401

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_37, © Springer Science+Business Media New York 2013
402 O. Koslowe and D.K. Chitkara

Table 37.1 Rome III diagnostic criteria for children esophageal discomfort associated with gastroe-
and adolescents with aerophagia two or more of the sophageal reflux disease (GERD) [17].
following occurring at least once per week for at least
2 months before diagnosis The retained intraluminal gas and frequently
associated flatus may also incorporate several
Air swallowing
mechanisms. We find it important to separate
Abdominal distention because of intraluminal air
abdominal distention from increased intraluminal
Repetitive belching and/or flatus
gas; while they may occur concomitantly (as they
Adapted from Rasquin et al. [5]
must, in order to meet Rome diagnostic criteria),
they are often distinct entities [18, 19]. Again,
Pathophysiology intraluminal gas may arise simply from swallow-
ing large quantities of air; however, gas is also
The mechanism of air entry into the intestinal tract, endogenously produced, and several factors may
which appears responsible for the symptoms of aid in increasing endogenous gas production or
aerophagia, is not entirely clear. Certainly, there is a delaying transit of intestinal gas. Small bowel bac-
population of children who swallow excessively, terial overgrowth, high-fiber diets, sugar malab-
whether volitionally or not, and in so doing increase sorption, and caloric content of meals have all
intraluminal air resulting in increased eructation been shown to have an impact on intestinal gas
and/or flatus and symptoms of gastrointestinal dis- production and/or transit [11, 18, 20, 21].
tention. The swallowing rate for normal adults is
approximately 818/24 h, and the rate of air swal-
lowing is approximately 176/24 h [10]; however, Treatment
the presence of increased air swallowing in the set-
ting of aerophagia is debatable. Clinically apparent Management of aerophagia depends on the severity
and excessive air swallowing alone may not be of symptoms generated. Certainly there are infre-
entirely responsible for the symptoms of aerophagia quent reports of severe sequelae associated with
[6, 7]. The availability of impedance monitoring has aerophagia including massive distention, ileus, and
allowed for better and more complete evaluations of volvulus [7, 22–25]. In such severe cases, a gastros-
swallows, and a recent study indeed showed an tomy or other means of relief may have to be uti-
increase in air swallowing in adults with aerophagia, lized [23, 26]. Most commonly, children with
though not in swallowing overall [11]. aerophagia are brought to the attention of care pro-
To the extent that increased eructation is asso- viders with complaints of abdominal pain and
ciated with aerophagia, there may be two primary abdominal distention which are present in the
mechanisms of action. The first, as stated above, majority of children at diagnosis [6, 7]. Notably,
is that excessive air is ingested. This results in those symptoms are very nonspecific and are pres-
proximal gastric distention which, aside from ent in many other functional disorders and organic
increasing intragastric pressure, promotes an diseases; additionally, abdominal pain is not
increase in transient lower esophageal relaxations required for, and would not contribute to, the
allowing for increased frequency of air expulsion definition of aerophagia in children according to the
[12, 13]. The second is that eructation does not Rome criteria. As an example of symptom overlap,
represent expelled intragastric air, but rather GERD patients were shown to swallow air and
supragastric air that accumulates in the esopha- belch more frequently than controls, although the
gus either by negative intrathoracic pressure increased air swallowing was not shown to increase
against the glottis or mechanical injection by acid reflux [10]. Once a diagnosis of aerophagia has
muscular contraction [14, 15]. The latter popula- been made, education, reassurance, and supportive
tion, with symptoms limited to frequent belching, techniques are the most often employed measures
may not truly belong to the category of aerophagia [6] and may represent the most effective interven-
[15, 16]. Interestingly, it has been suggested that tion [5, 8]. Hypnosis has been suggested as a mode
supragastric belching may be a response to of therapy in a case report [27]. Where primary psy-
37 Aerophagia 403

chological disorders are present, they should be evant” belching/burping in 3% of adults [37]; a
addressed [8, 15], although they do not appear to be larger figure than one would expect in children in
present to any greater degree in aerophagia than whom the prevalence of aerophagia in a Rome II
other functional conditions [6]. A variety of behav- validation study was noted to be 1.3% [38].
ioral and mechanical techniques that have incorpo-
rated biofeedback have been attempted, though only
in small-scale trials and rarely with children, to pro- Conclusion
mote self-awareness of swallowing and thereby
limit its frequency [28–31]. The duration of response Symptom overlap and phenotypic variability make
has come into question in most studies. One case the diagnosis and management of aerophagia in
report demonstrated sustained response at 18-month children a challenge. While symptoms are generally
follow-up [32]. Pharmacologic therapy may play an benign and either resolve spontaneously or are ame-
extremely limited role for the treatment of pediatric nable to therapy primarily involving education and
patients with aerophagia due to the significant side reassurance, in some children they may be more
effects of the medications that have been utilized. severe with both physical and social impact. There
Anxiolytic therapies have been employed likely on have been great strides in recent years understand-
the basis that mood or emotional state may impact ing and modeling the complex neuromuscular and
swallowing rates [33, 34]. In one report in which neuroenteric relationships in a host of functional
aerophagia was the result of paroxysmal opening of gastrointestinal disorders, and this comprehension
the upper esophageal sphincter associated with should provide opportunities for improved pharma-
reflex-induced swallowing, clonazepam was shown cologic and non-pharmacologic interventions for
to be effective [26]. Some reports have suggested a children with aerophagia in the future.
benefit in relieving gas retention using neostigmine
[35], but no controlled studies have shown benefit
with prokinetic agents for relieving intraluminal air References
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 Adolescent Rumination Syndrome
38
Anthony Alioto and Carlo Di Lorenzo

may be some degree of discomfort in making a

Introduction diagnosis of a disorder that has a behavioral compo-
nent. In this regard, rumination may be similar to
Rumination is a phenomenon considered normal functional dyspepsia or irritable bowel syndrome.
in ruminant animals, but its occurrence in humans In these conditions, physicians may feel more com-
is always pathologic. This condition had been fortable with a “medical” diagnosis such as gastri-
reported in the past as being typical of emotion- tis, reflux disease, or colitis rather than embarking
ally deprived and often cognitively impaired in a lengthy and at times antagonistic discussion
infants and adults. More recently, there have been with the family of the biopsychosocial components
large case series describing it as occurring in ado- of a functional disorder. Second, there is no “test” to
lescents and adults with intact cognitive abilities. conclusively diagnose rumination syndrome. In
Given the substantial differences in etiologic fac- Western culture, medicine (and patient expecta-
tors, phenotypic presentation, and treatment tions) often is based on the biomedical model which
strategies between infantile and adolescent forms, postulates that a symptom is due to a demonstrable
the current chapter will focus solely on adoles- anatomical, inflammatory, serologic, immune, or
cent rumination syndrome. other system dysregulation. Without a test demon-
Despite a recent increase in scientific publica- strating positive symptoms, many practitioners and
tions on the subject, adolescent rumination syn- patients feel uncomfortable with the diagnosis.
drome remains poorly understood and rarely Third, the lack of a standard and relatively easy to
recognized, even by practitioners with a great deal implement therapy for rumination syndrome may
of clinical experience. Its presentation is so charac- give some providers a sense of futility when making
teristic that the high frequency of misdiagnoses is such a diagnosis for which they have little therapeu-
perplexing and likely related to the unfortunate con- tic advise to offer. In order to guide the practitioner,
vergence of several factors. First and foremost, there we will discuss the most recent understanding of the
epidemiology, pathophysiology, diagnosis, and
therapy of adolescent rumination syndrome.
A. Alioto, Ph.D.
Division of Pediatric Gastroenterology, Department of
Psychology, Nationwide Children’s Hospital, The Ohio
State University, Columbus, OH, USA Epidemiology
C. Di Lorenzo, M.D. (*)
Department of Pediatrics, Nationwide Children’s There have been no population-based epidemio-
Hospital, The Ohio State University, logic studies of the prevalence of rumination syn-
700 Children’s Drive, Columbus, OH 43205, USA
e-mail: [email protected] drome in children. Traditionally, this condition has

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 405

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_38, © Springer Science+Business Media New York 2013
406 A. Alioto and C. Di Lorenzo

been considered as having a low prevalence in [3], although emptying studies are difficult to inter-
adolescents [1]. As described earlier, the insufficient pret in individuals who continuously regurgitate
recognition of rumination syndrome as a diagnostic during the test. A poorly accommodating fundus
entity undermines efforts to understand its preva- and an impaired antral pump may lead to postpran-
lence. Further complicating estimates, the symp- dial distress that the patient tends to relieve by
toms of rumination syndrome overlap with expelling the food just ingested. As such, the behav-
symptoms of more readily recognized conditions ior of regurgitating gastric contents serves to relieve
such as gastroesophageal reflux disease, gastropare- epigastric discomfort and becomes a learned
sis, pseudoobstruction, and eating disorders [2–6]. response to the ingestion of food or fluid. Upon
Due to these challenges, patients with rumina- ingestion of food (or even in anticipation of inges-
tion syndrome often are evaluated by multiple tion of food), a sequence of behaviors has been gen-
physicians over the course of several years prior to erated, including contraction of the abdominal wall,
receiving the correct diagnosis [5]. In the interim, opening of the lower and upper esophageal sphinc-
they undergo multiple fruitless and expensive ter, and subsequent expulsion of food [8].
medical evaluations and diagnostic testing. In one
sample of adolescents [3], onset of rumination
symptoms occurred around age 13 years, with the Clinical Features
diagnosis of rumination syndrome ultimately
given approximately 2 years later. The main clinical characteristic of rumination is the
Available evidence suggests that rumination timing of the act of vomiting. There are very few
syndrome is found in females significantly more other medical gastrointestinal diseases associated
often than in males. Physical or psychological with vomiting within seconds or minutes from food
stressors often occur just before the onset of the ingestion. Although the regurgitated gastric con-
symptoms in a sizable subset of subjects, and a tents may be re-swallowed, in adolescents they fre-
substantial portion of diagnosed patients have quently are expelled. Rumination persists up to an
associated physical illnesses or concomitant psy- hour after eating and rarely occurs at night [3].
chological disorders [3]. Table 38.1 shows some of the features differentiat-
ing rumination from other clinical entities. Weight
loss is a common feature of the most severe forms
Pathophysiology of rumination syndrome and may lead to the need
for tube feedings or even parenteral nutrition. Other
The precise etiology of rumination syndrome symptoms, particularly abdominal pain, heartburn,
remains unknown at this time. Even so, many and nausea are less frequently reported, but often
patients’ histories are suggestive of a trigger at serve as a “signal,” allowing patients to recognize
the onset of symptoms, such as a gastrointestinal when rumination is about to occur.
mucosal disease or stressors involving emotional
arousal. After the initial stressor has resolved, the
vomiting behavior appears to remain in place, Diagnosis
almost similar to a “tic.”
Gastric motor and sensory abnormalities have Rumination syndrome is a clinical diagnosis [6] and
been reported in rumination syndrome. Barostat very minimal testing should be needed in the classic
and manometric studies have demonstrated gastric cases. A patient who satisfies the symptoms-based
hypersensitivity with more frequent episodes of Rome III criteria for this condition (Table 38.2)
lower esophageal sphincter relaxation in response should need no further investigation. Pointing out to
to gastric distension [7]. Some individuals have the patients and to the parents how saliva is easily
impaired postprandial gastric accommodation [7]. swallowed but even a sip of water causes symptoms
A mild degree of gastroparesis may be found in is particularly enlightening with regard to the behav-
approximately 40 % of adolescents with rumination ioral component of this disorder.
38 Adolescent Rumination Syndrome 407

Table 38.1 Differential diagnosis of rumination syndrome from other conditions presenting
with emesis in adolescents
Vomiting Esophagitis Prokinetics Fundoplication
Rumination During or minutes No Not helpful Not helpful
after meal
Achalasia Hours after meal Often (from stasis) Not helpful Contraindicated
GERD After large meals or Often Helpful Helpful
when lying down
Gastroparesis Hours after meal No Helpful Not helpful
Cyclic vomiting Intermittent, During episodes Not helpful Not helpful
unrelated to meal

Table 38.2 Rome III criteria for adolescent rumination Postprandial impedance-manometry monitor-
syndrome ing allows distinction between rumination from
1. At least a 2 month history of repeated painless regurgitation postprandial belching and regurgitation. During
and re-chewing or expulsion of food rumination, esophageal liquid retrograde flow is
2. The behavior begins soon after ingestion of a meal first driven by an early small rise in intra-gastric
3. The behavior does not occur during sleep pressure preceding the peak pressure observed
4. There is no retching during straining [10].
5. Symptoms do not respond to standard treatment for
gastroesophageal reflux
6. No evidence of an inflammatory, anatomic, metabolic,
or neoplastic process considered likely to be an
Treatment
explanation for the subject’s symptoms
As practitioners and researchers strive to under-
stand the pathogenesis of this complex functional
Antroduodenal manometry is not always neces- disorder, many have proposed mechanisms by
sary to make the diagnosis, but it can be considered which rumination is maintained (e.g., habit disor-
as the “big convincer” in cases when the referring der, learned adaptation of the belch reflex, sympa-
physicians or the families are not yet confident with thetic nervous system arousal). Based on these
the diagnosis of rumination syndrome. Manometry postulates, several approaches to treatment have
may be used to clinch the diagnosis and rule out the been put forward and demonstrated to be effective.
presence of an underlying motility disorder, a com- Despite the variety of conceptualizations of rumi-
mon fear among family of patients with this dis- nation syndrome, similar treatment strategies
order. In patients with rumination syndrome, appear to be utilized across studies and treatment
antroduodenal manometry shows essentially nor- centers and are categorized and described below.
mal fasting and postprandial motor patterns [6, 9].
The characteristic manometric abnormality is a syn-
chronous increase in pressure (“r” waves) across Education and Reassurance
both gastric and duodenal recording sites when the
rumination occurs. The “r waves” are thought to Several authors have discussed how accurate diag-
represent the effect of an increase in intra-gastric or nosis and reassurance often provide considerable
intra-abdominal pressure generated by the contrac- relief to families and patients [1, 11]. Education
tion of the skeletal abdominal muscles. Interestingly, about rumination syndrome may allow for a reduc-
under the pressure of being in a laboratory setting tion in anxiety, as patients are provided with a
with constant attention being paid to their symp- diagnosis and understand that no structural or
toms, adolescents with rumination are often able to intrinsic motility problems exist. In addition, accu-
eat the test meal during the manometry study with- rate description of the disorder may allow patients
out symptoms (Fig. 38.1). to be a more active part in their own treatment.
408 A. Alioto and C. Di Lorenzo

Fig. 38.1 An example of an antroduodenal tracing from as such on the tracing. Those events are associated with a
an adolescent with rumination syndrome. The end of the simultaneous increase in pressure in all recording sites
meal is marked and almost immediately afterwards, the (known as “r waves”)
patient begins to have episodes of “small spit up,” marked

Presentation of rumination syndrome from a empirically supported in the treatment of habit

biopsychosocial perspective allows families to disorders [8, 12–14]. Traditional components
understand the interplay among physical, behav- of habit reversal training (HRT) include
ioral, emotional, and situational factors [12]. The increasing awareness of the behavior, introduc-
educational intervention should include a discus- ing a competing response to the behavior, pair-
sion of how no further testing is needed, how rumi- ing an aversive stimulus to the behavior,
nation syndrome can be diagnosed by symptoms encouraging relaxation, and providing social
(and it is not simply a diagnosis of exclusion), and support. Applied to rumination syndrome,
how the condition is treatable using behavioral effective interventions include charting and
interventions. In our experience, families who con- monitoring rumination episodes (“waves”) and
tinue to seek further diagnostic testing and a “medi- at times the use of electromyographic biofeed-
cal” explanation for the rumination tend to be less back to elucidate the contraction of the abdom-
invested and less successful with treatment. inal wall during rumination (i.e., awareness),
utilizing diaphragmatic breathing and deep
inhalation in order to relax the abdominal wall
Behavioral Strategies (i.e., competing response), having the patient
reswallow all emesis (i.e., aversive stimulus),
Many authors have conceptualized rumination diaphragmatic breathing and distraction (i.e.,
syndrome in terms of a learned “habit,” and relaxation), and family involvement in therapy
therefore have utilized strategies that have been (i.e., social support).
38 Adolescent Rumination Syndrome 409

Use of Self-regulation Strategies allows patients to practice and utilize their self-
management skills while working with increas-
Several authors have discussed the importance of ingly challenging quantities of food and tolerating
providing strategies for improving self-control over the discomfort that arises with gastric distension.
the behavioral manifestation of rumination. As The use of frequent, small feeding trials seems to
rumination involves contraction of the abdominal provide other benefits to patients. First, frequent,
wall, diaphragmatic breathing has been utilized to small eating/drinking trials allow for repeated re-
provide abdominal muscle relaxation [15]. Other exposure to a stressful stimulus (i.e., actual eat-
authors have utilized progressive muscle relaxation ing/drinking and/or anticipatory anxiety about
in order to achieve general relaxation [14]. eating/drinking). Second, smaller amounts of
Functional gastrointestinal disorders recently food and fluid are more manageable as patients
have been understood in terms of the multiple focus on reswallowing their food and not expel-
pathways that influence symptom presentation, ling the emesis. Finally, this measured approach
with autonomic nervous system dysregulation provides patients with a sense of self-efficacy as
playing an integral role [16]. The autonomic ner- they make progress and have successful experi-
vous system’s reactivity and recovery has been ences with keeping food down.
shown to have an impact on symptom presenta-
tion in patients with functional gastrointestinal
disorders such as irritable bowel syndrome [17]. Support Strategies
It has also been demonstrated that biofeedback
approaches (i.e., instruction on autonomic ner- In the early stages of treatment, progress can be
vous system regulation) allows for increased measured by the patient’s ability to refrain from
vagal tone as well as symptom improvement in expelling emesis (i.e., reswallowing the emesis)
patients with functional abdominal pain [18]. and reducing the frequency of the rumination
Given the role of autonomic dysregulation in behavior itself. To support patients as they achieve
functional disorders, it is likely that similar these goals, many strategies are employed to
mechanisms contribute to the challenges demon- reduce some of the barriers to success. Patients
strated by patients with rumination syndrome. frequently are encouraged to engage in distraction
The use of biofeedback has been described by activities. Distraction utilized includes listening to
several authors as a beneficial intervention in music, watching television, playing video games,
patients with rumination syndrome [3, 13, 15, or reading aloud. The goal of distraction is to direct
19], often with minimal description of the specific attention away from the physical sensations that
biofeedback modality employed or the proposed often prompt an episode of rumination (e.g., pain,
mechanism by which the biofeedback allowed pressure, nausea). Although medications alone
for improvement (e.g., as a “behavioral” inter- have not been shown to be an effective treatment
vention, to allow for general relaxation, targeted for rumination [2], several drugs may be beneficial
abdominal wall relaxation). It may be the case in reducing many of the sensations that serve as a
that biofeedback training plays a specific role in “signal” to ruminate. Amitriptyline, cyprohepta-
allowing the patient greater self-regulation of the dine, buspirone, ondansetron, acid suppression,
autonomic nervous system and a reduction in and prokinetics act on different gastric and central
sensitivity to gastric distension. nervous system targets and may provide benefit to
individual patients undergoing treatment. Special
means of alimentation with post-pyloric feedings,
Gradual Refeeding either through naso-jejunal or gastro-jejunal feed-
ing catheters, may be used initially to maintain
Many authors have discussed the importance of adequate nutritional status when weight loss is
having patients slowly reintroduce food and fluid significant and should always be attempted prior to
intake [20]. Gradual reintroduction of oral intake parenteral nutrition.
410 A. Alioto and C. Di Lorenzo

Address Accompanying Psychological that maintain rumination, and provide the patient
Factors with ongoing support tend to demonstrate better
recovery. Further research will serve to elucidate
A subset of patients with rumination syndrome patient and family variables that may be empiri-
also has comorbid emotional difficulties includ- cally predictive of treatment success.
ing depression, anxiety, histories of abuse, and
life stressors [3, 21]. The relationship between
emotional state, autonomic nervous system acti- References
vation, and the experience of pain has been widely
recognized [22, 23]. While these comorbid con- 1. Khan S, Hyman PE, Cocjin J, Di Lorenzo C.
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allow multiple disciplines to address similar com- syndrome: clinical features rather than manometric
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12. Dalton WT, Czyzewski D. Behavioral treatment of
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benefit from a simplified treatment protocol car- 54:1804–7.
ried out as an outpatient [6], more disabled 13. Green AD, Alioto A, Mousa H, Di Lorenzo C. Severe
patients may benefit more from an intensive, pro- pediatric rumination syndrome: successful interdisci-
plinary inpatient management. J Pediatr Gastroenterol
grammatic approach. Regardless of the approach, Nutr. 2011;52(4):414–8.
several factors seem to have an impact on treat- 14. Wagaman J, Williams D, Camilleri M. Behavioral
ment success. Families who accept the diagnosis, intervention for the treatment of rumination. J Pediatr
have a solid understanding of the mechanisms Gastroenterol Nutr. 1998;27:596–8.
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15. Shay SS, Johnson LF, Wong RK, et al. Rumination, 19. Olden K. Rumination. Curr Treat Options Gastro-
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 Constipation
39
Vera Loening-Baucke and Alexander Swidsinski

No significant difference in prevalence between

Introduction boys and girls has been reported [1].
Chronic constipation is functional in more
Many children experience constipation at one time than 90% of the cases. Functional constipation is
or another [1]. Constipation is the most common constipation not due to organic or anatomical
digestive complaint in the general population, both causes or use of medication. Despite the func-
in adults and children, and occurs worldwide [1]. tional nature of constipation, the health-related
Usually the problem persists for a short time; how- problems of affected children are extensive and
ever, some children are chronically constipated suf- their quality of life is reduced.
fering for months and even years. Three percent of
infants suffered from constipation in the first and
10% in the second year of life in a primary care Pathophysiology
clinic in North America [2]. Issenman reported that
16% of 22 month olds were thought by their parents Like many pediatric gastrointestinal disorders,
to be constipated [3]. Five percent of otherwise the etiology and course of functional constipation
healthy 4–11-year-old British school-children had are increasingly conceptualized within a broad
constipation lasting more than 6 months [4], 18% of biopsychosocial perspective that assumes that a
4–17-year-old children had functional constipation child’s condition is a function of multiple inter-
in a primary care clinic in USA [5], and 18–37% of acting determinants, such as genetic predisposi-
Brazilian children suffered from constipation [6–8]. tion, environmental factors, life stress,
psychological state, coping, social support, and
interactions between physiologic and psycholog-
V. Loening-Baucke, M.D. (*) ical factors via the central nervous and enteric
Pediatrics Department, General Pediatric Division,
nervous system.
University of Iowa, Beldon Avenue, Iowa City,
IA 52246, USA
Medizinische Klinik und Poliklinik, Gastroenterologie,
Hepatologie and Endokrinologie, Charité Infants and Toddlers
Universitätsmedizin, Berlin, Germany
e-mail: [email protected] In 90% of normal newborns the first bowel move-
A. Swidsinski, M.D., Ph.D ment occurs within the first 24 h after birth and in
Medizinische Klinik und Poliklinik, Gastroenterologie, 98% within 48 h. The first bowel movement may
Hepatologie and Endokrinologie, Charité
happen much later in the premature infant. A
Universitätsmedizin, Berlin, Germany
e-mail: [email protected] number of studies have revealed a decline in stool

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 413

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_39, © Springer Science+Business Media New York 2013
414 V. Loening-Baucke and A. Swidsinski

frequency from more than four stools per day movements. This notion is supported by 93% of
during the first week of life to 1.2 per day at 4 parents of infants and toddlers with functional con-
years of age with a corresponding increase in stipation reporting hard to rock-hard stools, 27%
stool size. Fontana et al. [9] showed that in the reported having seen blood around their child’s
first 3 years of life, 97% of healthy children had stool, and 42% of children were crying and scream-
at least one bowel movement every other day. ing when passing stools [2]. Then the fear of defe-
The Rome III Committee suggested these cation leads to voluntary withholding of stool, called
mostly symptom-based diagnostic criteria for retentive posturing. Instead of relaxing the pelvic
functional constipation in infants and toddlers up floor for defecation, the retentive infant will con-
to 4 years of age [10]. At least two of the follow- tract the pelvic floor and gluteal muscles in an
ing symptoms must occur for at least 1 month. attempt to avoid defecation. Infants will often grunt,
• <2 defecations per week arch back, and stiffen their legs. Toddlers often rise
• >1 episode per week of incontinence after the on their toes and rock back and forth while squeez-
acquisition of toileting skills ing the buttocks together and stiffening their legs, or
• History of excessive stool retention assume other unusual postures. These maneuvers
• History of painful or hard bowel movements are often misinterpreted by the parents as straining
• Presence of a large fecal mass in the rectum for defecation. Forty-five percent of our constipated
• History of large-diameter stools that may infants and toddlers exhibited stool withholding
obstruct the toilet behavior [2]. Only 10% had an abdominal fecal
Constipation in early life is a special situation mass present, and 53% of those with a rectal exami-
because of the possibility of serious congenital nation had a rectal impaction [2]. Incontinence may
disorders. If meconium passage is delayed for be mistaken for diarrhea by some parents. Other
more than 24 h, several rare diseases need to be accompanying symptoms may include irritability,
considered. Evaluation for Hirschsprung’s disease decreased appetite, and/or early satiety. These
may include a barium enema, anorectal manome- accompanying symptoms disappear immediately
try, and rectal suction biopsy. The barium enema following passage of a large stool.
most often shows a transition zone, but the transi- The second period in which the toddler is prone
tion zone can be absent in the newborn period. The to develop constipation is during toilet training. In
anorectal manometry shows an absent anorectal order to master toileting, the toddler must develop
(recto-sphincteric) reflex. The diagnosis is the ability and interest in retaining a bowel move-
confirmed by the absence of ganglion cells in the ment until it can be deposited into the toilet. The
submucosal and myenteric plexus in the rectal attempt to retain stool leads to less frequent bowel
biopsy. Defects of the spinal cord (such as myelom- movements and sometimes to hard and painful
eningocele), or anomalies of the anorectum (such bowel movements. A power struggle may develop
as anal atresia and anal stenosis), must be ruled out if toilet training is forced on the toddler by the par-
by examination and, if necessary, by appropriate ent, potentially leading to constipation. Parents
imaging studies. Meconium plugs may cause neo- should avoid pushing for early toilet training, but
natal constipation, and may be associated with rather wait till the child shows signs of readiness
either Hirschsprung’s disease or cystic fibrosis. for toilet training. These signs include signs of
Other organic causes of constipation include endo- physiologic maturation, such as the ability to sit,
crine, metabolic, and neuromuscular diseases. walk, dress and undress, the child understands and
There are two periods in which the infant and responds to instruction, has the desire to imitate
toddler are prone to develop constipation. The first and identify with the parent, has self-determina-
occurs during the change from breast milk to com- tion, and shows signs of independence.
mercial formula or introduction of solids, the sec- The physical examination should be complete
ond during toilet training. The most common cause with special attention to the size of the rectal
of constipation in infants and toddlers is an acquired fecal mass during abdominal examination and, if
behavior after experiencing painful bowel none is felt, during the rectal examination.
39 Constipation 415

Infant dyschezia and infrequent bowel move- when a child begins to attend school, when toilet
ments in breastfed infants, both accompanied by use is reserved to special times and toilets may not
soft to loose stools, are often misinterpreted as con- be clean and private. Children who have been con-
stipation. Infant dyschezia is the term used for oth- stipated for years may have had withholding behav-
erwise healthy infants in the first few months of life ior long before the visit to the physician, and by the
who appear to have significant discomfort and time they are evaluated, the rectum has become
excessive straining associated with defecation and dilated and has accommodated to the point that
crying for over 10 min, followed by successful pas- withholding is no longer necessary in order to delay
sage of soft to liquid stools. It is speculated that this the passage of stools. The term excessive volitional
disorder occurs when neonates fail to coordinate stool retention is used to describe older children
increased intra-abdominal pressure with relaxation who still withhold their stools without necessarily
of the pelvic floor. Symptoms resolve without inter- displaying retentive posturing. Many parents of
vention in most cases. Breastfed infants may defe- constipated children give a history of passage of
cate after each feeding and other exclusively enormous stools, obstruction of the toilet by the
breastfed infants may have infrequent soft bowel stool, retentive posturing, abdominal pain and irrita-
movements. In our review of 4,157 infants and tod- bility, anal or rectal pain, anorexia, and unusual
dlers, we found that 18 well-nourished exclusively behaviors, such as a nonchalant attitude regarding
breastfed infants had long intervals between soft to the fecal incontinence, hiding their dirty underwear,
loose bowel movements (2–14 days, mean 5.4 ± 3.0 and lack of awareness of an incontinence episode.
days) [2]. This bowel pattern is considered normal Most symptoms disappear dramatically following
for breastfed infants. the passage of a huge stool.

Children and Adolescents Complications of Constipation

The Rome III Committee recommended symp- Fecal Incontinence

tom-based diagnostic criteria for functional con-
stipation in children and adolescents [11]. Fecal incontinence, also known as encopresis or
Symptom must occur at least once per week for fecal soiling, is the most obvious complication of
at least 2 months and include 2 or more of the constipation. Fecal incontinence is the involuntary
following in a child with a developmental age of loss of formed, semi-formed, or liquid stool into
>4 years with insufficient criteria for a diagnosis the child’s underwear and is considered a problem
of irritable bowel syndrome. after the child has reached a developmental age of
• Two or fewer defecations in the toilet per 4 years. Fecal incontinence in children is most
week often associated with functional constipation.
• At least 1 episode of fecal incontinence per Loening-Baucke [5] showed a 4% prevalence rate
week for functional fecal incontinence in a retrospective
• History of retentive posturing or excessive review in 482 children, 4–17 years of age, attend-
volitional stool retention ing a primary care clinic in the USA. In this study
• History of painful or hard bowel movements fecal incontinence was associated with constipa-
• Presence of a large fecal mass in the rectum tion in 95% of the children [5].
• History of large diameter stools that may Seventy-nine percent of children with functional
obstruct the toilet constipation and fecal incontinence were reported
A positive family history has been found in to have a history of retentive posturing [13]. When
28–50% of constipated children, and a higher inci- stool withholding is successful, greater amounts of
dence has been reported in monozygotic than dizy- stool accumulate in the rectum with longer expo-
gotic twins [12]. Often the onset of functional sure to its drying action, and a vicious cycle is
constipation in children >4 years of age occurs started. When stool retention remains untreated for
416 V. Loening-Baucke and A. Swidsinski

a prolonged period of time, the rectal wall stretches nighttime urinary incontinence and urinary tract
and a megarectum develops. The intervals between infections. Daytime urinary incontinence occurred
bowel movements become increasingly longer and in 29%, bed wetting in 34%, and one or more uri-
the rectum becomes so large that the stored stool nary tract infections in 33% of girls and 3% of boys
can be felt as an abdominal mass that sometimes of our constipated and fecal incontinent children
reaches up to the umbilicus, above the umbilicus, [16]. Other less common urinary complications are
and occasionally up to the sternum. The progressive vesicoureteral reflux, urinary retention, megacystis,
fecal accumulation eventually leads to pelvic floor and ureteral obstruction.
muscle fatigue and poor anal sphincter competence,
leading to leakage of stools. Usually, the consis-
tency of stool found in the underwear is loose or Behavioral Problems
clay-like. Sometimes the core of the impaction
breaks off and is found as a firm stool in the under- Behavioral problems are common in children with
wear. Occasionally, what appears to be a full bowel functional constipation and in children who have
movement is passed into the underwear. A period fecal incontinence [17, 18]. Children with constipa-
free of fecal incontinence may occur after a huge tion and fecal incontinence score above the means
bowel movement is passed and fecal incontinence but not in the abnormal range on all behavior sub-
will resume only after several days of stool reten- scales when compared to sex- and age-matched
tion. The social stigma which goes along with controls [19]. Behavior problems can be the cause
increased flatulence and the odor of fecal inconti- or the consequence of constipation with or without
nence can be devastating to the child’s self-esteem fecal incontinence. Several intervention studies
and his/her acceptance by siblings, parents, peers, have shown an association between successful treat-
and teachers. ment and the reduction of behavior problems, sug-
gesting that behavior problems are secondary to the
clinical problem of constipation, in particular when
Abdominal Pain fecal incontinence is also present.

Abdominal pain and anal and rectal pain are reported

by approximately half of the constipated children. Quality of Life
Severe attacks of abdominal pain can occur either
just before a bowel movement, for several days It has been shown that functional constipation
prior to a large bowel movement, or daily. Many has a great impact on the child’s emotional well-
children suffer from vague chronic abdominal pain. being. Children with constipation report a lower
Some patients with large stool masses throughout quality of life than a healthy control group, chil-
the entire colon may not experience any abdominal dren with inflammatory bowel disease or children
pain. A chart review at the University of Iowa in a with gastroesophageal reflux [20].
primary care setting revealed that 9% of 962 chil-
dren >4 years of age had a visit for acute abdominal
pain and 12.7% for chronic abdominal pain. Acute Diagnosis
and chronic constipation were the most frequent
causes of abdominal pain [14, 15]. History

The history should include information regarding

Urinary Complications the general health of the child and the presenting
signs and symptoms. A careful history needs to
Anorectal and lower urinary tract function are inter- elicit the intervals, amount, diameter, and consis-
related. As a result, constipation is often associated tency of bowel movements deposited into the toi-
with urinary symptoms such as daytime and/or let and of stools deposited into the underwear.
39 Constipation 417

The amount, intervals, diameter, and consistency with perineal fistula or a tight rectal ampulla,
of bowel movements are important because some suggestive of Hirschsprung’s disease. Rarely, a
children may have daily bowel movements but sacral tumor obstructing the rectum has been
evacuate incompletely, as evidenced by periodic found. Failure to appreciate the degree of fecal
passage of very large amounts of stool of hard to retention in these children, can lead to erroneous
loose consistency. Do the stools clog the toilet? Is treatments, can further delay effective treatment
or was stool withholding/retentive behavior pres- or lead to misdirected psychotherapy.
ent? What was the age at onset of constipation?
Was there a problem with the timing of passage
of meconium? The character of the stools is Laboratory Investigation
reviewed from birth for consistency, caliber, and
frequency. Is abdominal pain present? Is urinary Most children with functional constipation need
incontinence or urinary tract infection present? no or minimal laboratory testing. Laboratory and
What are the dietary habits? radiologic testing should be selected based upon
the history and physical examination and should
be pursued only if the child fails to respond to the
Physical Examination treatment program and in patients with signs and
symptoms suggestive of an organic cause. Rarely,
The physical examination should be thorough in serologic studies (deficiency or excess of thyroid
order to rule out an underlying disorder and often or adrenal hormones, electrolyte imbalances, and
includes a rectal examination. Weight and height calcium level, celiac antibodies), urine culture,
should be plotted. An abdominal fecal mass can X-ray studies, anorectal manometric studies, or
be palpated in many constipated children during rectal biopsy will be necessary.
abdominal examination. Sometimes the mass
extends throughout the entire colon, but more
commonly the mass is felt suprapubically and Occult Blood Testing
midline, sometimes filling the left or the right
lower quadrant. The anal size and location need It is recommended that stool is tested for occult
to be assessed. A low anal pressure during digital blood in all infants with constipation as well as in
rectal examination suggests either fecal retention any child who has abdominal pain, failure to
with inhibition of the anal resting pressure or a thrive, intermittent diarrhea, or a family history
disease involving the external or internal anal of colon cancer or colonic polyps.
sphincter or both. The neurological examination
should include perineal sensation testing in coop-
erative children using a Q-tip. Loss of perianal Abdominal Radiographs
skin sensation can be associated with various
neurologic diseases of the spinal cord. Radiologic studies usually are not indicated in
In most cases, a carefully performed rectal uncomplicated functional constipation. A plain
examination causes a minimal degree of physical abdominal film can be useful in assessing the
or emotional trauma to the child. Often the rec- presence or absence of retained stool, its extent,
tum is packed with stool, either of hard consis- and whether or not the lower spine is normal.
tency or, more commonly, the outside of the fecal It should be pursued in children with symptoms
impaction feels like clay and the core of the fecal suggestive of constipation and absence of a fecal
retention is rock hard. No rectal fecal impaction mass on abdominal and rectal examination, in
is felt in children with a recent large bowel move- children who vehemently refuse the rectal
ment. Occasionally, the rectal examination will examination, in children who are markedly
reveal an organic cause for the constipation, such obese, and in children who are still symptomatic
as a large anal fissure, anal stenosis, anal atresia while on laxatives.
418 V. Loening-Baucke and A. Swidsinski

Barium Enema Study motility study may be helpful in children with

suspected dysmotility of the colon or the total
A barium enema is unnecessary in uncomplicated gastrointestinal tract.
cases of functional constipation.

Treatment in Infants and Toddlers

Colonic Transit Study
After assessment of the constipated infant/tod-
A colonic transit study provides an objective mea- dler, all parents should receive education,
sure of presence and the severity of constipation including explanation that passing hard stools
in children, but is unnecessary in most children and experiencing painful defecation are the
with functional constipation. It does not influence primary precipitants of constipation and with-
the initial decision how to treat the child. It may holding behavior during infancy and the tod-
be helpful to differentiate children with nonreten- dler years [2, 24–26].
tive fecal incontinence from those with functional
constipation with overflow fecal incontinence.
Disimpaction

Anorectal Manometry Most fecal impactions at this age can be resolved

with a few days of laxative treatment.
Anorectal manometry is unnecessary in children Occasionally, a glycerin suppository is necessary
with functional constipation with or without func- and if unsuccessful, a 6 mL/kg bodyweight phos-
tional fecal incontinence. The main clinical role of phate enema can be used.
anorectal manometry is in the evaluation of infants
and children with severe constipation, where the
diagnosis of Hirschsprung’s disease needs to be Diet and fiber
excluded. It may also be helpful in evaluating other
conditions, such as spinal defects and anal achala- Acute, simple constipation in infants and toddlers
sia. We have performed numerous manometric frequently resolves with ingestion of non-digest-
studies in children with functional constipation ible, osmotically active carbohydrates, including
with fecal incontinence and have documented sorbitol-containing juices, such as prune, pear,
many abnormalities, including increased threshold and apple juice; addition of pureed fruits and
to rectal distention and decreased rectal contractil- vegetables; or medications with high sugar con-
ity as compared to controls [17]. After 3 years of tent (barley malt extract or corn syrup). Several
therapy, many children will show persistent abnor- studies have claimed a causal relationship
malities of anorectal function, leaving them at risk between cow’s milk exposure and constipation in
for recurrent problems [19, 21]. Another abnor- children [27–32], but this could not be confirmed
mality often reported is the contraction of the by Simeone et al. [33], Loening-Baucke [2], and
external anal sphincter and pelvic floor muscles Benninga et al. [34].
instead of relaxation of these muscles during def-
ecation attempts (a pattern characteristic of dys-
synergic defecation) [17, 22, 23]. Laxative

If despite dietary changes, the stool is still hard

Colonic Manometry and painful to evacuate, then osmotic laxatives are
given, such as polyethylene glycol, lactulose, sor-
Colonic manometry study is unnecessary in most bitol, or milk of magnesia (see Table 39.1). The
children with functional constipation. A colonic key to effective maintenance is assuring painless
39 Constipation 419

Table 39.1 Suggested medications and dosages for maintenance therapy of

constipation in infants and toddlers
Medication Age (month) Dose
Polyethylene glycol 3350 >1 0.7 g/kg body weight/day [24, 35]
Lactulose or sorbitol >1 1–3 mL/kg body weight/day,
divide in 1–2 doses
Milk of magnesia >1 1–3 mL/kg body weight/day,
divide in 1–2 doses
Mineral oil >12 1–3 mL/kg body weight/day,
divided in 1–2 doses

defecation. Parents are counseled on how to adjust Parents must understand that the fecal inconti-
the laxative dose according to the clinical response nence is due to overflow incontinence and does
every 3 days until the infant or toddler has 1–2 soft not constitute willful or defiant behavior of the
bowel movements per day. Laxatives should be child. The physician must make clear to the fam-
continued until the child is comfortable or acquisi- ily that the rock-hard stools are difficult and pain-
tion of toilet learning is complete. ful for the child to pass. The child therefore
associates bowel movements with pain, which
leads to stool withholding, which in turn leads to
Toilet training rock-hard stools. Thus, a vicious cycle is started
that leads to chronic fecal retention and eventually
Toilet training should be postponed till defeca- to overflow fecal incontinence. The child and par-
tion is pain free, the fear of painful bowel move- ent are told that many children are troubled with
ments has resolved and rectal awareness is this condition. The parents need to understand
restored. Behavior modification using rewards that there is no quick solution for this condition
for successes in toilet learning is helpful. and that months to years of treatment will be nec-
essary, until the stretched rectal muscles and the
impaired rectal perception readjusts, and the child
Treatment in Children and has learned to properly coordinate the muscles for
Adolescents defecation. A caring and trustworthy relationship
between medical provider and family needs to be
Most children with functional constipation benefit established, because the treatment of functional
from a detailed, well-organized plan. The treat- constipation is a long-term process and without
ment is comprehensive and has four phases: educa- the family’s and the child’s compliance, the rec-
tion, disimpaction, prevention of re-accumulation ommended therapy will not be successful.
of stools, and withdrawal of treatment.

Disimpaction
Education
When the evaluation shows that a large fecal mass
Effective education is an important first step in the is present, then the impaction needs to be removed
treatment and includes developmentally appropri- using oral or rectal interventions. Suggested medi-
ate description to parents and child about the anat- cations and dosages for disimpaction are given in
omy and physiology of defecation and its Table 39.2. Disimpaction can be achieved without
associated disorders and explanation of the preva- the use of enemas with oral laxatives, such as poly-
lence of constipation. If fecal incontinence is ethylene glycol-without electrolytes [36, 37] and
present then a discussion of the related shame, with electrolytes [38, 39]. A study by Youssef
embarrassment, and social issues is necessary. et al. [36] demonstrated that 1.5 g/kg body weight/
420 V. Loening-Baucke and A. Swidsinski

Table 39.2 Suggested medications for fecal disimpaction in children and adolescents
Medication Age Dose
Slow oral disimpaction
PEG without electrolytes (for 3 days) [36] 1.5 g/kg body weight/day
PEG with electrolytes (for 6 days) [38, 39] 2–4-year olds 52 g/day
5–11-year olds 78 g/day
Milk of magnesia (for 7 days) 2 mL/kg body weight twice/day
Mineral oil (for 7 days) 3 mL/kg body weight twice/day
Lactulose or sorbitol (7 days) 2 mL/kg body weight twice/day
Rapid rectal disimpaction
Phosphate enema >6 months 6 mL/kg body weight, up to
135 mL 1–2 times
PEG polyethylene glycol 3350

day of electrolyte-free polyethylene glycol for 3 Prevention of Re-accumulation

days was efficient in removing the rectal fecal of Stools (Maintenance Therapy)
impaction. In a study by Candy et al. [37], 92% of
the children were disimpacted using an escalating Behavior Modification
dose of up to 78 g of polyethylene glycol 3350 The child needs to be reconditioned to normal
plus electrolytes for 6 days. The fecal impaction bowel habits by regular toilet use. The child is
can also be softened and liquefied with large quan- encouraged to sit on the toilet for up to 5 min,
tities of oral mineral oil or other osmotic laxatives three to four times a day, following meals. The
with the oral administration continued daily until gastrocolic reflex, which goes into effect during
the fecal mass is passed. Fecal incontinence, and shortly after a meal, should be used to his or
abdominal pain, and cramping may increase dur- her advantage. The children and their parents
ing oral disimpaction. need to be instructed to keep a daily record of
Enemas and polyethylene glycol were equally bowel movements and medication use. This helps
effective in treating rectal fecal impaction in chil- to monitor compliance and allows parents and
dren [40]. Enemas are invasive and can cause psy- physician to make appropriate adjustments in the
chological harm to an occasional child, but are more treatment. If necessary positive reinforcement
rapidly effective, may be a powerful motivator for and rewards for compliant behavior are given for
toilet sitting, and can rapidly relieve the severe pain effort and later for success, using star charts, little
being present in some children due to stool reten- presents, or television viewing time and computer
tion. Hypertonic phosphate enemas are often used game time as rewards.
and can be repeated twice if necessary. Severe vom-
iting with hypernatremia, hyperphosphatemia, Fiber
hypocalcemia, hypokalemia, dehydration, seizures, The modern diet has been cited as a chief suspect
coma, and death have been reported after the first in the etiology of childhood constipation. Dietary
phosphate enema in a few children with functional fiber increases water retention, provides substrate
constipation less than 5 years of age [41]. Therefore, for bacterial growth with increase of colonic
the first hypertonic enema may be given in the clinic motility and gas production during colonic fer-
or doctor’s office to those children who have never mentation of fiber. Several studies have reported
received a phosphate enema before. Enemas are that the fiber intake is lower [42, 43] or similar
nowadays rarely necessary and can be combined [44] in constipated children as compared to con-
with oral medication. The use of tap water, soap- trols. Unlike past generations, children today
suds, or Epsom salt enemas is not recommended. consume large amounts of highly processed food
Manual disimpaction is performed rarely, and if items at the expense of fruit and vegetables. It is
necessary, should be done under anesthesia. commonly believed that functional constipation
39 Constipation 421

Table 39.3 Suggested medications and dosages for maintenance therapy of constipation for children
and adolescents
Medication Dose
For long-term treatment (years)
Polyethylene glycol
3350 (MiraLax®) 0.7 g/kg body weight/day [13, 24] or 0.4 g/kg body weight/
day [52]
3350 + electrolytes (Movicol®) 13.8–40 g/day [38, 39]
4000 (Forlax®) 0.5 g/kg body weight/day [37]
Lactulose or sorbitol 1–3 mL/kg body weight/day, divide in 1–2 doses
Milk of magnesia 1–3 mL/kg body weight/day, divide in 1–2 doses
Mineral oil 1–3 mL/kg body weight/day, divided in 1–2 doses
For short-term treatment (months)
Senna (Senokot®) syrup/tablets 5–10 mL with breakfast, max. 15 mL daily or 1–2 tablets with
breakfast, maximum 3 tablets daily
Bisacodyl suppositories 10 mg daily
Phosphate enema 135 mL daily
Glycerin enema 20–30 mL/day (1/2 glycerin and 1/2 normal saline)

can be improved by providing appropriate for long-term daily use in infants, toddlers, and
amounts of fiber and fluids. The dietary recom- older children [24, 37–39, 50–54]. PEG with-
mendation for children older than 2 years of age out electrolytes is tasteless, odorless, colorless,
is to consume an amount of dietary fiber equiva- and has no grit when stirred in juice, Kool-aid,
lent to age in years plus 5 g/day [45]. or water for several minutes. PEG is not
Recommended are several servings daily from a degraded by bacteria, is not readily absorbed
variety of fiber-rich foods such as whole grain and thus, acts as an excellent osmotic agent,
breads and cereals, fruits, vegetables, and and is safe [13, 39, 50, 54]. Preparations of
legumes. Synthetic preparations are available, PEG with electrolytes are available outside the
such as guar gum and pectin fiber, glucomannan USA. The addition of electrolytes alters the
[46, 47], cocoa husk [48], or a yogurt drink with taste and therefore these medications are more
a fiber mixture [49]. Treatment with fiber or fiber often refused by children then PEG without
supplementation alone for functional constipa- electrolytes. Polyethylene glycol 3350 has
tion that is severe enough to come to medical become the first-line drug to use for pediatric
attention is inadequate. constipation [55].
Lactulose and sorbitol are nonabsorbable
Laxatives carbohydrates. They cause increased water con-
In most constipated patients, daily defecation tent by the osmotic effects of lactulose, sorbitol,
is maintained by the daily administration of and their metabolites. They are fermented by
laxatives. Suggested dosages of commonly colonic bacteria, thereby producing gas and
used laxatives are given in Table 39.3. There is sometimes causing abdominal discomfort. Both
no evidence that tolerance develops to osmotic are easily taken by the children when mixed in
laxatives. Polyethylene glycol (PEG) without soft drinks. The mechanism of action of milk of
added electrolytes (PEG 3350, MiraLax®, magnesia is the relative nonabsorption of mag-
Braintree Laboratories, Inc., Braintree, MA, nesium and the resultant increase in luminal
PEG 4000, Forlax®, Ipsen, Paris, France) and osmolality. Mineral oil is converted into hydroxy
polyethylene glycol 3350 with electrolytes fatty acids, which induce fluid and electrolyte
(Movicol®, Norgine Pharmaceuticals Ltd., UK) accumulation. Mineral oil should never be force-
have been developed and have now been tested fed or given to patients with dysphagia or
422 V. Loening-Baucke and A. Swidsinski

vomiting because of the danger of aspiration Follow-Up Visits and Weaning

pneumonia. from Medication
Senna has an effect on intestinal motility as Since the treatment of functional constipation
well as on fluid and electrolyte transport and requires months to years of considerable
stimulates defecation. We use senna when liquid patience and effort on the part of the child and
stools produced by osmotic laxatives are retained parents, it is important to provide necessary sup-
and in children with fecal incontinence and con- port and encouragement through regularly
stipation due to organic or anatomic causes. The scheduled office visits. Progress should be ini-
North American Society for Pediatric tially assessed monthly, later less frequently by
Gastroenterology, Hepatology and Nutrition rec- reviewing the stool records and repeating the
ommended senna products for short-term therapy abdominal and possibly the rectal examination
[56]. There is very little evidence that tolerance to assure that the problem is adequately man-
develops to stimulant laxatives [57]. Occasionally, aged. If necessary, dosage adjustment is made
the use of a 10-mg bisacodyl suppository or either and the child and parents are encouraged to con-
a phosphate or a glycerin enema daily is advised tinue with the regimen. After regular bowel hab-
as initial treatment for several months in an older its are established, the frequency of toilet sitting
constipated child who would like immediate con- is reduced and the medication dosage is gradu-
trol of his/her fecal incontinence. ally decreased to a dosage that maintains one
Laxatives should be used according to body bowel movement daily and prevents the abdom-
weight and severity of constipation. The choice inal pain and the fecal incontinence. Once the
of medication for functional constipation does child feels the urge to defecate and initiates toi-
not seem as important as the children’s and par- let use on his/her own the scheduled toilet times
ents’ compliance with the treatment regimen. are discontinued. After 6–12 months, reduction
There is no set dosage for any laxative. There is with discontinuation of the medication is
only a starting dosage for each child (Table 39.3) attempted. Treatment (laxatives and/or toilet sit-
that must be adjusted to induce one to two bowel ting) needs to resume if constipation, fecal
movements per day that are loose enough to incontinence, or abdominal pain recur.
ensure complete daily emptying of the lower
bowel and to prevent fecal incontinence and
abdominal pain. Parents and children should be Treatment Failure
warned that some leakage or incontinence may
continue at first, especially if the child continues Errors by physician, parents, and children may
to resist the use of the toilet. lead to treatment failures. More common mistakes
by physicians are treating with stool softeners and
Psychological Treatment laxatives but not removing the fecal impaction,
Functional constipation and particularly fecal removing the fecal impaction but failing to start
incontinence affect the lives of these children and maintenance therapy, recommending a laxative
families in several areas: physically, psychologi- dose that is too low, not controlling the adequacy
cally, educationally, socially, and in terms of self- and success of therapy with enough follow-up vis-
esteem. If coexisting behavior problems are its, stopping the laxative too soon, and not provid-
secondary to functional fecal incontinence and/or ing education, anticipatory guidance, continuing
constipation, then they will improve with treat- support and regular follow-up. Frequent mistakes
ment. The presence of coexisting behavioral by parents and children include not insisting that
problems often is associated with poor treatment the child uses the toilet at regular times for defeca-
outcome. Children who do not improve should be tion trials, not giving the medication daily or dis-
referred for further evaluation, because continued continuing the laxatives as soon as symptoms have
problems can be due to noncompliance or control improved, and not restarting the laxative after the
issues by the child and/or the parent. child had a relapse. Sometimes the fault lies with
39 Constipation 423

the child who refuses to take medications or to sit fered no abdominal pain, independent of laxa-
on the toilet. Issues may also arise in school. The tive use [ 16, 58 ] . Recovery has been de fi ned
teacher needs to permit the child to use the bath- by the same criteria, except that the child
room without having to draw attention to his/her needs to have been off laxatives for at least 1
need. A change of clothing should be available in month [ 17, 19, 21, 22, 59– 61] .
school, so that the parent does not have to bring a
change of clothing or have to take the child home, Behavior modification: The only study to exam-
should an incontinence episode occur. ine behavior modification as single therapy for
children with functional constipation and fecal
incontinence was by Nolan et al. [60] from
Outcome in Infants and Toddlers Australia. In this randomized study, they found
that 1 year after start of behavior modification,
Improvement can be expected in virtually every 36% had recovered but more children had recov-
infant and toddler whose parents cooperate with ered with behavior modification and, 51%, addi-
the treatment plan. Complete recovery is often tional laxative treatment.
seen. Dietary changes resolved all symptoms of
constipation in 25% of constipated infants [2]. Fiber: Three randomized double-blind controlled
Ninety-two percent of constipated infants and studies to evaluate fiber in constipated children
toddlers responded to laxative treatment [2]. have been published [47–49]. Glucomannan,
Several retrospective chart reviews have shown 100 mg/kg body weight daily (maximal 5 g/day)
that PEG can be effective, safe, and well tolerated with 50 mL fluid/500 mg and placebo for 4 weeks
in children younger than 2 years of age [2, 24, each was evaluated in 31 constipated children,
35]. The length of treatment with PEG varied using a crossover design [47]. While on additional
between 1 and 37 months [24] and 3 weeks to 21 fiber, significantly fewer children complained of
months [35]. The individual effective dose varied abdominal pain as compared to placebo (10 vs.
between 0.3 and 2.1 g/kg bodyweight per day [2, 42%) and significantly more children were relieved
24, 35], but the mean effective dose was 0.8– from constipation (45 vs. 13%). In another study, a
1.0 g/kg body weight per day in all studies. The significantly higher number of parents and chil-
results of laboratory evaluations during long-term dren reported subjective improvement in stool
PEG use were within normal limits [24, 54]. consistency while on cocoa husk [48]. Kokke et al.
[49] reported that a mixture of dietary fiber was
similar to lactulose in an 8-week trial in regards to
Outcome in Children and Adolescents stool frequency, frequency of fecal incontinence,
and presence of abdominal pain and flatulence.
The goal of treatment is to accomplish one
soft stool per day. Weeks, months, and some-
times years of treatment may be necessary Laxatives and Behavior Modification
before this goal is achieved. Improvement can
be achieved in most patients, but complete Short-term outcome: A double-blinded, placebo-
recovery is less often seen. Outcome in most controlled trial of PEG 3350 without electrolytes
publications of functional constipated chil- showed that a significantly higher proportion of
dren (>4 years of age) with or without fecal constipated children responded to treatment com-
incontinence has been assessed by rates of pared to placebo in the second week of treatment
“successful treatment” and “recovery.” The [52]. PEG plus electrolytes was significantly
constipation has been rated as successfully more effective than placebo in a 2-week treat-
treated if the child had in the previous month ment trial [62]. PEG 3350 was similarly effective
>3 bowel movements per week, <2 fecal as lactulose in improving stool frequency, stool
incontinence episodes per month, and suf- consistency, and ease of stool passage [63].
424 V. Loening-Baucke and A. Swidsinski

Table 39.4 1-year recovery rates in constipated children with or without fecal incontinence
Author Subject number Laxative Recovery rate (%)
Constipation with or without fecal incontinence
Abrahamian et al. [64] 68 Multiple laxatives 47
Staiano et al. [65] 31 Lactulose 47
van Ginket et al. [59] 212 Lactulose 31
van Ginket et al. [58] 399 Lactulose 59
Constipation with fecal incontinence
Levine et al. [66] 110 Mineral oil 51
Loening-Baucke [17] 97 Milk of magnesia 43
Nolan et al. [60] 83 Multiple laxatives 51
Loening-Baucke [67] 181 Milk of magnesia 39
Loening-Baucke et al. [13] 39 Polyethylene glycol 3350 33
Overall 6–12 months recovery rates [68] 40

1-year outcome: At least 9 well-designed stud- outcome [69]. Of 90 children who were followed for
ies have evaluated 1-year outcome (Table 39.4). a mean of 7 years after beginning treatment, 63%
Laxative treatment with behavior modification had recovered. Staiano et al. [65] found that early
dramatically improved constipation, abdominal age of onset of constipation and family history of
pain, and functional fecal incontinence. Four of constipation were predictive of persistence of consti-
these studies evaluated children who had consti- pation [65]. The largest follow-up study is by van
pation with or without functional fecal inconti- Ginkel et al. [58]. They initially enrolled 418 chil-
nence [58, 59, 64, 65]. They showed that 47% of dren with functional constipation, 2/3 with and 1/3
these children in the USA [68], 47% in Italy without fecal incontinence. All were older than 5
[65], and 31–59% in the Netherlands [58, 59], years of age at initiation of therapy. Some of the chil-
had recovered 1 year after start of treatment dren were followed for as long as 8 years, with a
(Table 39.4). median follow-up of 5 years. Fifty-nine percent had
Five of the nine studies evaluated children recovered at the 1-year follow-up. Three-year data
with functional constipation with fecal inconti- showed a decline in the recovery rate to about 50%,
nence. The 1-year recovery rates ranged from 33 as some children relapsed and were not restarted on
to 51% [13, 17, 60, 66, 67]. They showed that laxative therapy and others recovered. The recovery
33–51% of the children in the USA [13, 17, 66, rate of 193 children was 63% after 5 years, 69% of
67] and 51% of children in Australia [60] had 120 children had recovered after 7 years, and 68% of
recovered 1 year after start of therapy with milk 48 children had recovered after 8 years [58].
of magnesia, lactulose, or polyethylene glycol. However, 50% of recovered children had at least one
Pijpers et al. [68] summarized the outcome of 14 relapse and approximately 30% of children, who
publications of prospective follow-up studies. had reached adolescence, were still having problems
They found that 6–12 months after start of treat- with constipation or fecal incontinence.
ment, 40% of constipated children had recovered
and 61% were successfully treated. All studies
suggest that constipation is not a problem that all Other Treatments
children will eventually outgrow.
Probiotics: One rational for the use of probiotics
Long-term outcome: Long-term outcome studies for the treatment of constipation in children is
(4–10 year follow-up) report recovery rates between that dysbiosis has been reported in the intestinal
48 and 69% (Table 39.5) [58, 65, 69–72]. One study flora of these children [73]. The dysbiosis con-
specifically targeted younger children (<4 years) to sisted of a change in the selected bacterial spe-
examine whether early intervention might improve cies. A high clostridia count in comparison to
39 Constipation 425

Table 39.5 Long-term recovery rates in children with constipation only, constipation with and without fecal inconti-
nence, and constipation with fecal incontinence
Subject Age Years of Recovery
Author number (years) Laxative follow-up rate (%)
Constipation only
Loening-Baucke [69] 90 1–4 Milk of magnesia Mean 7 year 63
Michaud et al. [72] 45 0.5–14 Lactulose 10 year 54
Constipation with and without fecal incontinence
Staiano et al. [65] 62 1–11 Lactulose 5 year 48
van Ginket et al. [58] 193 >5 Lactulose 5 year 69
Constipation with fecal incontinence
Loening-Baucke [70] 129 >4 Milk of magnesia Mean 4 year 53
Procter et al. [71] 76 0.3–16 Laxative 6 year 64
From Loening-Baucke V. “Constipation and fecal incontinence.” In: Pediatric Gastrointestinal and Liver Disease, 4th
edition. Wyllie R, Hyams JS, Kay M., Elsevier Ltd., Philadelphia 2011, pp 127–135. Reprinted with permission from
Elsevier

Bacteroides and Escherichia coli was seen and a benefit of additional biofeedback treatment [76];
substantial presence of clostridia and enterobac- however, four other randomized studies have
teriaceae species were observed, bacteria which found no statistically significant benefit of addi-
are rarely isolated in healthy children [73]. A ran- tional biofeedback treatment in children when
domized controlled trial concluded that 109 col- compared to conventional treatment alone, in
ony forming units of Lactobacillus GG given 6-month, 1-year, and long-term follow-up studies
twice daily was not an effective adjunct to lactu- [23, 61, 70, 77].
lose [74]. Lactobacillus casei rhamnosus 8 × 108
colony forming units given twice daily has shown
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 Functional Fecal Incontinence
40
Rosa Burgers and Marc A. Benninga

absence of constipation and to unravel possible

Introduction different pathophysiological mechanisms [2, 3].
Functional fecal incontinence in children can
Fecal incontinence (FI) is defined as defecation into also be categorized as either primary, in those chil-
places inappropriate to the social context, at least dren that have never been toilet trained, or second-
once per month, for a minimum period of 2 months. ary, in those in which the incontinence comes back
It represents one of the most upsetting and psycho- after successful toilet training. It has been proposed
logically distressing problems of childhood. These that the occurrence of secondary incontinence is
children leak stools into their underwear, smell bad, associated with better response to treatment.
and are rejected by their peers. It has a great impact
on the development, social interactions, and educa-
tion of the affected children. Prevalence
The amount of feces lost in the underwear was
the basis for the differentiation of FI in two The exact prevalence of functional fecal inconti-
definitions; encopresis encompassed expulsion nence associated with constipation varies depend-
of a normal bowel moment in inappropriate ing on the population being studied and changes
places and soiling the leakage of small amounts with age. Bellman, in her landmark study, reported
of stool. In the literature, fecal incontinence in incidence rates for FI in Stockholm school chil-
children is frequently described by the terms dren in 1963, of 2.8% in 4 year olds and 1.5% in
“encopresis” and “fecal soiling,” but given the 7–8 year olds [4]. Recently van de Wal et al.
different meanings that these terms have across showed a prevalence of fecal incontinence of 4.1%
different cultures and different nations, Rome III in a 5- to 6-year-old age group and 1.6% in an
have adopted the term “functional fecal inconti- 11-to 12-year-old age group in the Netherlands,
nence” which will be used in this chapter [1]. The with a 1.5-fold higher prevalence in boys [5]. In a
accompanying symptoms should be evaluated to retrospective review in 482 children of 4–7 years
find out whether FI exists in the presence or of age attending a primary care clinic in the USA a
prevalence rate for fecal incontinence of 4.4% was
reported [6]. In this study fecal incontinence was
coupled with constipation in 95% of the children.
R. Burgers, M.D. • M.A. Benninga, M.D., Ph.D. (*) A recent study evaluating the applicability of the
Department of Pediatric Gastroenterology, Emma new Rome III criteria, reported fecal incontinence
Children’s Hospital/Academic Medical Centre, in 9% of the patients referred to a tertiary Italian
H7-Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
e-mail: [email protected] hospital with complaints of chronic constipation

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 429

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_40, © Springer Science+Business Media New York 2013
430 R. Burgers and M.A. Benninga

of at least 2 months duration [7]. An epidemio- rectum. FI is reported in approximately 80% of

logic study in Sri Lanka showed that fecal inconti- children with functional constipation, whereas a
nence was present in 2% of the general population. defecation frequency below three times per week is
Approximately 82% had constipation-associated found in up to 88% of children with chronic func-
FI and 18.2% had nonretentive FI [8]. The highest tional constipation [15, 16]. A painful defecation is
prevalence was found in children aged 10 (5.4%). reported by half of the children. The involuntary
FI was significantly higher in boys (boys 3.2%, loss of stool can occur at any time during the day,
girls 0.9%), those exposed to recent school- and whenever the child tries to expel gas or the muscles
family-related stressful life events, and those from used to withhold the rectal contents become
lower social classes (P < 0.05). Inconsistent data fatigued. Children suffering from extreme fecal
exist about the prevalence of fecal incontinence in impaction may have fecal incontinence episodes
obese children, varying from 21 to 33% [9, 10]. even during the night [17]. Furthermore, accumula-
Also FI without constipation, functional non- tion of feces in the rectum causes decreased motility
retentive fecal incontinence (FNRFI), is more in the foregut, resulting in loss of appetite, irritabil-
common in boys with male to female ratio’s rang- ity, and abdominal distension [16].
ing from 3:1 to 6:1[2, 3, 11, 12]. An association between constipation and uri-
nary tract dysfunction (i.e., urine incontinence and
recurrent urinary tract infections) is well estab-
Causes lished [2, 3, 18–20]. A higher frequency of day-
time and nighttime urinary incontinence in children
Four main groups of children present with fecal without constipation (around 45%) was found by
incontinence: (1) children who have functional con- van Ginkel, while daytime and nighttime inconti-
stipation with overflow incontinence, (2) children nence was found in 25–29% of those with consti-
with functional non-retentive fecal incontinence, (3) pation [3, 21–23]. A high prevalence of urine
children with anorectal malformations, and (4) chil- incontinence in children with FI without constipa-
dren with spinal problems [3]. In approximately 95% tion, suggests an overall delay in the achievement
of the children, no organic cause can be identified and of toilet training or the neglect of normal physio-
these children are considered to have a functional logical stimuli to go to the toilet [11, 21].
defecation disorder. In approximately 90% of the
children with a functional defecation disorder the
loss of feces in the underwear is the result of consti- Functional Non-retentive Fecal
pation and treatment with laxatives is recommended. Incontinence
The remaining 10% have fecal incontinence with no
other symptoms or signs of constipation, these chil- Apart from the FI episodes, children with FNRFI
dren are classified as functional non-retentive fecal present with a normal defecation pattern, with-
incontinence (FNRFI). Figure 40.1 presents an over- out other symptoms or signs of constipation or
view of the different causes of fecal incontinence in organic malfunctioning. They have daily bowel
children [1–3, 6, 13, 14]. movements of normal size and on physical
Epidemiology, diagnosis and treatment of examination they have no palpable abdominal
fecal incontinence as result of either anorectal or rectal fecal mass. According to the Rome III
malformations or spinal problems will not be fur- classification, the definition for FNRFI in a child
ther discussed in this chapter. with a developmental age of at least 4 years is a
history of defecation into places inappropriate
to the social context at least once per month
Functional Constipation with no evidence of an inflammatory, anatomic,
metabolic, or neoplastic process and no evi-
In children with constipation, fecal incontinence is dence of fecal retention for at least 2 months
the consequence of overflow in an already impacted prior to diagnosis [1].
40 Functional Fecal Incontinence 431

Fig. 40.1 Organic and functional causes of fecal incontinence in children

The underlying mechanism of FNRFI is Quality of Life and Behavioral

largely unknown. The pathophysiology seems Problems
to be complex and is considered to be multifac-
torial. Historically, FI was seen as a manifesta- Quality of life scores of children with constipation
tion of emotional disturbance, although the and fecal incontinence are significantly reduced
association between FI and stress has not been [25, 26]. Children with functional defecation dis-
well documented. In the mid-1990s it was sug- orders and their parents report impaired quality of
gested that children with FNRFI deny or life in relation to physical complaints and long
neglect their normal physiological stimuli to duration of symptoms [25]. Moreover, parent-re-
defecate and contract the external anal sphinc- ported quality of life in children with constipation
ter to retain stool in the rectum [2]. This was even lower than that reported by their chil-
hypothesis is supported by the normal anorec- dren. Although, young adults with constipation,
tal sensorimotor function, anorectal manome- which already started in childhood, report a good
try, and rectal barostat testing but abnormal quality of life, persistence of childhood constipa-
defecation dynamics and high rates of urinary tion into adulthood is associated with impaired
incontinence [2, 24]. This is possibly due to an HRQoL at adult age. It is noteworthy that symp-
abnormal interpretation of rectal sensation or toms affect social contacts in a fifth of adults with
disturbed rectoanal coordination. Further unsuccessful clinical outcome [26].
research is indicated to explore disruptions in Behavioral problems are more common in
the rectum or the anal sphincter complex in children with FI (40%), with and without consti-
this condition. pation compared to their healthy controls. These
Patients presenting with FNRFI undergo less behavioral problems might be a reflection of the
therapy before intake (5.5 months vs. 15 months), impact of defecation disorders on the normal
visit the outpatient clinic at a higher age (age of development of children [11, 12, 27, 28]. A study
9.2 years vs. 6.5 years) and are more likely to by van der Plas et al. showed that successful treat-
have a positive family history (20% vs. 13%) ment of children with FNRFI normalized scores
compared to children with constipation [11, 23]. for behavioral problems [12]. This implies that FI
It is unknown why patients visit the outpatient is an important factor in the occurrence and main-
clinic at a higher age. Parents might postpone a tenance of behavioral problems in these children.
visit to the doctor because of shame that they are The question whether fecal incontinence results
not capable in getting their child properly toilet in behavior problems or vice versa is an impor-
trained before the age of 4 years. tant issue and still under debate.
432 R. Burgers and M.A. Benninga

The Constipation Guideline Committee of the

Clinical Presentation North American Society for Pediatric Gastroen-
terology, Hepatology and Nutrition (NASPGHAN)
A timely and correct diagnosis is essential for the recommended performing a rectal examination at
appropriate treatment of FI. Medical history and least once in children presenting with FI [30].
a thorough physical examination are often Both in children and adults digital rectal examina-
sufficient for an adequate assessment regarding tion has been shown to provide useful information
the underlying cause. Only in rare cases, addi- regarding anal sphincter function in patients with
tional tests might be useful. constipation and fecal incontinence [31, 32].
Furthermore it is done to assess the presence of a
fecal lump in the rectal ampulla. However, a
History recent study showed that there is a lack of empha-
sis on the use of digital rectal examination during
A careful history needs to elicit the specific medical school [33]. Moreover, it is either not per-
symptoms related to the FI episodes. The amount formed or inadequately used in clinical practice in
of feces (leakage of small amounts or normal the evaluation of children with functional anorec-
stools), the frequency, the time of the day when tal disorders. Interestingly, the vast majority
FI accidents occur and the age the problem started (85%) of primary care physicians do not perform
are all relevant. The majority of FNRFI children digital rectal examination in their patients, result-
have FI accidents after school during the late ing in missed diagnoses and treatment [34]. Based
afternoon and before bedtime [2]. To be able to on their study in 128 children referred for func-
differentiate between the separate causes under- tional constipation, Gold et al. stated that digital
lying FI, additional more detailed information examination can help to differentiate functional
about the bowel habits and any accompanying constipation from an organic process and may
symptoms has to be obtained. It is important to alter the course of therapy [35].
ask about the defecation frequency, stool charac-
teristics (consistency, caliber, and volume), pain
at defecation, abdominal pain, and stool with- Diagnostic Tests
holding behavior. Also urinary problems and
neurologic deficits have to be evaluated. Functional defecation disorders accompanied by
fecal incontinence are clinical diagnoses that can be
made in most cases on the basis of a medical history
Physical Examination and an essentially normal physical examination. In
these cases, it is not necessary to perform diagnostic
Physical examination is important to establish or tests before treatment is started. The marker test to
rule out constipation. Furthermore it is essential evaluate colonic transit time (described below) has
to look for signs of other underlying causes for FI been proven useful in differentiating between chil-
symptoms. A thorough physical and neurological dren with constipation and children with FNRFI. In
examination should be performed including peri- atypical cases or when conventional treatment fails,
anal inspection and anorectal digital examination. additional diagnostic tests can be performed to
To exclude signs of spinal dysraphism it is diagnose an underlying organic cause [11].
important to inspect the perineum and perianal
area. Physicians should consider the possibility
of sexual abuse, especially if anal fissures and Abdominal Radiography
scars are found. Only recently, gluteal cleft devi-
ation was found to be an important sign of lum- Insufficient evidence exists for a diagnostic asso-
bosacral spine abnormalities in children with ciation between clinical symptoms of constipa-
either functional constipation or FNRFI [29]. tion and fecal loading on abdominal radiographs,
40 Functional Fecal Incontinence 433

colonic transit time, and rectal diameter on ultra- MRI

sonography in children [30, 36–38]. However, in
case of doubt about the presence of a fecal mass, MRI is not required to assess lumbosacral spine
in a child who is obese or when rectal examina- abnormalities in the standard workup of children
tion is not possible when a child refuses or when with intractable constipation or non-retentive
it is considered traumatic, an abdominal X-ray in fecal incontinence. We recommend only per-
combination with radio-opaque markers might be forming an MRI in those children presenting with
useful. As described above, in our center we use alarming neurological signs including motor and
the colonic transit test to discriminate between sensory dysfunction of the lower extremities and
functional constipation and FNRFI. Based on the abnormal reflexes, or abnormal anorectal sensa-
results of this test we decide to either start with tion, gluteal cleft deviation, and anal wink sug-
laxatives or a strict regime of education and toilet gestive of spinal cord abnormalities [29, 43].
training in the case of children with FNRFI.

Manometry and Barostat

Colonic Transit Time
Several techniques can be used to assess anorec-
Colonic transit time (CTT) can be assessed by tal function. Anorectal manometry measures,
performing one or more abdominal X-rays after through volume-controlled distension, pressures
the ingestion of radio-opaque markers [39–41]. in the anorectal region and is useful to assess
With this technique both overall colonic transit sphincter function and contraction patterns.
and segmental transit can be determined to dis- Barostat measurements, using pressure-con-
tinguish different transit patterns: (1) normal trolled distension, give valuable information
colonic transit time: normal transit through all about rectal sensitivity and contractility. At this
colonic segments, (2) outlet obstruction: delayed moment, there is no indication for routinely per-
transit through the anorectal region, and (3) slow forming anorectal manometry or barostat in chil-
transit constipation: prolonged transit through dren with constipation and fecal incontinence, as
the entire colon [16]. Normal CTT for children is findings have no clinical implications. Therefore
based on the upper limit (mean + 2 SD, hours) in these techniques will not be discussed in detail
healthy controls. Based on the CTT data in here [44–46].
healthy children by Arhan et al., colonic transit Colonic manometry is a diagnostic test per-
time is considered delayed when the total CTT formed in specialized motility centers to differ-
exceeds 62 h [39]. In approximately 50% of con- entiate between normal colonic motor function
stipated children CTT is delayed [15, 16, 42]. In and colonic neuromuscular disorders in the eval-
the majority of these children the delay of transit uation of children with intractable constipation
is found in the anorectal region [15]. In children and in children with rare organic causes such as
and adults a good correlation is found between intestinal pseudo-obstruction [47]. Manometry
symptoms of constipation such as defecation fre- can also help predict whether antegrade enema
quency and fecal incontinence frequency and treatment through a Malone stoma or cecostomy
colonic transit time [15]. A delay of colonic tran- will be successful [48].
sit <100 h is not predictive for treatment out-
come. Only those patients with CTT > 100 h have
a less favorable outcome at 1-year follow-up. In Abdominal Ultrasound
contrast to children with constipation a normal
CTT is found in more than 90% of the children Pelvic ultrasound can show the impression of the
with FNRFI. Thus, a normal CTT in combina- rectum behind the urinary bladder. With this non-
tion with a normal defecation frequency and no invasive technique, which does not involve radia-
rectal mass indicates FNRFI [2]. tion, urologists are able to measure the transverse
434 R. Burgers and M.A. Benninga

rectal diameter. Some studies show that measur- and fears should be addressed, a positive atmo-
ing rectal diameter correlates with the results of sphere towards the treatment approach is essen-
digital rectal examination and therewith seems to tial. The child and the parents should be prepared
assess fecal impaction [49, 50]. However, as for for a long-lasting treatment process with many
now, there is insufficient evidence that the trans- “ups and downs” [1, 3, 11].
verse diameter can be used as a predictor of con-
stipation and fecal impaction.
Functional Constipation

Treatment Education and behavior modification (no with-

holding with urge to defecate), toilet training, a
The lack of randomized controlled studies in bowel diary, and medical treatment are the cor-
children has made the treatment of constipation nerstones of the treatment of children with func-
and fecal incontinence largely based on clinical tional constipation. The toilet training program
experience rather than on evidence-based con- consists of trying to defecate for 5 min after each
trolled clinical trials [11, 51]. Acute simple meal. Defecation frequency, episodes of FI,
constipation is traditionally treated with a high- abdominal pain, the use of laxatives, and compli-
fiber diet and sufficient fluid intake, filling out a ance with toilet training are registered daily in the
bowel diary and toilet training. The NASPGHAN diary. Besides these behavior changes, oral and
recommendations include four important phases sometimes rectal laxatives are necessary in almost
in the treatment of chronic constipation: (1) all constipated children. A recent trial showed
education, (2) disimpaction, (3) prevention of that enemas and PEG are equally effective in
re-accumulation of feces, and (4) follow-up treating severe rectal fecal impaction [54]. Stool
[30]. In contrast to children with constipation, softeners are preferred to stimulant laxatives for
no laxatives should be used in children with maintenance therapy [51]. Bongers et al. showed
functional non-retentive fecal incontinence [11, that enemas as maintenance therapy had no addi-
52]. Treatment in these children consists of tional effect compared to oral laxatives alone for
education, toilet training, a daily bowel diary severely and chronically constipated children
with rewarding system, and loperamide [53]. between 8 and 18 years treated in a tertiary center
The role of enemas in these children is still [55]. The duration of maintenance therapy is
unclear but should be investigated in a large unclear, but is usually necessary for at least 3
randomized controlled trial. months [30]. Only when the child has been hav-
The ultimate treatment goals in children with ing regular bowel movements without difficulty
FI are preventing stool accidents and have regular is discontinuation considered. Health carers and
bowel movements. How to achieve this depends families should be aware that relapses are com-
on the underlying pathophysiology, with differ- mon and that difficulty with bowel movements
ent approaches and prognoses for the different may continue into adulthood [56, 57].
causes. Treatment can be directed towards the
stool itself (consistency, volume), stool transit,
rectosigmoid/anorectal function, and the child’s Functional Non-retentive Fecal
behavior. An essential first step is educating both Incontinence
the child and the parents about the gastrointesti-
nal tract with specific attention to the rectum, Education, strict toilet training, and positive
defecation, and FI. It is also important to explain motivation are the cornerstones of treating chil-
that FI is a common disorder in childhood and dren with FNRFI. An additional reward system
that the child may not always be aware of fecal (praise and small gifts) can enhance motivation
accidents. Drawings, illustrating the pathophysi- as well in these cases [11, 52]. After this demys-
ological mechanisms are often helpful. The myths tifying process, we emphasize to patients and
40 Functional Fecal Incontinence 435

parents that treatment is often long-lasting and increased to 90% in patients with FNRFI, whereas
that progress is often irregular and marked by the percentage remained at 70% in children with
periods of improvement alternating with deterio- constipation [23, 58].
ration. Not surprisingly, FNRFI patients do not
benefit from laxatives. Van Ginkel and colleagues
showed that indeed laxatives soften stool and Conclusions
have a positive effect on gastrointestinal motility,
but they subsequently lead to an increase of urge Fecal incontinence is a common and frustrating
to defecate, which finally results in an increase in symptom in children and requires much effort
the number of fecal incontinence episodes [21]. and patience from their parents. In the majority
In contrast, beneficial effects were reported with of patients a functional disorder, such as func-
the use of loperamide in a father and son with tional constipation or functional non-retentive
long-lasting fecal incontinence. These effects can fecal incontinence, is the underlying condition.
be explained by increasing the basal internal anal FNRFI as a separate clinical disorder is often not
sphincter pressure and by decreasing rectal con- recognized by medical professionals. This often
tractions [53]. A large randomized control is war- causes a delay in referral and frequently leads to
ranted confirming these observations. Biofeedback inadequate treatment, which negatively influences
training includes feedback about the voluntary long-term outcomes. Although 40% of these chil-
controlled muscles such as the external anal dren have behavior scores within the clinical
sphincter, the muscularis puborectalis, and pelvic range, children with FNRFI can be characterized
floor and aims to enhance rectal sensation. After as having only mild psychiatric problems, sug-
a training session, which lasts approximately gesting that these children should be treated pri-
25 min, the therapist impresses upon the children marily in a pediatric setting and not in a psychiatric
that they should immediately go to their home outpatient clinic. A thorough clinical history and
toilet the moment they feel the same sensation a physical examination are essential to discrimi-
that they learned during biofeedback training. nate between the different underlying entities. An
However, a randomized controlled trial compar- intensive, positive and long-lasting approach is
ing conventional therapy (dietary and toilet required for successful treatment of fecal inconti-
advice in combination with oral laxatives) with nence in children.
conventional therapy alone with 5 biofeedback
sessions in 71 children with FNRFI showed that
50% of children in each group was successfully References
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 Part VI
Treatments
 Drugs Acting on the Gut:
Prokinetics, Antispasmodics, 41
Laxatives

Aileen F. Har and Joseph M.B. Croffie

Introduction Prokinetic Agents

Disorders of gastrointestinal motility result from Available prokinetic medications generally fall
abnormal contractions of the smooth muscles of under three groups of drugs: dopamine receptor
the gastrointestinal tract. This may result in diar- antagonists, motilin receptor agonists, and 5-hy-
rhea and bloating or constipation with or without droxytryptamine-4 (5HT4) receptor agonists.
accompanying abdominal pain. Drugs that act on
the gastrointestinal tract may be categorized into
three groups: (1) agents that enhance smooth Dopamine-2 (D2) Receptor Antagonists
muscle contractions, referred to as prokinetic
agents; (2) agents that inhibit contractions, which Domperidone
may be agents that retard normal peristalsis Domperidone is a peripheral dopamine-2 (D2)
referred to as antimotility agents (opiates and receptor antagonist that is used to treat gastroe-
opiate receptor agonists) or agents that reduce sophageal reflux, gastroparesis, functional dys-
abnormally elevated gastrointestinal smooth pepsia, nausea, and vomiting. While it is available
muscle tone, referred to as antispasmodics (anti- in over 50 countries worldwide, it is only avail-
cholinergics, direct smooth muscle relaxers, and able in the USA as an investigational drug. D2
calcium channel blockers); (3) agents that act to receptors are located both within the brain and in
promote evacuation of stool, referred to as laxa- the peripheral nervous system, however since
tives. This chapter discusses prokinetics, antimo- domperidone has poor penetration of the blood–
tility agents, and antispasmodics, as well as brain barrier, most of its effects are derived from
laxatives commonly used in clinical practice. peripheral receptors. Domperidone has the abil-
ity to cross the placenta and small amounts are
excreted in breast milk (2 ng/mL when dosed at
10 mg PO TID) [1]. It is rapidly metabolized in
the liver and has a half-life of 7.5 h [2, 3]. In the
gastrointestinal tract, D2 receptor stimulation
leads to inhibition of gastric motility, therefore
A.F. Har, M.B., B.Ch • J.M.B. Croffie, M.D., M.P.H. (*) D2 receptor antagonists decrease the symptoms
Division of Gastroenterology, Pediatrics Department,
of bloating, premature satiety, nausea, and vomit-
James Whitcomb Riley Hospital for Children,
702 Barnhill Dr, ROC 4210, Indianapolis, IN 46202, USA ing by accelerating gastric emptying, increasing
e-mail: [email protected] antroduodenal contractions, and promoting

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 441

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_41, © Springer Science+Business Media New York 2013
442 A.F. Har and J.M.B. Crof fie

esophageal motility [4]. Domperidone also exerts Due to poor CNS penetration, domperidone
an antiemetic effect on the chemoreceptor trigger does not have the neurologic side effects seen
zone, which is not protected by the blood–brain with metoclopramide, which is also a D2 recep-
barrier. One of the side effects of domperidone is tor antagonist. Domperidone is a CYP3A4 inhib-
hyperprolactinemia and it has been used off-label itor and should be avoided in combination with
to increase milk production for mothers of pre- other CYP3A4 inhibitors. There is the potential
term infants. for prolongation of the QT interval leading to
Safety and efficacy has not been adequately arrhythmias as it acts similar to class III antiar-
established for the pediatric population. In chil- rhythmic agents. Arrhythmia and sudden cardiac
dren admitted to the hospital for vomiting, com- death have been associated with patients given
pared to placebo and metaclopramide (10 mg) the intravenous domperidone in the setting of
symptoms of nausea and vomiting were hypokalemia and as a result the IV formulation is
significantly lower using domperidone (30 mg), no longer available [17, 18]. Risk of cardiac
however this study was conducted for a 24 h period events associated with oral domperidone use
only [5]. Using domperidone to treat gastroesoph- compared to PPI use and nonuse of either medi-
ageal reflux in children, a double-blind placebo- cation was evaluated in a large-scale nested case–
controlled trial was done on 17 patients [6]; after 4 control study [19]. 83,212 patients were exposed
weeks of therapy there was a significant decrease to oral domperidone, PPI, or both and within this
in the number of measured postprandial reflux epi- group there were 49 confirmed cases of serious
sodes but no decrease in reported symptoms. The ventricular arrhythmia and 1,559 confirmed cases
most commonly reported adverse event was diar- of sudden cardiac death. Up to four controls were
rhea. Two systematic reviews of pediatric GERD matched to each case and the adjusted odds ratio
treatments did not recommend the use of domperi- for serious ventricular arrhythmia and sudden
done in this patient population due to lack of data cardiac death with current use of domperidone
showing its efficacy [7, 8]. Oral domperidone in was 1.59 (95% CI: 1.28–1.98) compared to non-
neonates is associated with prolonged QTc inter- use of PPI and 1.44 (95% CI: 1.12–1.86) com-
val in patients ³32 weeks of gestation [9]. Mean pared to current use of PPI. Past use of
QTc prolongation was 14 ms with increasing ges- domperidone was not associated with increased
tational age and serum potassium at the upper limit risk of cardiac events. Risk may also be increased
of normal being independent risk factors. in patients older than 60 years, males, and those
A systematic review of qualified studies in without diabetes.
adults found that approximately 64% of studies Domperidone is available in oral tablet, oral
showed that domperidone was effective in improv- suspension, and rectal formulations. The recom-
ing symptoms of diabetic gastroparesis and 60% mended dosing is 10–20 mg two to four times
showed efficacy in improving gastric emptying daily 15–30 min before meals. Pediatric dosing is
[10]. In cases of GERD without evidence of gas- 0.3 mg/kg/dose two to four times daily, not
tric dysmotility, domperidone does not provide exceeding adult dose. Tablets may be crushed
increased benefit to adult patients in comparison to and given through gastrostomy, nasogastric, or
acid suppression alone [11]. For adult treatment of jejunostomy tubes.
functional dyspepsia, a meta-analysis revealed that
there was significant improvement in the patient’s Metoclopramide
global assessment with an OR of 7 (95% CI Metoclopramide is a dopamine (D2) receptor
3.6–16), however there was not enough data to antagonist that stimulates the stomach and duode-
support measured improvement in gastric empty- num by causing efferent myenteric cholinergic
ing [12]. Patients with postoperative nausea as neurons to release acetylcholine. There is also an
well as nausea from cytotoxic medications have increase in the lower esophageal sphincter tone
improvement of their symptoms compared to pla- [20, 21]. Metoclopramide’s antiemetic properties
cebo; however domperidone was given in the IV are due to its effects on the central nervous system
form which is no longer available [13–16]. D2 receptors in the chemoreceptor trigger zone.
41 Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives 443

However, due to its ability to cross the blood–brain the small intestine from the enterochromaffin
barrier it also has the potential to cause acute cells [30]. The receptors for motilin are found
extrapyramidal reactions [22, 23] and tardive dys- mainly in the smooth muscle and cholinergic
kinesia with long-term or high-dose use [24, 25]. neurons of the stomach antrum and proximal
Metoclopramide is used to treat gastroesophageal duodenum [31]. The effect of motilin pertains
reflux, chemotherapy-induced nausea, postopera- to stimulation of phase 3 MMCs in the inter-
tive nausea and vomiting, and gastroparesis. digestive state [31]. Janssens et al. first studied
Evidence for use in pediatric gastroesophageal the effect of erythromycin on gastric motility
reflux is conflicting as some studies show that in 10 adult diabetic patients with gastroparesis
there is no significant improvement in symptoms in 1990 [32]. Compared with placebo, an IV
and esophageal pH measurements compared to dose of 200 mg significantly improved gastric
placebo, while others show significant improve- emptying from a 120 min mean retention of
ment [26, 27]. Metoclopramide is used frequently 63 ± 9–4 ± 1%. This preliminary study also
to treat postoperative nausea and vomiting, and in showed an improvement in gastric emptying in
the setting of strabismus surgery where, a review the same 10 patients after 4 weeks of 250 mg,
determined that there was significant improvement PO, TID, but to a lesser degree.
in symptoms for the early postoperative period Erythromycin may be given through both oral
compared to that of placebo [28]. and intravenous routes. Adult dosing ranges from
Metoclopramide is available in the PO, SC, IM, 50 to 250 mg, three or four times a day and pedi-
IV forms. The adult dose is 10 mg three to four atric dosing is typically 5 mg/kg/dose. Different
times daily. The pediatric dose is 0.4–0.8 mg/kg/ motor patterns are elicited from varying erythro-
day divided 4 times a day not to exceed adult dos- mycin dosages [33]. Low dose erythromycin
age. A black box warning issued by the United (1–3 mg/kg IV) stimulates the neural motilin
States Food and Drug Administration cautions that receptors leading to augmentation of phase 3
cumulative use greater than 12 weeks in duration, MMCs [33, 34]. A higher dose of the drug stimu-
increases risk of tardive dyskinesia, which may be lates the smooth muscle motilin receptors leading
irreversible. Extrapyramidal symptoms occur to sustained contractions in the antrum and
more commonly within 24–48 h of initiation of antroduodenal coordination [33–35]. Long-term
therapy and children are at increased risk espe- therapy appears to be safe; however, decreased
cially with higher dosing. Pseudoparkinsonism efficacy is seen after prolonged treatment due to
has also been reported and is usually reversible. downregulation of motilin receptors. There has
Other side effects include sedation and hyperpro- been no evidence that erythromycin has any pro-
lactinemia. The half life in children is around 4 h kinetic effect on the colon as shown by adminis-
with 85% being eliminated in the urine; therefore, tration of the drug during colonic manometry
dosing should be adjusted in cases of renal dys- studies [36, 37].
function. Metoclopramide does cross the placenta Commonly reported side effects include nau-
and is excreted in breast milk. Onset of action is sea, vomiting, and abdominal pain. There have
15–30 min after oral dosing and 1–3 min after been reports of erythromycin being associated
intravenous administration [29]. with serious cardiac arrhythmias and prolonged
QTc [38–40]. Erythromycin should not be used
concurrently with medications metabolized by
Motilin Agonists cytochrome P450 3A4 (CYP3A4) such as cisap-
ride, terfenadine, pimozide, or astemizole as it is a
Erythromycin CYP3A4 inhibitor. Caution must be used in young
Erythromycin is a macrolide antibiotic, and it infants as there is an eight- to tenfold increased
also acts as a motilin agonist and its primary risk of developing hypertrophic pyloric stenosis
prokinetic use is for the treatment of gastropa- in term or near-term infants when used within the
resis. Motilin is a peptide hormone secreted by first 2 weeks of life and when the treatment course
444 A.F. Har and J.M.B. Crof fie

is >14 days [41]. There is insufficient data in the it should be used with caution in asthmatics.
preterm infant population as to whether there is Bethanechol does produce other cholinergic
increased risk of pyloric stenosis and a recent effects including urinary frequency, miosis, lacri-
review did not show increased incidence for this mation, and flushing.
particular population for treatment of dysmotility
due to immaturity of the gastrointestinal tract Neostigmine
[42]. Erythromycin is excreted in breast milk at Neostigmine is a synthetic, reversible acetylcholin-
levels ranging from 50 to 100% of maternal serum esterase inhibitor. It is used in the treatment of
levels [43] and should be taken into consideration myasthenia gravis and for reversing nondepolariz-
when treating nursing mothers. ing muscle relaxants. Neostigmine has also been
used to treat patients with acute colonic pseudo-
obstruction (ACPO), known as Ogilvie’s Syndrome.
Cholinergics Its use as a promotility agent has not been well stud-
ied in pediatric patients. The first reported case of
Bethanechol successful treatment of a pediatric patient with
Bethanechol is a cholinergic medication, which ACPO was in a 4-year-old male with spastic quad-
acts as a muscarinic receptor agonist leading to riplegia who was 10 days postoperative for bilateral
stimulation of esophageal peristalsis and increased femoral varus derotational osteotomies and botuli-
antral contractility. It is also used to treat urinary num toxin injections of the gastrocnemius muscles
retention secondary to neurogenic bladder. It [53]. Neostigmine was administered intravenously
causes decreased episodes of esophageal reflux by at a total dose of 0.05 mg/kg over 5 h [53]. In a
increasing lower esophageal sphincter (LES) pres- group of 10 pediatric patients with hematologic
sure and increasing esophageal clearance [44–47]. malignancies who experienced ACPO, 8 responded
Bethanechol’s effect on the amplitude and dura- to doses of neostigmine at 0.01 mg/kg/dose admin-
tion of esophageal contractions are more pro- istered subcutaneously, given twice a day for no
nounced in the distal esophagus and there is less more than 5 doses [54]. One patient reported diplo-
effect on upper esophageal motility [48]. In pia and one reported abdominal pain [54]. In another
patients with normal lower esophageal sphincter case report, a 9-year-old boy with cerebellar
tone and normal esophageal motility, it is ques- medulloblastoma, on chemotherapy, was success-
tionable if bethanechol is useful in the treatment of fully treated for ACPO with the same subcutaneous
uncomplicated gastroesophageal reflux and acid dosage after 3 injections [55]. In a third case report,
suppression may better serve this population [49, a 3-year-old girl with sickle cell disease with acute
50]. Patients with known esophageal dysmotility colonic pseudo-obstruction had resolution after 2
and abnormal LES tone, such as those post-trache- doses of neostigmine at 10 mcg/kg [56]. The patient
oesophageal fistula or esophageal atresia repair, was in vaso-occlusive crisis and had a colon mea-
may benefit from bethanechol [51]. It improves suring 6.5 cm in diameter and no mechanical
smooth muscle function in patients with ineffec- obstruction found on gastrograffin enema. She
tive esophageal motility documented by esopha- started passing stool within 6 h of neostigmine
geal manometry [52]. injection.
Bethanechol is available by oral and subcuta-
neous administration only and the onset of action
is 30–90 min. It should not be used in combina- 5-Hydroxytryptamine-4 Receptor
tion with anticholinesterase inhibitors. The Agonists
mechanism of metabolism and excretion is
unclear. Pediatric dosing is 0.1–0.2 mg/kg/dose Cisapride
before meals up to four times a day and the adult Cisapride is a 5HT4 receptor agonist which acts
dose is 10–50 mg two to four times a day. Side on the myenteric plexus of the bowel wall to
effects to note include bronchial constriction and stimulate smooth muscle contraction by release
41 Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives 445

of acetylcholine. 5HT4 receptors are found ever in many of these cases the medication was
throughout the gastrointestinal tract and stimula- dosed above the recommended dosing and some
tion causes increased peristalsis as well as intralu- were taking a macrolide antibiotic concurrently
menal fluid secretion. Stimulation of the stomach [71–75]. Arrhythmias have also been reported
smooth muscle leads to accelerated gastric emp- ranging from notched t waves to torsades de
tying. Amplitude of esophageal peristalsis as well points [71, 74, 76]. In a multicenter, double-blind
as resting lower esophageal sphincter tone is placebo-controlled trial of 49 children (age
increased [57]. Cisapride also decreases mouth to 6 months–4 years), however, a dose of 0.2 mg/kg
cecum time and colonic transit time [58]. given three times a day in patients without car-
While cisapride has never been approved for diac risk factors, for a treatment duration of at
children under the age of 12, it has historically least 6 weeks, did not show a statistically
been used extensively in this population. The con- significant increase in QTc interval and no sub-
sensus statements issued by NASPGHAN and jects experienced cardiac events [62].
ESPGHAN in 2000 states that cisapride is recom- Cisapride is metabolized in the liver by cyto-
mended for pediatric GERD when non-pharmaco- chrome P450 into norcisapride. It is eliminated in
logic treatment fails, but that the medication does urine and feces and its half-life is 7–10 h. Adult
require close monitoring, and specific precautions dosing should start at 10 mg PO two to four times
should be taken [59, 60]. However, more recently a day 15 min before meals; dose may be increased
the 2010 Cochrane Review did not show any dif- to 20 mg for efficacy. Pediatric dosing is 0.8 mg/
ference in symptom improvement or weight gain kg/day divided into 3–4 doses and not exceeding
when cisapride is compared to placebo [61]. Nine adult dose. 50% of the recommended dose should
studies comparing cisapride with placebo or no be started in the case of renal or hepatic failure. It
treatment, that met inclusion criteria, were included is contraindicated in combination with macrolide
in the meta-analysis [62–69]. The authors reviewed antibiotics, azole antifungals, and any drug that
five studies comparing results of esophageal pH prolongs the QT interval. It should be avoided
probe in patients being treated with cisapride vs. while CYP3A4 inhibitors are being used. Also
placebo and while there was improvement in the grapefruit juice should be avoided as it can increase
reflux index, there was no significant improvement cisapride serum concentrations. Caution must be
in the number of reflux episodes and episodes last- taken in infants who are breastfed as mothers may
ing longer than 5 min. Histologic examination of excrete medications in their breast milk that are
the esophagus was performed in three studies and contraindicated while using cisapride. Patients
in 2 (n − 6, n = 20) studies there was no statistical with known history of prolonged QTc should not
difference between cisapride and placebo [63, 67], be prescribed cisapride and patients with other
however 1 study (n = 17) did have histologic known arrhythmias need careful monitoring.
improvement from baseline. Further large-scale Electrolyte imbalance, especially hypokalemia,
studies are needed to assess the utility of cisapride increases the risk of serious cardiac side effects.
for GERD, though due to limited access, it is
unlikely this information will be obtained. Tegaserod
Although cisapride may be efficacious in treating Tegaserod is a 5HT4 receptor partial agonist. It
constipation, it is not recommended for treatment was previously approved for treatment of females
of standard constipation as the risks do not out- £55 years of age with constipation-predominant
weigh the benefits [70]. IBS or for chronic idiopathic constipation; how-
Availability of cisapride is restricted due to ever, it has subsequently been withdrawn from
risk of prolonged QTc interval and serious car- the US market due to an increased risk of cardio-
diac arrhythmias and it is only available in most vascular events. In an open label study, 22 adult
countries through limited-access programs. patients with symptoms of upper intestinal dys-
Multiple studies have shown increase in QTc motility underwent a 24 h antrodoudenal motility
interval in neonates, infants and children, how- study comparing the effects of tegaserod (12 mg
446 A.F. Har and J.M.B. Crof fie

PO) and erythromycin (125 mg IV) [77]. Both Use of prucalopride has mostly been in adult
medications showed significantly increased patients with chronic constipation. No pediatric
motility in the antrum, duodenum, and jejunum. studies have been published. Evaluation of pruca-
There were differences in the timing and where lopride in healthy volunteers showed accelerated
the two medications exerted their prokinetic orocecal transit, colonic transit, and total gastro-
effects—tegaserod had higher motor responses in intestinal transit time [83–85]. Treatment of
the duodenum and jejunum, which occurred patients with chronic constipation showed simi-
2–3 h after administration, whereas erythromycin lar improvements in transit times [86–89] and
had stronger motor effects on the antrum that significant increases in spontaneous complete
occurred within 30 min. Both tegaserod and bowel movements, stool consistency, urge to def-
erythromycin induced phase III migrating motor ecate, and quality of life compared to placebo
complexes (MMCs) in 55 and 36% of patients, [86, 88–92]. No significant increase in QTc inter-
respectively. val has been reported and the most common com-
While tegaserod was never approved for pedi- plaints have been abdominal pain, abdominal
atric use, it was widely used off label in many distension, diarrhea, nausea, flatulence, back
practices. A report on a single center’s experi- pain, headache, and dizziness [89–91, 93].
ence in pediatric patients reviewed 72 patients Prucalopride is approved in Europe for use in
with a median age of 10 (1.1–18.3) [78]; most of women with chronic constipation that is not
these children were treated for functional consti- relieved by laxatives. Recommended adult dose
pation and the mean follow-up time was 11.3 is 2 mg, PO, daily. The half life is 24–30 h, it is
months (2.3–45.2). Patients reported a statisti- minimally metabolized, and excreted mainly by
cally significant improvement in bowel frequency the kidneys [94]. Dosing for geriatrics and
and fecal continence. The most common adverse patients with severe renal or hepatic dysfunction
events were diarrhea (20%), abdominal pain should start at 50% of the recommended dose.
(8%), and headache (4%). No cardiovascular
events were reported. Velusetrag (TD-5108)
Adult dosing is 6 mg, PO, BID before meals Velusetrag is a highly selective 5HT4 receptor
and the tablets come in 2 and 6 mg forms. agonist. A phase 2 study has investigated the
Bioavailability is 11% and decreased by up to effect of velusetrag on colonic transit, colonic
65% when taken with food [79, 80]. It is metab- filling and emptying, and gastric emptying in
olized in the liver and 66% is excreted unchanged healthy volunteers and patients with chronic
in stool and 33% as metabolites in urine. Use is constipation [95]. In this double-blind placebo-
contraindicated in severe hepatic or renal impair- controlled study, healthy subjects were given 5,
ment. Adverse reactions include diarrhea, 15, 30, and 50 mg of Velusetrag or placebo.
abdominal pain, nausea, flatulence, headache, Gastric emptying was not affected after a single
and back pain. dose, however there was a significant increase in
emptying after 6 days of consecutive treatment
Prucalopride for the 15, 30, and 50 mg dosing. Small bowel
Prucalopride is a highly selective, high affinity transit as measured by colonic filling at 6 h was
5-HT4 receptor agonist, which increases colonic significantly increased after a single dose at 30
motility by stimulating serotonin release leading and 50 mg, but there was no statistical
to giant migrating contractions [81]. Gastro- significance after multiple day dosing. Colonic
pyloro-duodenal motility as well as gastric emp- transit as measured by t1/2 of ascending colon
tying is also enhanced in the canine model [82]. emptying, and colonic geometric center at 24 h
Prucalopride is structurally different from previ- was increased for the 30 and 50 mg doses after a
ously available 5-HT4 receptor agonist and due to single dose; however, there was no significant
its selectivity; the cardiac side effects seen with increase in colonic transit compared to placebo
cisapride and tegaserod have not been reported. after multiple doses. Patients with chronic
41 Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives 447

constipation were age- and sex-matched to the measured by hydrogen breath testing and had
control group and given a single oral dose of reported decrease in bloating, nausea, vomiting,
15 mg. There was no significant difference in and abdominal pain [99]. A single case report
pharmacokinetics between the control and con- described a 12-year-old girl with chronic idio-
stipation groups. The two study groups reported pathic pseudo obstruction who was successfully
similar stool consistency, time to first bowel treated using 50 mcg of subcutaneous octreotide
movement, and number of bowel movements in daily [100].
the 24 h after administration. There was an
increase in heart rate by 10 bpm at 4 h after Methylnaltrexone
ingestion, but no change in blood pressure or Methylnaltrexone is a peripheral m-opiate antag-
EKG tracings. Subjects reported nausea, diar- onist that has been used to treat patients in the
rhea, and headache as the most common adverse setting of opiate-induced constipation [101]. It is
events, which was dose related. A single subject a quaternary ammonium derivative of naltrexone
on 30 mg experienced palpitations and one which, due to its low polarity, has reduced pene-
patient on 50 mg developed asymptomatic junc- tration of the blood–brain barrier [102, 103].
tional escape rhythm. m-Receptors are found throughout the gastroin-
testinal tract [106] and their stimulation leads to
delayed transit and non-propulsive activity [107].
Other Prokinetic Agents Decreased intestinal secretion as well as increased
absorption in the small bowel and colon also con-
Octreotide tributes to the constipating effect of opioid medi-
Octreotide is a synthetic cyclic tetradecapeptide cations [108]. Opioid-induced constipation is
that is a long acting somatostatin analogue used reversed, without inducing withdrawal symptoms
to treat many disease processes including gastro- or decreasing analgesic effect, by methylnaltrex-
intestinal bleeding, pancreatitis, secretory diar- one [101, 104, 105].
rhea, chylous leakage, hypoglycemia, and In the treatment of adult patients receiving
gastrointestinal dysmotility. For the purposes of chronic opioids for nonmalignant pain doses of
this section, only the use of octreotide in gastro- 12 mg every day and every other day have been
intestinal dysmotility will be discussed. used; both regimens significantly decreased the
Somatostatin, studied in patients with normal time to rescue-free bowel movement as well as
gastrointestinal motility as well as the canine increased the number of weekly bowel move-
model, causes inhibition of gastric activity and ments compared to placebo [109]. In the treat-
stimulation of small intestinal phase 3 migrating ment of adults with advanced illness and
motor complexes (MMCs) beginning in the duo- opioid-induced constipation using doses of 0.15
denum [96, 97]. It is commercially available for and 0.3 mg/kg, subjects had significantly
SC, IV, and IM use. Subcutaneous absorption is increased rates of rescue-free bowel movements
rapid and IM is released slowly in a depot formu- within 4 h of administration compared to placebo
lation. Metabolism is through the liver with 32% [104, 105].
unmetabolized excretion through the urine [98]. A single case report of the use of methylnal-
Half-life is 1.7–1.9 h, but it is 3.7 h in patients trexone to treat postoperative ileus in a neonate
with cirrhosis and 3.1 h in patients with renal demonstrated success in restoring bowel motility
impairment [79]. 15 min after a 0.15 mg/kg IV infusion [110]. The
Octreotide has been studied in adult patients infant had undergone two separate exploratory
with scleroderma and pseudo obstruction; subcu- laparoscopies for necrotizing enterocolitis and
taneous octreotide increased the frequency of was on a fentanyl drip for pain control. Five doses
intestinal migrating complexes in this group of were given in total on POD 8–12.
patients [99]. After 3 weeks of treatment patients Methylnaltrexone is available in subcutane-
had a reduction in bacterial overgrowth as ous form with onset of action between 30 min
448 A.F. Har and J.M.B. Crof fie

to 4 h and a half life of 8–9 h [109, 111, 112]. Diphenoxylate

It is administered every other day with dosing
based on body weight. Excretion is through Diphenoxylate is a synthetic opioid receptor
both urine and feces, primarily as unchanged agonist related to meperidine and fentanyl [113].
drug [112]. Side effects include flatulence, Like loperamide it inhibits gastrointestinal pro-
abdominal pain, nausea, dizziness, excessive pulsion and has been shown to be effective in
sweating, and diarrhea. Intestinal perforation treating acute diarrhea. Unlike loperamide how-
has been reported with use and it should be ever, diphenoxylate crosses the blood–brain bar-
used with caution in patients with diminished rier and therefore can be habit forming. Atropine
gastrointestinal wall integrity. Patients with is reportedly added to the preparation to reduce
severe renal impairment (creatinine clearance the abuse potential [118, 119]. Side effects
<30 mL/min) should be dosed at 50% of rec- include sedation, euphoria, lethargy, confusion,
ommended dosing Table 41.1. respiratory depression, restlessness, hyper-
thermia, tachycardia, nausea, vomiting, paralytic
ileus, and toxic megacolon. Like loperamide,
Antimotility Agents diphenoxylate should not be used in the setting
of acute diarrhea caused by enteric bacterial
The commonly used agents are the opioid recep- pathogens and acute ulcerative colitis because of
tor agonists loperamide and diphenoxylate. potential to precipitate toxic megacolon.
Diphenoxylate should not be used in children
less than 2 years old; opiate and atropine toxicity
Loperamide from diphenoxylate-atropine overdosage leading
to death has been reported in children less than 2
Loperamide is a synthetic opioid receptor ago- years old [120].
nist acting on the m opioid receptors in the
myenteric plexus of the large intestine [113]. It
is a peripherally acting agent and does not cross Antispasmodics
the blood–brain barrier. It has been shown in
meta-analysis of randomized controlled trials to Antimuscarinics
be safe and effective in treating acute diarrhea in
adults and children [114, 115]. In children seri- Antimuscarinics are a class of drugs that work by
ous side effects were reported more often in blocking the action of acetylcholine at postgan-
those younger than 3 years old [115]. Loperamide glionic parasympathetic receptors in the intesti-
has also been shown in clinical trials to be effec- nal smooth muscle. They are the most frequently
tive in reducing stool frequency and urgency in prescribed antispasmodics in the USA. Meta-
patients with diarrhea-predominant irritable analysis of placebo-controlled trials of drugs
bowel syndrome [116]. It is available in tablet used to treat irritable bowel syndrome confirm
and liquid suspension. The side effects include the therapeutic benefit of this class of drugs in
abdominal pain and bloating, constipation, seda- adults, although many of the trials were report-
tion, dry mouth and, rarely, paralytic ileus. This edly of low quality [121]. Similar studies in chil-
medication should not be used in the setting of dren are lacking. The antimuscarinics currently
acute diarrhea caused by enteric bacterial patho- available in clinical practice are derivatives of
gens such as salmonella and Shigella and in belladonna, a naturally occurring plant alkaloid,
acute ulcerative colitis as it can precipitate toxic and include drugs such as hyoscyamine, dicyclo-
megacolon. It should also not be used in chil- mine, cimetropium, scopolamine, clidinium, and
dren less than 2 years old; indeed deaths have trimebutine.
been reported in young children given loper- Hyoscyamine is the levorotatory Isomer of
amide to treat acute diarrhea [117]. atropine. It is available as oral tablets, extended
 41

Table 41.1 Prokinetics

Medication Dosing Notes
Domperidone 0.3 mg/kg/dose two to four times dailya (PO, PR) Adult dose 10–20 mg two to four times daily
Metoclopramide 0.4–0.8 mg/kg/day divided four times dailya (PO, SC, IM, IV) Adult dose 10 mg three to four times daily
Erythromycin 1–3 mg/kg/dose ( IV); 5 mg/kg/dose (PO) up to four times a day Adult dose 50–250 mg three or four times a day
Bethanechol 0.1–0.2 mg/kg/dose up to four times a daya (PO,SC) Adult dose 10–50 mg 2–4 times a day
Neostigmine 0.01 mg/kg/dose (IV, SC) Oral formulation is available, but absorption is poor and not studied
for treatment of acute colonic pseudo-obstruction
Cisapride 0.8 mg/kg/day divided three to four times dailya (PO) Adult dose 10–20 mg two to four times a day
Tegaserod Not determined in children Adult dose 6 mg PO twice a day
Prucalopride Not determined in children Adult dose 2 mg, PO, daily
Octreotide 1–10 mcg/kg every 12 h (SC, IV, IM) Adult dose 50 mcg up to three times a day. IM route is delayed
Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

release
Methylnaltrexone <38 kg—0.15 mg/kg/dose Round to nearest 0.1 mL
38 to £62 kg—8 mg Administered every other day
62–114 kg—12 mg
>114 kg—0.15 mg/kg/dose
a
Not to exceed maximum adult dose
449
450 A.F. Har and J.M.B. Crof fie

release tablets, sublingual tablets, oral solutions, bowel syndrome, although there are no random-
elixirs, and drops. It has been used to treat symp- ized controlled trials showing its safety or efficacy
toms of colic and irritable bowel syndrome [122, in treating this condition.
123]. Although commonly used, there are no ran- Trimebutine is an antimuscarinic drug which
domized controlled trials establishing the safety also has some opioid agonistic effects; it acceler-
and efficacy of this medication in treating gastro- ates gastric emptying and induces premature
intestinal disorders, particularly in children. Anti- phase III of the migrating motor complex in the
cholinergic poisoning has been reported in some small bowel, but it inhibits colonic motility
colicky infants treated with hyoscyamine [122]. through its antimuscarinic activity [132]. This
Dicyclomine is an m1-specific muscarinic drug has been found to be efficacious in the treat-
antagonist which has been used to treat symp- ment of recurrent abdominal pain and irritable
toms of colic, irritable bowel syndrome and bowel syndrome in children and adults. It was
diverticulitis. It has been shown in many double- found in a meta-analysis study to be effective in
blind studies to be effective in the treatment of the treatment of irritable bowel syndrome in
infantile colic [124, 125]; however, 5% of treated adults [129].
infants had side effects [126]. Although com- Common side effects of antimuscarinic agents
monly used to treat irritable bowel syndrome, include dry mouth, urinary retention, blurred
there are no randomized controlled trials estab- vision, constipation, sedation, and palpitations.
lishing the safety and efficacy of the drug in treat-
ing irritable bowel syndrome in children. It has
been shown in only one study to reduce symp- Direct Smooth Muscle Relaxers
toms of irritable bowel syndrome including pain
and fecal urgency in adults [127]. Mebeverine and related drugs including alverine,
Scopolamine (hyoscine) is another m1-specific otilonium, and drotaverine [133–135] are not
muscarinic antagonist which has been used to available in the USA but are available in many
treat various gastrointestinal disorders including countries. They are antispasmodics which are
irritable bowel syndrome and motion sickness believed to be mostly musculotropic. These drugs
[128]. Methscopolamine and butylscopolamine exert their antispasmodic effect by acting directly
are derivatives of scopolamine which have also at the cellular level of the gastrointestinal smooth
been used to treat irritable bowel syndrome. muscle. They have been used to treat irritable
Scopolamine was found in a meta-analysis study bowel syndrome. A systematic review of several
to offer benefit in the treatment of irritable bowel studies in adults found these agents to be
syndrome in adults [129] however, there are no efficacious in improving the symptoms of abdom-
published randomized controlled studies estab- inal pain in adult patients with irritable bowel
lishing its effectiveness in treating this condition syndrome [136, 137].
in children.
Cimetropium is a synthetic derivative of sco-
polamine which has both antimuscarinic and OnabotulinumtoxinA (Botox®)
direct myolytic activity [130]. It has been shown
to be more effective than placebo in reducing the Onabotulinumtoxin A is the drug name for botu-
duration of crying in children with infantile colic linum toxin A—it is used commonly in cosmetic
[130] and a double-blind placebo-controlled procedures, but is also used to treat strabismus,
study in adults showed that it is effective in reliev- blepharospasm, muscle spasticity, cervical dysto-
ing pain in patients with irritable bowel syndrome nia, and hyperhidrosis. It has been used off-label
[131]. to treat esophageal achalasia, gastroparesis, anal
Clidinium is a rarely used muscarinic antago- fissure, and anal achalasia. Botulinum toxin A is
nist which is marketed in combination with one of seven serotypes of botulinum neurotoxins
chlordiazepoxide as a treatment for irritable produced by the aneorobic bacteria Clostridium
41 Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives 451

Botulinum [138]. The neurotoxin targets the neu- than one session. Complications included pain
romuscular junction and blocks acetylcholine following the injection and fecal incontinence.
release causing flaccid paralysis. Botox injections have also been used to treat
In a single center report, postoperative follow- chronic anal fissures. At one center, 13 children
up of adult patients treated for esophageal acha- (age 1–10 years) were given Botox injections in
lasia revealed recurrent or persistent symptoms in the external anal sphincter under light sedation to
71.4% (n = 7) of patients treated with endoscopic treat chronic anal fissures [151]; patients under
botulinum injection [139] compared to recurrent/ age 2 were injected with 1.25 U ×2 doses and
persistent symptoms in 50% of patients who patients over age 2 were injected with 2.5 U × 2
underwent endoscopic balloon dilation (n = 30) doses. 11 of the 13 patients had resolution of their
and recurrent/persistent symptoms in 30% of symptoms within 1 week of treatment and no
patients who underwent surgical myotomy adverse events were reported. In a systematic
(n = 20). Thus in this report, patients who under- review of nonsurgical therapies for chronic anal
went surgical myotomy had the most reliable out- fissures, Botox was found to be equivalent to
come. Treatment with Botox injections has an topical nitroglycerin in efficacy; however, nitro-
initial success rate of 70%, however the effect glycerin itself was only marginally better than
usually lasts 6–12 months and repeated injections placebo [152].
are required [140]. There have been conflicting There is a paucity of data on the usefulness of
reports on whether prior injection with Botox intrapyloric injections of Botox for treatment of
decreases the effectiveness of a later Heller myo- gastroparesis. One randomized controlled cross-
tomy or whether it impacts the ease of the proce- over study of 23 adult patients with gastroparesis
dure [141–144]. A single center reviewed their showed no benefit of Botox injection (25 U/quad-
experience with pediatric patients diagnosed with rant; 100 U total) compared to placebo [153] and
esophageal achalasia; out of their 33 patients, 7 no pediatric studies have been published.
were treated with Botox [145]. They used 100 U
of Botox per session with 25 U injected into each
quadrant of the lower esophageal sphincter. Six Topical Nitrates
of the seven required 2–3 repeated injections and
the longest duration of symptom-free period Topical nitrates have been used to treat painful
postinjection was 10 months. Four eventually had anal conditions. There are three formulations
a Heller myotomy. One case report also reported available—mono, di, and trinitrates—all act to
response for 8 months postinjection in an 11-year- relax smooth muscle by stimulating production
old boy [146]. A single case report of the use of of cGMP, irrespective of autonomic innervations
Botox to treat a diabetic, obese adult with esoph- [154]. The only topical formulation available in
ageal achalasia was complicated by mediastinitis the USA is nitroglycerin, which is a trinitrate. Its
[147]. The development of a sinus tract between most common use in gastroenterology is for treat-
the esophagus and gastric fundus has been ment of chronic anal fissures.
reported in a 10-year-old girl following her fifth In children with anal fissures, 0.2% glyceryl
Botox injection for esophageal achalasia [148]. trinitrate (GTN) applied topically to the distal
In two studies, pediatric patients treated with anal canal twice a day resulted in improvement of
Botox injections for anal outlet obstruction (post- symptoms by day 10 of treatment and higher
surgical repair of Hirschsprung Disease and pri- rates of complete resolution after 8 weeks com-
mary internal anal sphincter achalasia) had pared to placebo and topical lidocaine [155, 156].
variable outcomes [149, 150]. The dosage used However, one study comparing GTN plus oral
was 3–6 U/kg/session to a maximum of 100 U. senna and lactulose with placebo plus oral senna
31–53% of patients had good long-term outcome and lactulose, found similar response rates, with
and 62–89% had initial clinical improvement 84% healing overall [157]. Concentrations of
after a single injection. About 75% required more 0.05 and 0.1% ointments were also found to be
452 A.F. Har and J.M.B. Crof fie

effective for fissure healing after 8 weeks of treat- include headaches, lightheadedness, and
ment [158]. Results at 8 weeks of treatment were constipation.
similar to results using a eutectic mixture of 5% Meta-analysis studies of controlled trials of
prilocaine and 5% lidocaine (EMLA) [156]. antispasmodics in the treatment of irritable bowel
Long-term treatment of chronic anal fissure in syndrome have found them to be superior to pla-
31 children using 0.2% GTN resulted in a 32% cebo, at least for the short term, in the manage-
relapse 1 year after treatment and no relapses for ment of irritable bowel syndrome in both adults
4 years following initial treatment in 68% [159]. and children [121, 129, 178, 179].
Glycerine trinitrate has also been used to treat
proctalgia fugax, which mainly occurs in patients
aged 30–60 years [160, 161]. Other Antispamodic Agents

Oral Nitrates have been used in adults to treat

Calcium Channel Blockers spastic disorders of the esophagus, although there
are no randomized controlled studies supporting
It has been suggested that calcium channel block- their effectiveness [167]. Sildenafil, a
ers may be effective in the treatment of some gas- Phosphodiesterase inhibitor, has been found in a
trointestinal motility disorders because of their double-blind placebo-controlled study to reduce
ability to relax smooth muscles. Nifedipine and lower esophageal sphincter pressure [167]. No
verapamil have been shown to inhibit sigmoid studies of nitrates or sildenafil for these purposes
colon myoelectric response to eating in healthy have been reported in children Table 41.2.
adult volunteers [162] and reduce internal anal
sphincter pressures in patients and controls with
high resting anal sphincter pressures [163]. Laxatives
Nifedipine has been used to treat disorders of
esophageal hyper motility such as nutcracker Laxatives can be divided into osmotic/lubricant
esophagus and achalasia in children and adults laxatives and stimulant laxatives (see Table 41.3).
[164–167]. Diltiazem has been used anecdotally First-line treatment for constipation starts with
to treat diffuse esophageal spasm in adolescents osmotic/lubricant laxatives followed by stimu-
[168]. Verapamil has anecdotally been used to lants for cases that are poorly responsive.
treat antral spasms in children [169]. Pinaverium
is a calcium channel blocker which acts selec-
tively on the gastrointestinal tract; it has been Osmotic and Lubricant Laxatives
found to reduce the duration of abdominal pain in
randomized, placebo-controlled studies of adult Lactulose
patients with irritable bowel syndrome [170, Lactulose (1-4-beta-galactosidofructose) is a
171]. Peppermint oil is believed to be a calcium semi-synthetic disaccharide created through the
channel blocker which has been found to relax isomerization of lactose [180]. Lactulose
the lower esophageal sphincter, and reduce increases osmotic load as well as decreases the
colonic spasms in patients undergoing colonos- stool pH thereby increasing colonic propulsion
copy [172, 173]. It has been found in double- [181]. It passes through the small intestine intact
blind randomized controlled studies to be without degradation by dissacharidases and is
effective in treating children and adults with irri- broken down by bacteria in the colon to produce
table bowel syndrome [174, 175] and in meta- lactic and acetic acid [182]. Systemic absorption
analysis studies of published trials, it was found is minimal with majority of excretion through the
to be effective in the treatment of both adults and stool and <3% excretion in urine. Formulations
children with irritable bowel syndrome [176, contain both lactose and galactose so use is con-
177]. Side effects of calcium channel blockers traindicated in patients with galactosemia. Onset
 41
Table 41.2 Antimotility and antispasmodic agents
Medication Dosing Notes
Loperamide Acute Diarrhea (first 24 h) Adult dose acute and chronic diarrhea—first dose 4 mg, then 2 mg
– 2–5 years (13–20 kg): 1 mg three times a day after each loose stool, maximum 16 mg daily
– 6–8 years (21–30 kg): 2 mg twice a day
– 9–12 years (>30 kg): 2 mg three times a day—After first 24 h–0.1 mg/
kg doses after each loose stool not exceeding initial dose
Chronic diarrhea—0.08–0.24 mg/kg/day divided 2–3 times a day,
maximum: 2 mg/dose(PO)
Diphenoxylate – 2–5 years—2 mg three times a day Adult dose 5 mg four times a day
– 5–8 years—2 mg four times a day
– 8–12 years—2 mg five times a day
(PO)
Hyoscyamine 2–12 years—0.0625–0.125 mg every 4 h as needed—maximum daily dose Adult dose—0.125–0.25 mg every 4 h as needed—maximum daily
0.75 mg (PO, SL) dose 1.5 mg (PO, SL)
Adult dose—0.25–0.5 mg every 4 h for 1–4 doses only (IV, IM)
Dicyclomine >6 months old—5 mg, three to four times a day Adult dose 20 mg, four times a day—may increase to 40 mg, four
Children—10 mg, three to four times a day times a day (PO)
(PO) Adult IM dose 20 mg, four times a day
Scopolamine Antiemetic Adult dose for antiemetic 0.3–0.65 mg/dose every 6–8 h (PO, IV,
– 6 mcg/kg/dose (maximum 0.3 mg per dose) every 6–8 h (PO, IV, SC) SC)
Adult dose and children >12 years—for motion sickness 10–20 mg
every 8 h as needed (PO)
Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives

Adult dose for transdermal patch—1 patch behind the ear every
72 h as needed
Trimebutine Children >12 years—100–200 mg three times a day (PO) Adult dose 100–200 mg three times a day (PO)
Mebeverine Children >10 years—100 mg three times a day (PO) Adult dose 100–135 mg three times a day (PO) OR 200 mg twice a
day (PO modified release)
Onabotulinumtoxin A Esophageal achalasia Adult gastroparesis
– 20–25 U into each quadrant (80–100 U total per treatment) – 25 U into each quadrant (100 U total per treatment)
Anal outlet obstruction
– 3–6 U/kg/session to a maximum of 100 U divided into 4 quadrants
Chronic anal fissure
1.25–2.5units ×2 per session
Glyceryl trinitrate (0.2%) Apply ointment to the distal anal canal twice a day
Nifedipine Adult dose 10–20 mg before meals (PO, SL)
453
454 A.F. Har and J.M.B. Crof fie

Table 41.3 Laxatives

Therapy Dosage
Osmotic agents
Lactulose – 1–3 mL/kg/day in divided doses
Magnesium citrate – May use divided doses
– <6 years—1–3 mL/kg/day
– 6–12 years—100–150 mL/day
– >12 years—150–300 mL/day
Magnesium hydroxide – May use divided doses
– 1–3 mL/kg/day of 400 mg/5 mL solution
Polyethylene glycol – 1 g/kg/day
Sorbitol – 1–3 mL/kg/day in divided doses
Lubricants
Mineral oil – 1–3 mL/kg/day
Stimulants
Bisacodyl – 3–12 years—5 mg/day
– >12 years—5–15 mg/day
Senna – 2–5 years—2.5–7.5 mL at bedtime
– 6–12 years—5–15 mL at bedtime
Lubiprostone (adult dosing only) – Chronic idiopathic constipation—24 mcg BID
– Female IBS with constipation—8 mcg BID
From Har AF, Croffie JM. Encopresis. Ped in Rev 2010;31(9):368–374. Reprinted with
permission from American Academy of Pediatrics

of action is 24–48 h and side effects include ance. When compared to PEG solution over a
cramping, abdominal distension, flatulence, diar- 12-month period, 95% of children using PEG
rhea, nausea, vomiting, and electrolyte imbal- were compliant vs. 65% using magnesium
ances. Long-term use is safe with few reported hydroxide [186].
adverse events [70].
Polyethylene Glycol
Magnesium Salts Polyethylene glycol (PEG) is a high molecular
Magnesium salts are available commercially as weight, non-soluble polymer that acts as an
magnesium citrate and magnesium hydroxide. osmotic laxative. Hydrogen bonds are formed
All magnesium salts promote bowel evacuation between PEG and water, which prevents reab-
by osmotic fluid retention. Absorption is 15–30% sorption of water in the colon. With increased
and excretion is in the urine. Use is contraindi- water retention, stool is thereby softened and its
cated in patients with renal failure and renal bulk is increased. The onset of action is 24–96 h;
insufficiency as hypermagnesemia is a significant excretion is 93% through feces with minimal sys-
risk. Caution should be used even in patients who temic absorption and a bioavailability of 0.2%
do not have renal dysfunction as excessive inges- [187]. Contraindications to PEG include hyper-
tion can lead to severe hypermagnesemia in oth- sensitivity, ileus, bowel perforation or obstruc-
erwise healthy children [183, 184]. Other side tion, and toxic megacolon.
effects include diarrhea, abdominal cramps, PEG is available with or without electrolytes
flatulence, hypotension, and respiratory depres- added. In general PEG with electrolytes is used
sion. There are few studies evaluating the efficacy for colonoscopy preparation or disimpaction.
of magnesium salts in treatment of constipation, PEG without electrolytes is more commonly used
however compared to a bulk laxative, it may pro- for daily management of chronic constipation,
duce more frequent bowel movements [185]. but has been used in children for colonoscopy
Palatability of magnesium may decrease compli- preparation as well [188, 189]. High-dose PEG
41 Drugs Acting on the Gut: Prokinetics, Antispasmodics, Laxatives 455

without electrolytes can be as successful as rectal are actively secreted, while sodium and potas-
enemas for disimpaction in the pediatric popula- sium are passively effluxed into the bowel.
tion [190] with highest success for doses of Sodium and chloride are then inhibited from
1–1.5 g/kg/day [191]. PEG is safe and well toler- reabsorption back into the enterocyte. Contraction
ated for long-term treatment of chronic constipa- of the colonic smooth muscle is caused by
tion with few noted side effects [186, 192–195]. increasing the myoelectrical activity through
direct irritation of the bowel wall [206, 207].
Sorbitol Systemic absorption is <5% with onset of action
Sorbitol is a polyalcoholic sugar and acts as a between 4 and 6 h for oral administration and
hyperosmotic laxative. Absorption is minimal 0.25–1 h for rectal administration [207, 208]. The
and it is metabolized in the liver mainly into fruc- small fraction that is absorbed is conjugated by
tose. There is a paucity of studies evaluating the the liver and excreted in urine. Most formulations
efficacy of sorbitol for treatment of constipation. are enteric coated and should not be administered
Compared to lactulose it has similar safety and within 1 h of antacids. Side effects include nau-
efficacy in the geriatric population [196]. sea, vomiting, diarrhea, abdominal cramping,
Excessive ingestion of sorbitol in non-constipated proctitis, and electrolyte imbalance.
pediatric patients is known to cause loose stool Bisacodyl and other stimulant laxatives should
and diarrhea [197, 198]. Side effects include diar- be used as second-line agents for patients who
rhea, nausea, vomiting, lactic acidosis, and elec- are refractory to osmotic/lubricant laxatives [70].
trolyte imbalances. There is no data on safety and efficacy of bisaco-
dyl for treatment of constipation, particularly in
Mineral Oil the pediatric population [209]; however, there is
Mineral oil is a lubricant laxative with minimal clear evidence that it does increase colonic transit
systemic absorption and primary elimination in and stimulates colonic motor activity [210–212].
the feces. It is a mixture of hydrocarbons derived Chronic and prolonged use of stimulant laxatives
from petroleum. The oil lubricates the colon, but may lead to loss of haustra and anatomic changes
it also decreases water reabsorption and softens in the colon, possibly due to muscular or neu-
the stool. It should not be used in infants and ronal injury [213, 214]; it is unclear, however, if
patients with swallowing dysfunction since there this is a true risk of long-term usage of bisacodyl
is a risk for lipid pneumonitis with aspiration [215].
[199–201]. Other adverse effects include diar-
rhea, nausea, vomiting, anal itching, and anal Senna
seepage. Chronic use could theoretically decrease The mechanism of action of senna as a stimulant
absorption of fat soluble vitamins; however, there laxative is unclear; however, it may increase pro-
is no published evidence to support this [202, duction of cyclic-AMP in the colon leading to
203]. One study showed a reduction in beta-caro- increased ion secretion and increased peristalsis,
tene levels after just 1 month of treatment [203]. by direct irritation of the colon [216]. Senna is
derived from the plant Senna alexandrina and has
been used for centuries. Absorption is minimal
Stimulant Laxatives and onset is 6–12 h after ingestion. Senna is metab-
olized in the liver and excreted through feces and
Bisacodyl urine. Reported adverse events include hepatitis,
Bisacodyl is a diphenolic laxative that stimulates hypertrophic osteoarthropathy, analgesic nephrop-
intestinal fluid secretion and motor activity. It athy, and melanosis coli, which is reversible. There
induces intestinal fluid secretion by direct action is poor evidence for development of cathartic
on the enterocyte, activating adenylate cyclase colon with long-term use of senna [217]. As with
and causing an increase in production of cyclic- other stimulant laxatives, it is a second-line agent
AMP [204, 205]. Chloride and bicarbonate ions and is used in constipated patients failing first-line
456 A.F. Har and J.M.B. Crof fie

treatment. Although it is commonly used, there is tance regulator causing secretion of chloride and
a paucity of studies evaluating its efficacy in treat- bicarbonate into the small intestinal lumen [223].
ment of constipation [209]. Visceral hypersensitivity is suppressed by cGMP
acting on submucosal afferent pain fibers to
Lubiprostone decrease nerve reactivity [224] and a decrease in
Lubiprostone is a prostone that acts locally on the abdominal pain compared to baseline and to pla-
gastrointestinal tract by activation of type-2 chlo- cebo has been reported [225]. Doses ranging
ride channels (CIC-2) [218]. It is approved for use from 75 to 600 mcg improved bowel habits in
in adults with chronic idiopathic constipation and men and women >18 years of age with IBS-C
females older than 18 years of age with constipa- [225]. In adult women with IBS-C, colonic tran-
tion-predominant irritable bowel syndrome. sit was improved over a 5-day treatment period
Prostones are bicyclic fatty acids derived from with 1,000 mcg of linaclotide [226]. For adult
prostaglandin E1 that do not significantly act on patients with chronic constipation, bowel move-
prostaglandin E or F receptors or cause smooth ment frequency, stool consistency, and straining
muscle contractions [219]. Activation of the chlo- as well as overall quality of life were improved
ride channels increases intestinal fluid chloride on trials of linaclotide [227, 228] (Table 41.3).
concentration and fluid secretion, leading to
increased stool passage without causing significant
change in serum electrolyte levels [218]. References
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 Gastric Electrical Stimulation
42
Carlo Di Lorenzo, Hayat Mousa,
and Steven Teich

ventions. In order to improve gastric emptying

Introduction and decrease nausea and vomiting, electrical
stimulation of the stomach began to be used in
It may be successfully argued that the pharmaco- human subjects in the 1990s [3, 4] and eventually
logical armamentarium available to the gastroen- led to the approval by the Food and Drug
terologist who specializes in the care of patients Administration of the Enterra™ Therapy System
with motility disorders has shrunk in the past sev- (Medtronic Inc., Minneapolis, MN) as a humani-
eral years. After the withdrawal from the market tarian device for drug-refractory gastroparesis
of cisapride, tegaserod, and alosetron, there are in 2000. Humanitarian Device Exemption
very few prokinetic drugs currently available, (HDE) is a terminology used for devices which
and their efficacy in treating severe motility provide treatment to uncommon conditions
disorders is modest at best. Surgery rarely pro- (<4,000 implantations/year) for which no less
vides significant symptom relief in patients with invasive, equally effective therapy is available.
generalized gut dysmotility. Thus, alternative Marketing of the system is allowed under
interventions have been actively explored. restricted conditions, and its use requires approval
Gastroparesis and severe dyspepsia represent two by Institutional Review Boards. Since that time,
conditions that affect quality of life, are associ- gastric electrical stimulation (GES) has been
ated with high medical cost [1, 2], and are often performed in hundreds of adults with gastropa-
refractory to dietary and pharmacological inter- resis and in few patients with more generalized
motility disorders. Use in pediatrics is more
recent, and there are probably <100 children who
C. Di Lorenzo, M.D. (*) have received GES placement so far.
Division of Pediatric Gastroenterology, Department of
Although it is now clear that GES improves
Pediatrics, Nationwide Children’s Hospital, The Ohio
State University, 700 Children’s Drive, Columbus, nausea and vomiting, the mechanism behind its
OH 43205, USA effects remains unclear. The low-energy electri-
e-mail: [email protected] cal stimulation provided by GES has not been
H. Mousa, M.D. shown to directly induce muscle contraction.
Division of Pediatric Gastroenterology, Hepatology Proposed mechanisms have included modulation
and Nutrition, Department of Pediatrics, Nationwide
of enteric or afferent neural activity that influences
Children Hospital, Ohio State University,
Columbus, OH, USA symptom perception, enhanced vagal activity,
acceleration of gastric emptying, alterations in
S. Teich, M.D.
Pediatric Surgery, Nationwide Children’s Hospital, CNS control mechanisms of nausea and vomit-
The Ohio State University, Columbus, OH, USA ing, and improved gastric accommodation [5].

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 465

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_42, © Springer Science+Business Media New York 2013
466 C. Di Lorenzo et al.

Fig. 42.1 Endoscopic pictures of temporary GES placement. The lead is screwed clockwise into the gastric mucosa
(a). Clips are placed endoscopically to anchor the lead to the mucosa between the gastric body and antrum (b)

There seems to be little correlation between the pacing lead so that the tip remains in position
changes in gastric emptying time or electrogas- with an extra length of approximately 10 cm left
trographic patterns and symptomatic improve- in the stomach. The endoscope is reinserted into
ment. Symptomatic improvement has been the stomach and an endoscopic clipping device
observed after GES therapy in patients with nor- is passed through the biopsy channel. Two to
mal baseline gastric emptying. GES does not four clips are applied to hold the lead in place,
appear to negatively impact adjacent organs, with at least one clip placed near the distal
likely because the stomach already contains natu- metallic part of the lead (Fig. 42.1b). The endo-
ral pacemakers. scope is again withdrawn and the lead is brought
out through the nares and connected to the
external GES device that is placed in a cardiac
Temporary Gastric Stimulation telemetry pouch.
When placing the temporary GES lead via a
In some patients, temporary GES is used to pre- gastrostomy site a shorter temporary lead (model
dict whether a patient will respond to GES [6]. 6416–100; Medtronic, Inc.) is passed through the
A temporary GES electrode can be introduced gastrostomy and screwed into the gastric mucosa
through a previously created gastrostomy site. at the junction of the body and antrum of the
If there is no gastrostomy, then a temporary stomach. Again, the lead is secured in place using
GES electrode is placed through the mouth or an endoscopic clipping device but is then brought
the nose by endoscopy. A standard pediatric out through the gastrostomy site and connected
endoscope is utilized for the placement of the to the external GES device. The gastrostomy tube
temporary GES electrode. The endoscope is is then replaced.
inserted into the stomach, and a cardiac pacing After placement of the temporary GES elec-
lead with a corkscrew tip (model 6414–200; trode, the lead is connected to the external GES
Medtronic, Inc.) is advanced through the biopsy pulse generator and the impedance is determined
channel and screwed into the gastric mucosa (desirable 400–1,500 Ω). The pulse generator is
with a clockwise motion at the junction of the initially programmed at relatively high settings
body and antrum of the stomach (Fig. 42.1a). (voltage, 5 V; pulse width, 450 ms; frequency
This temporary lead has an inner bipolar elec- ~28 Hz; time on 1.0 s; time off 4.0 s), so that the
trode pacing lead and an outer covering sheath. The patient response to temporary GES can be ascer-
endoscope is then withdrawn while advancing tained within 2–3 days. In general, the lead
42 Gastric Electrical Stimulation 467

remains in place for 7–10 days before dislodge- since the site for placement of the electrodes is
ment. The temporary electrode is easily removed often very close to the gastrostomy site. The loca-
by rotating it counterclockwise and applying tion for lead placement on the stomach wall is
gentle traction. determined in the same manner as with the lap-
aroscopic placement and the leads are again
placed under direct endoscopic visualization.
Permanent Gastric Stimulation The two permanent GES leads are then con-
nected to the GES pulse generator (Fig. 42.2c), a
The electrodes for the permanent gastric electri- superficial abdominal pocket is created, and the
cal stimulator can be placed laparoscopically or generator is placed within the pocket (Fig. 42.2d).
via laparotomy. However, most patients with a Using the external programming device the
previously placed gastrostomy require a laparo- impedance is determined (desirable 400–800 Ω)
tomy for lead placement. and the GES pulse generator is initially pro-
Using laparoscopy, abdominal access is grammed (voltage, 5 V; pulse width, 330 ms; fre-
obtained at the umbilicus and pneumoperitoneum quency ~14 Hz; time on 1.0 s; time off 4.0 s).
is established. Two 5 mm ports are placed in the Postoperatively, in patients who have not had sat-
umbilicus and on the right side at the level of the isfactory symptom relief, the GES parameters
umbilicus, while a 12 mm port is placed in the can be modified. However, there is no agreed
left axillary line superior to the umbilicus. Two upon algorithm for adjustment of the settings. In
electrodes (model 4351; Medtronic, Inc.) are general, we initiate gastric stimulation at a volt-
passed through the 12 mm port into the abdomen. age of 5 V (current ~10 mA; assuming an imped-
In adults, a point 10 cm proximal to the pylorus ance of ~500 Ω). We usually leave the voltage
along the greater curvature of the stomach is unchanged and increase the pulse width and fre-
marked. This corresponds to the junction between quency. We have had greater success with this
the antrum and body of the stomach. In children, strategy rather than with increasing the current
the site on the gastric wall for placement of the while leaving the other parameters unchanged.
electrodes is determined with the aid of an endos- Theoretically, increasing pulse width and fre-
copist who, during the initial phases of the sur- quency is a quicker way to build up energy in a
gery, identifies the junction of the body and nerve and reach an action potential than simply
antrum of the stomach with the surgeon marking increasing current. Adjustments are usually per-
the point on the external gastric surface along the formed every few weeks to months, as indicated.
greater curvature. Starting adjacent to the greater
curvature, the needle of the first electrode enters
and traverses the seromuscular layer of the gas- Outcome
tric wall for at least 2 cm and then exits
(Fig. 42.2a). The second electrode is placed par- According to most reports, GES is associated
allel to the first electrode 1 cm away (Fig. 42.2b). with long-term success in adults with gastropa-
The electrodes are placed under direct endoscopic resis. McCallum et al. recently showed overall
visualization to ensure that they do not pass full improvement in symptoms and nutritional status
thickness through the gastric wall. If this occurs, and decreased medication use during an average
the needle is withdrawn from the gastric wall and 56-month follow-up after placement of the GES
repositioned. The electrodes are secured to the in adults [7]. Lin et al. reported the outcome of
gastric wall and the needles are removed. The 63 adults diagnosed with gastroparesis and
distal ends of the electrodes are extracted from treated with GES [8]. After at least 1 year fol-
the abdomen through the 12 mm port. low-up, the severity of each symptom (abdomi-
Traditional laparotomy is usually required for nal pain, bloating/distention, nausea, vomiting,
placement of the permanent GES electrodes in early satiety) was significantly reduced although
patients with a previously placed gastrostomy the 4-h gastric emptying did not accelerate
468 C. Di Lorenzo et al.

Fig. 42.2 Surgical placement of a GES via laparotomy. are sutured to the gastric wall (b). The leads are attached
Gastric stimulator leads placed parallel to each other in to the pulse generator (c). The pulse generator is sutured
the gastric wall along the greater curvature (a). The leads into the superficial pocket (d)

significantly, confirming the lack of correlation therapy both for idiopathic pseudoobstruction
between symptoms and scintigraphic data. The and for non-idiopathic cases and its use should
group did not report significant adverse events. be considered irrespective of whether gastric
There is some evidence that patients with emptying is normal or delayed [9]. Electrical
more generalized motility disturbances may stimulation of the jejunal limb has also been
also benefit from the use of GES, probably due described as a potential effective treatment for
to its effects on afferent nerves. In a case series Roux stasis syndrome [10]. In general, GES has
of adult patients with intestinal pseudoobstruc- been found to be safe. However, Becker et al.
tion, vomiting improved just as much as it did in described the case of a 37-year-old woman who
patients with gastroparesis and the authors con- suffered gastric wall perforation from device
cluded that GES may be considered as a viable leads years after placement [11].
42 Gastric Electrical Stimulation 469

Fig 42.2 (continued)

Islam et al. first reported on the use of GES in implantation site. The remaining participants
pediatrics by describing nine adolescents with were able to return to normal diet and activity
chronic nausea and vomiting [12]. With tempo- levels. Elfvin et al. published their experience
rary stimulation, the group reported significant with GES implantation in three children under
improvement of both symptoms. After permanent the age of 3 years [13]. All three patients
stimulation improvement persisted, although two responded positively to GES therapy, demon-
subjects experienced adverse events. Symptoms strating 50 % improvement in symptom fre-
recurred in one child who later needed enteral quency. These results indicate that this therapy in
nutrition support and another patient had the the pediatric population seems to be safe. Our
device removed due to tissue deterioration at the own, yet unpublished data, in more the 25 children
470 C. Di Lorenzo et al.

who have received temporary and permanent electrical stimulation for gastroparesis—physiological
GES go along with the results of the previously foundations, technical aspects and clinical implica-
tions. Aliment Pharmacol Ther. 2009;30:681–94.
published studies, showing very encouraging 6. Ayinala S, Batista O, Goyal A. Temporary gastric
results in a heterogeneous group of children pre- electrical stimulation with orally or PEG-placed elec-
senting mostly with nausea and vomiting. trodes in patients with drug refractory gastroparesis.
Pediatric patients who have received implanta- Gastrointest Endosc. 2005;61:455–61.
7. McCallum RW, Lin Z, Forster J, Roeser K, Hou Q,
tion of a GES pose significantly more challenges Sarosiek I. Gastric electrical stimulation improves
than adults, due to their active lifestyle that may outcomes of patients with gastroparesis for up to
make them more prone to the risk of abdominal 10 years. Clin Gastroenterol Hepatol. 2011;9:314–9.
traumas that might damage the pacemaker. The 8. Lin Z, Hou Q, Sarosiek I, Forster J, McCallum RW.
Association between changes in symptoms and gas-
effect of growth on the connection between the tric emptying in gastroparetic patients treated with
pacemaker and the stomach has not been evalu- gastric electrical stimulation. Neurogastroenterol
ated and long-term follow-up of pediatric GES Motil. 2007;20:464–70.
patients has not been reported yet. 9. Andersson S, Lönroth H, Simrén M, Ringström G,
Elfvin A, Abrahamsson H. Gastric electrical stimula-
tion for intractable vomiting in patients with chronic
intestinal pseudoobstruction. Neurogastroenterol
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1. Dudekula A, O’Connell M, Bielefeldt K. Taylor M, Sheehan JJ, Abell TL. Novel application of
Hospitalizations and testing in gastroparesis. J GI electrical stimulation in Roux stasis syndrome
Gastroenterol Hepatol. 2011;26:1275–82. (with video). Gastrointest Endosc. 2011;74:
2. Aro P, Talley NJ, Agréus L, Johansson SE, Bolling- 683–6.
Sternevald E, Storskrubb T, Ronkainen J. Functional 11. Becker JC, Dietl KH, Konturek JW, Domschke W,
dyspepsia impairs quality of life in the adult popula- Pohle T. Gastric wall perforation: a rare complication
tion. Aliment Pharmacol Ther. 2011;33:1215–24. of gastric electrical stimulation. Gastrointest Endosc.
3. Familoni BO, Abell TL, Voeller G, Salem A, Gaber 2004;59:584–6.
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Parkman H, Policker S, Ordog T. Review article: gastric 2011;46:655–61.
 Cognitive Behavioral Therapy
for Children with Functional 43
Abdominal Pain

Nader N. Youssef and Miranda A.L. van Tilburg

based conditions which have some biological

Background base, such as mood, anxiety, personality, and
eating disorders, and also established organic
Over the past decades it has increasingly become disorders, such as inflammatory bowel disease,
evident that functional gastrointestinal disorders diabetes, and cardiovascular disease [1–8] which
(FGIDs) are explained by dysregulation of the conversely have been found to have a significant
brain–gut axis. FGID symptoms are not only psychosocial component. When considering evi-
caused and maintained by gut processes but may dence-based treatment, where specific treatments
also be modified by extraintestinal components for symptom-based diagnoses are utilized, CBT
such as those related to cognition, emotions, and has been recommended over other psychosocial
behavior. Currently, therapies for FGIDs can be approaches.
divided into two main categories: those directed Within childhood FGIDs, CBT is being used
to the predominant symptom (or-end organ ther- to treat various conditions, and data for its effec-
apy) and treatment aimed at psychosocial aspects tiveness exists for fecal incontinence [4], rumina-
of the disorder with a focus on providing patients tion [6], aerophagia [7], and cyclic vomiting [9].
with adequate tools for modifying disease per- But the most evidence for the effectiveness of
ception and responses to pain. CBT is in treating functional abdominal pain
Among the various psychosocial interven- (FAP) in childhood [10–12]. Therefore, in the
tions available, cognitive behavioral therapy remaining part of this chapter, we will discuss the
(CBT) has recently gained more popularity as a use of CBT in the treatment of FAP. First, we will
modality in the treatment for FGIDs. This is not explore the common components of CBT for the
surprising, as CBT has a large evidence base in treatment of FAP and show the versatility of the
many conditions that have a psychosomatic com- approach to many different situations such as the
ponent. These include traditional behaviorally application of CBT in school, family, and at
home. Last, we will discuss the literature on
mechanisms that may be responsible for the posi-
N.N. Youssef, M.D., F.A.A.P., F.A.C.G. (*) tive effect seen with CBT [13–15].
Digestive Health Care Center, 511 Courtyard Drive, It is equally important that the role of parent/
Hillsborough, NJ 08844, USA family of the affected child be acknowledged
e-mail: [email protected] when planning a successful intervention for chil-
M.A.L. van Tilburg, Ph.D. dren with FAP and utilizing CBT [11, 12]. Human
Division of Gastroenterology and Hepatology, behavior is routinely motivated and rewarded by
Department of Medicine, University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA positive reinforcement. Many well-meaning

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 471

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_43, © Springer Science+Business Media New York 2013
472 N.N. Youssef and M.A.L. van Tilburg

parents show empathy and sympathy for their and reacting, and keeping a diary of significant
child’s pain and may give extra attention, gifts, or events and associated feelings, thoughts, and
excuse the child from chores, a behavior which behaviors [17–23]. Relaxation, mindfulness,
unintentionally reinforces pain complaints and guided imagery, and distraction techniques are
disability. Teaching parents to withhold rein- usually also included.
forcement of their child’s pain and replacing it
with other techniques such as distraction can
improve symptoms in children [16].
Major Components to Cognitive
Behavioral Therapy

Aims of Cognitive Behavioral Therapy Education. An explanation of the prevalence and

nature of FAP, including the role of the brain–gut
As the name implies, cognitive behavioral ther- axis forms the foundation of therapy. It is impor-
apy combines cognitive and behavioral treat- tant for the family to understand and “buy” into
ment approaches with the aim to provide the the role of stress and maladaptive thoughts in
child with the skills to promote pain relief and symptom initiation and maintenance. It is gener-
feelings of well-being [17]. Within a course of ally preferable to shift the focus from monitoring
3–12 weekly treatment sessions, the therapist of symptoms to participation in daily activities
generally uses cognitive techniques to help (e.g., school attendance, social activities) to
patients overcome distorted and negative think- emphasize treatment success. The child and care-
ing patterns that amplify physical symptoms, giver are often reminded of the ultimate goal of
and behavioral techniques to change dysfunc- returning to a normal routine.
tional responses to pain. Under the guidance of
a trained therapist, the child learns how to Cognitive techniques. Once the foundation has
reduce pain and distress and gradually these been laid with education that the primary goal of
techniques become self-administered. For chil- CBT is to examine, identify, and correct irratio-
dren, CBT can also include changing the nal beliefs and automatic thoughts, the therapist
thoughts and behaviors of the caregivers. There guides the patient in discovering his or her cogni-
is no generic model for CBT, in fact CBT refers tive distortions that contribute to the etiology or
to a set of behavioral and cognitive interven- maintenance of abdominal pain and/or disability.
tions which can be used in many different com- Several techniques are used to counter these dis-
binations. It is therefore highly adaptable to the tortions. For example, children are taught to iden-
disease or disorder and individual to maximize tify and replace negative self-talk (e.g., “This
therapeutic benefit [18–24]. This also means pain will never go away”) with more adaptive
that the content of CBT can be very different cognitions (e.g., “I have handled pain like this
across therapists, disorders, age range, and before, so I can handle it again”). Or children
other individual or situational characteristics. may be asked to test the validity of their beliefs
by defending his or her thoughts. If the patient
cannot produce objective evidence supporting his
Therapeutic Delivery Techniques or her assumptions, the invalidity, or faulty nature,
is exposed (e.g., “When I’m bloated nobody
The particular therapeutic techniques vary within wants to be my friend” in a child that has a rich
CBT, but commonly may include questioning social life).
and testing cognitions, assumptions, evaluations,
and beliefs that might be unhelpful and unrealis- Behavioral techniques. The therapist has a
tic; gradually facing activities which may have large arsenal of behavioral techniques to induce
been avoided; trying out new ways of behaving relaxation, improve coping, and extinct unwanted
43 Cognitive Behavioral Therapy for Children with Functional Abdominal Pain 473

behaviors. Some of the most commonly used strat- Homework. In order to encourage self-discovery
egies are guided imagery and relaxation training: and reinforce techniques learned in therapy, the
therapist usually asks the patient to do homework
Guided imagery. This is a form of relaxed, assignments. These may include practicing newly
focused concentration similar to hypnosis. The learned skills or journaling of symptoms,
therapist uses verbal guidance to help the patient unwanted thoughts, or difficult situations.
experience specific detailed vivid imagery that The techniques described above are some of
has beneficial effects on the patient behavior, the most used approaches in CBT but this list is
cognitions, emotions, or physiology. With input not exhaustive. Therapists can draw on many
from a therapist, children develop and imagine a more cognitive and behavioral techniques to help
vivid scene such as going to a favorite place, and their patients, modify unwanted thoughts and
focus on the elements and sensations of the scene. behaviors that impact symptoms and disability.
This imagery makes children calm and relaxed In addition, these techniques are simple to learn
while they also achieve a state of focused atten- and safe, without any major side-effects, making
tion not unlike playing imaginary games or them an ideal treatment option for children and
watching a movie and feeling you are part of a adolescents at a vulnerable age of development.
story. During this focused state of attention, chil-
dren are more open to therapist suggestions for
pain reduction and increased well-being. Who Benefits from CBT?

Relaxation training. Two commonly used relax- In the early management of children with FGID,
ation techniques are deep breathing exercises and it is of paramount importance to identify from
progressive muscle relaxation; in deep breathing both patient and their families the “willingness or
exercises, children are taught diaphragmatic acceptance” of psychosocial therapies including
breathing which is deep abdominal breathing, by CBT [20, 21]. Once established, children are
flexing the diaphragm, rather than shallow breath- highly responsive to many CBT techniques due
ing by raising the rib cage. Children may learn this to their natural ability to use imagination, high
by pretending to blow up and deflate a balloon in suggestibility, and sense of play. However, CBT
their stomachs or by lying on the ground trying to requires children to be willing participants with a
keep a book or hand placed on one’s chest from relatively long attention span and fairly good
moving, while raising a book/hand on one’s stom- concentration. In addition, cognitive strategies
ach with each breath. In progressive muscle relax- within CBT have the most appeal to children who
ation, children are taught to systematically tense have developed meta-cognition. This means that
and relax various muscle groups. Age-appropriate children need to have an awareness of their own
explanations are employed to assist children with thinking, an ability to understand how to control
this task (e.g., young children are asked to pretend and manipulate their thinking, and being able to
to be a “robot” and then a “rag doll”). evaluate success of making changes to their
thinking. In short, cognitive strategies appeal the
Mindfulness training. Mindfulness training most to children who can think about their think-
involves learning to attend to present moment ing. Therefore, CBT usually is suggested for
experiences without evaluating them based on children age 8 and up but developmental level
past or future fixations. For example, children should be taken into account in all children before
may be instructed to observe and describe recommending and starting CBT [22–24]. In
unwanted thoughts and feelings as they come and practice, young children can master some of these
go, rather than suppressing them. This process concepts and may become more proficient at
increases children’s ability to know their sensa- using them over time. Children under the age of 8
tions better and ultimately to reduce the suffering can benefit from behavioral approaches and some
associated with pain. simple cognitive strategies (such as imagery or
474 N.N. Youssef and M.A.L. van Tilburg

positive self-talk) under the guidance of a coach,

usually the parent, who prompts and helps the CBT for Abdominal Pain
child to implement strategies at home.
Physicians, parents, and patients can often be A number of randomized controlled trials to
unintentional obstacles to the early initiation of test the effectiveness of pain interventions on
CBT. They feel CBT is only warranted when children and their families using a self-manage-
significant psychiatric overlap such as anxiety ment approach that includes components of
and depression is present. Therefore, few chil- cognitive behavior therapy have been con-
dren are referred for CBT who do not have ducted, yielding encouraging findings for this
comorbid psychiatric problems. Although CBT approach [10–12]. The following techniques
is well suited to treat children with these comor- are a sample of novel approaches utilized by
bid conditions, it can also be effective in children investigators recently showing that CBT is
who do not have any obvious mental health prob- efficacious in treating FAP and can be delivered
lems but still struggle with significant symptoms in ways to increase access and feasibility.
and disability.

Therapeutic Delivery Techniques

Effective CBT for Chronic Pain
Family Intervention
Investigators from Oregon and others have
recently published an updated metanalytical Increasingly, parents are recognized as critical
review of randomized controlled trials of psy- partners in CBT programs. Success often depends
chological therapies for management of chronic on the parent’s willingness to encourage the
pain in children and adolescents [23, 24]. The child to practice, including practicing with him
purpose of this meta-analytic review was to or her, and using positive reinforcement for
quantify the effects of psychological therapies cooperation and successful outcomes. Acceptance
for the management of chronic pain in youth by parents of a biopsychosocial model of illness
[23]. Specifically, systematic reviews of ran- is important for the resolution of FAP in children
domized controlled trials by including new tri- [11, 12]. Discussing these issues in clinical prac-
als, and by adding disability and emotional tice is difficult as parents often feel misunder-
functioning to pain as treatment outcomes were stood and blamed for their child’s pain.
assessed. Twenty-five trials including 1,247 Discussing parents’ fears and worries about their
young people met inclusion criteria and were children’s chronic abdominal pain may facilitate
included in the meta-analysis. Meta-analytic discussions of social learning of gastrointestinal
findings demonstrated a large positive effect of illness behavior.
psychological intervention on pain reduction at In a randomized controlled trial [11], investi-
immediate post-treatment and follow-up in gators tested the efficacy of an intervention
youth with headache, abdominal pain, and designed to improve outcomes in idiopathic
fibromyalgia. Small and non-significant effects childhood abdominal pain by altering parental
were found for improvements in disability and responses to pain and children’s ways of coping
emotional functioning, although there were and thinking about their symptoms. Two-
limited data on these outcomes. All cognitive hundred children with persistent FAP and their
behavioral therapy, relaxation therapy, and bio- parents were randomly assigned to one of two
feedback produced significant and positive conditions: a three-session intervention of cog-
effects on pain reduction. Studies directly com- nitive behavioral treatment targeting parents’
paring the effects of self-administered versus responses to their children’s pain complaints
therapist-administered interventions found and children’s coping responses, or a three-
similar effects on pain reduction. session educational intervention that controlled
43 Cognitive Behavioral Therapy for Children with Functional Abdominal Pain 475

for time and attention. Children in the cognitive post-intervention and 3-month follow-up were
behavioral condition showed greater baseline to collected. Guided imagery was associated with
follow-up decreases in pain and gastrointestinal greater improvement in pain than RR. At 3
symptom severity (as reported by parents) than months, pain was still reduced from baseline in
children in the comparison condition. Also, par- both GIM and RR group. No child was diagnosed
ents in the cognitive behavioral condition with alternate disease in the 3-month follow-up.
reported greater decreases in solicitous responses Investigators concluded that school nurse admin-
to their child’s symptoms compared with par- istered guided imagery for abdominal pain was
ents in the comparison condition. Investigators feasible and that larger, prospective studies were
concluded that an intervention aimed at reduc- needed to confirm these positive results.
ing protective parental responses and increasing
child coping skills is effective in reducing chil-
dren’s pain and symptom levels compared with Home-Based Interventions
an educational control condition.
Despite the good evidence in support of CBT for
treating FAP in children, psychological services
Community-School Based Intervention are often difficult for patients to access and may
not be covered by insurance. It is also important
Because assessment of FAP is frequently made at to note that there is a paucity of therapists who
the school nurse level, schools may represent an are well trained in cognitive behavioral approaches
excellent opportunity for intervention [25]. with children. In addition, families may be resis-
A questionnaire was sent to 425 school nurses to tant to a referral to a mental health professional
evaluate perceptions about FAP. Questions seek- when they are not well educated about the goals
ing to address perceived causes and treatment of treatment (learning to cope with pain and dis-
needs for children with chronic abdominal pain ability reduction) and rather see the referral as a
revealed that school nurses are unclear about epi- sign the physician thinks the pain is “all in the
demiologic and etiologic features of FAP and child’s head.” As a consequence few patients with
have negative views that may inadvertently con- FAP are referred to mental health specialists
tribute to the anxiety felt by affected children. unless they have additional psychiatric symp-
Investigators concluded that increased education toms, with most children being treated exclu-
of school nurses and communication from physi- sively by pediatricians or family physicians
cians may advance strategies designed to reduce without integration with mental health care.
the fiscal and social costs associated with FAP. Therefore, home-based interventions have been
In order to help school nurses in the commu- developed including delivery of CBT by phone,
nity, the same investigators utilized a novel Internet, and CD which may increase access to
approach to deliver guided imagery directly to this type of therapy.
children presenting with FAP at school. In a pilot
study, the feasibility and efficacy of a school CD Delivered CBT Components
nurse administered guided imagery program was Investigators have developed home-based, guided
assessed [26]. Nurses recruited children with imagery treatment protocols, using audio and
FAP and no other distress symptoms such as video recordings, which are inexpensive, easy for
weight loss, fever, or change in bowel habits. health-care professionals and patients to use, and
Children were randomized to six sessions of may be applicable to a wide range of health-care
Guided Imagery (GIM) or Rest and Relaxation settings [27]. In a pilot study, 34 children, 6–15
(RR) over 1 week. Initial session was 15 min and years of age, with a physician diagnosis of FAP
five booster sessions lasted 7 min. GIM was were assigned randomly to receive 2 months of
delivered via a compact disc. Questionnaires for standard medical care with or without home-
abdominal pain and disability at initiation, 1-week based, guided imagery treatment. Children who
476 N.N. Youssef and M.A.L. van Tilburg

had received only standard medical care initially, problems can be off-putting. In this respect,
received guided imagery treatment after 2 computerized CBT can be a good option.
months. Patients were monitored for 6 months Investigators from the Netherlands have piloted a
after completion of guided imagery treatment. feasibility and efficacy program utilizing PDA
All treatment materials were reported to be self- (personal digital assistants) or hand-held com-
explanatory, enjoyable, and easy to understand puters for the self-management of adults with
and to use. The compliance rate was 98.5%. In an irritable bowel syndrome [30]. The trial was con-
intention-to-treat analysis, 63.1% of children in ducted with 38 control group patients receiving
the guided imagery treatment group were treat- standard care and 37 intervention group patients
ment responders, compared with 26.7% in the receiving standard care supplemented with a
standard medical care-only group. When the chil- 4-week CBT intervention on PDAs. Between-
dren in the standard medical care group also group comparisons between baseline and follow-
received guided imagery treatment, 61.5% up showed improved quality of life improvement,
became treatment responders. Treatment effects and less catastrophizing thoughts as well as pain
were maintained for 6 months (62.5% respond- in the intervention group. Only improvement in
ers). Investigators concluded that guided imagery catastrophizing thoughts persisted in the long
treatment plus medical care was superior to stan- term. Investigators concluded that CBT relying
dard medical care only for the treatment of on pocket-type computers appears feasible and
abdominal pain, and treatment effects were sus- efficacious for improving IBS-related complaints
tained over a long period. and cognitions in the short term. Future studies
should focus on unraveling the effective compo-
Internet Delivered CBT nents of this innovative e-health intervention.
Investigators from Sweden have investigated the
treatment of adults with irritable bowel syndrome
by CBT delivered via the World Wide Web [28, Proposed Mechanism of CBT:
29]. The aim of this study was to investigate if Physiological, Parent, Impaired
CBT based on exposure and mindfulness exer- Coping, or All Three?
cises delivered via the Internet would be effec-
tive. Eighty-six participants were included in the Even though CBT has been found to be effective
study and randomized to treatment or control in FAP, it is still largely unknown by which
condition (an online discussion forum). mechanism these changes are driven. Identifying
Participants in the treatment condition reported a the active ingredients of treatment is of utmost
42% decrease and participants in the control importance given the variety of CBT approaches
group reported a 12% increase in primary IBS a therapist can choose from. Some approaches
symptoms. Investigators concluded that CBT applied in CBT, such as guided imagery, have
based on exposure and mindfulness delivered via been shown to be effective by itself without addi-
the Internet can be effective in treating IBS tion of other techniques. This suggests that there
patients, alleviating the total burden of symptoms may be active ingredients of therapy that are more
and increasing quality of life. important than other techniques in reducing
symptoms. Cognitive behavioral intervention is
Computerized CBT based on the assumption that changes in active
These are cognitive behavioral therapy sessions coping, cognitions, emotions, and care-giving
in which the user interacts with computer soft- strategies are responsible for improvement in
ware (either on a PC, or sometimes via a voice- FAP; however, these assumptions have not yet
activated phone service), instead of face to face been widely validated as research on the mecha-
with a therapist. For people who are feeling nism of change is lacking from most treatment
depressed and withdrawn, the prospect of having trials. Below we will discuss the evidence for
to speak to someone about their innermost various purposed mechanism of change.
43 Cognitive Behavioral Therapy for Children with Functional Abdominal Pain 477

Physiological Changes to the Brain Changes in Parental Solicitousness

and Gut?
As described earlier in this chapter, Levy and col-
Despite CBT’s main focus on psychosocial vari- leagues tested the effect of CBT directed not only
ables, it has been suggested that it can be accompa- at the child but also at the cognitions, emotions,
nied by physiological changes as well, especially in and behaviors of the parents. Specifically par-
the central nervous system [31–33]. It has been ents’ responses to their child’s pain were targeted
speculated that CBT may affect symptoms through as well as children’s coping responses. The
changes in the brain. Brain changes with CBT have authors reported greater decreases in parental
been found with other disorders such as Obsessive solicitous responses to their child’s symptoms as
Compulsive Disorder, Panic Disorder, Major well as decreases in parental perceived threat of
Depressive Disorder, and phobias. In addition, their child’s pain following CBT. In another study
there is some evidence that treatment of psychoso- on family CBT, parental strategies such as rein-
cial symptoms in adults with IBS is associated with forcing well-behavior, using distraction, ignoring
changes in the central nervous system. For exam- pain, and avoiding modeling the sick role, were
ple, Drossman and colleagues followed a young independent predictors of child pain behavior
woman with a history of abuse, posttraumatic stress post-treatment [16]. These data suggest that
disorder, and functional GI complaints, before and changing parental behaviors and beliefs may be
after treatment. Treatment consisted of removing an active ingredient in reducing child’s pain and
her from an abusive relation, treating posttraumatic disability.
distress, and weaning from narcotics. Clinical
recovery was associated with reducing psychoso-
cial distress and visceral hypersensitivity to normal Changes in Coping
levels. Functional Magnetic Resonance Imaging
showed increases in area 40, 22 and the anterior Explanations of chronic pain increasingly high-
insula as well as decreases in prefrontal area 6/44, light the role of coping in understanding FAP.
midcingulate cortex, and the somatosensory cortex. The type of coping response used by the child has
A study on the placebo effect in adult irritable been shown to mediate the impact of pain. Active
bowel syndrome patients showed a robust positive coping responses (efforts to function despite pain
correlation between symptom amelioration and or to distract oneself from pain) are thought to
increases in regional cerebral blood flow as well as increase the child’s sense of control, whereas
the ventrolateral prefrontal cortex, and this correla- more passive reactions (depending on others for
tion was mediated by changes in the dorsal anterior help and restricting activities) lead to withdrawal,
cingulate (dACC), typically associated with pain decreased activity, and greater pain.
unpleasantness [34]. Children with severe and persistent FAP often
Similar studies among children have not been have inadequate coping responses and perceive
performed but two trials show no effect of psycho- themselves as having little control over their
social treatments on pain thresholds. A random- symptoms. The potential usefulness of coping
ized controlled trial of CBT among 32 children skills training for children with FAP has been
with FAP showed no decreases in somatic pain suggested by uncontrolled clinical case reports.
thresholds [35]. Similarly, a large study among 46 Relaxation training as a specific coping skill has
children with FAP receiving hypnosis did not show been used in conjunction with other behavioral
changes in rectal sensitivity to pain despite clinical and dietary interventions. In addition, CBT has
recovery [36]. These studies suggest that at least in been found to improve active coping such as the
children no physiological changes in pain thresh- use of distraction and pain minimization. No
olds can be found with psychosocial treatments. studies have examined whether a change in a
Evidently more research is needed to study the child’s coping strategies is the mechanism respon-
physiological effects of CBT in FAP. sible for improvement in the child’s pain.
478 N.N. Youssef and M.A.L. van Tilburg

brain–gut access often leading to an amplification

It is not all in their Heads! of pain in the setting of impaired coping environ-
ment. Thus, it is reasonable to accept that chang-
It is accepted that many FAP patients may suffer ing maladaptive cognitions is at the heart of CBT
from a combination of subtle to overt comorbid therapy and ultimately its success. As clinicians
psychological and related gastrointestinal dysfunc- become increasing comfortable with the under-
tions often unfairly termed a FGIDs. The role of standing of the role of the brain–gut axis in the
brain–gut physiology cannot be ignored, and the etiology of these common disorders, it is expected
effects of longstanding symptoms that may indeed that they ultimately will begin to offer CBT deliv-
cause significant anxiety and depression in both ered in a variety of novel ways much earlier in the
child and caregiver need to be addressed. Given the treatment paradigm rather than waiting for other
effects of psychosocial factors on the expression comorbid conditions to develop such as anxiety,
and trajectory of FAP, it could be argued that the depression, and impaired function which may
effects of CBT are mainly mediated through changes lead to a more refractory patient.
in psychological distress. Although studies in adults
with irritable bowel syndrome have shown decreases
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43 Cognitive Behavioral Therapy for Children with Functional Abdominal Pain 479

training in a case of cyclic vomiting syndrome. stress responses in children with recurrent abdominal
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 Complementary and Alternative
Treatments for Motility and Sensory 44
Disorders

Arine M. Vlieger and Marc A. Benninga

of conventional treatment and/ or experience

Introduction significant school absenteeism [4]. Both situa-
tions occur frequently in motility and sensory
Complementary and alternative medicine (CAM) disorders. For example, 30–50% of the children
is “diagnosis, treatment, and/or prevention which with functional constipation continue to have
complements mainstream medicine by contribut- severe complaints despite intensive treatment
ing to a common whole, by satisfying a demand with laxatives [5, 6]. Many patients are therefore
not met by orthodoxy or by diversifying the con- dissatisfied with conventional treatment options.
ceptual frameworks of medicine” [1] a definition Also for pain-related disorders like functional
adopted by the Cochrane Collaboration. CAM abdominal pain, irritable bowel syndrome, and
incorporates many different approaches and infantile colic, treatment options have limited
methodologies ranging from ancient techniques efficacy, resulting in dissatisfied patients and par-
like acupuncture and Ayurvedic medicine to chi- ents. Moreover, Youssef et al. showed that ado-
ropractics, homeopathy, spiritual healing, and lescents with daily abdominal pain suffer from
body–mind medicine. CAM has a significant significant school absenteeism [7]. With the cur-
popularity with pediatric gastroenterology rent increasing popularity of CAM in mind, it
patients with a 1-year prevalence of CAM use of therefore seems just a matter of time before
36–41% [2–4]. Because of this high prevalence patients with chronic abdominal pain will con-
and the fact that some complementary therapies sider an alternative route.
are not without adverse effects and may interfere Another reason for parents to use CAM is a
with allopathic medications, it is important for fear of side effects of allopathic medication,
pediatricians and gastroenterologists to become especially in young children. Many CAM thera-
familiar with these therapies. CAM is especially pies are considered “natural” by the general pub-
used by children who have low perceived effect lic and thus safer and gentler in some way than
the armamentarium of modern medicine. This
may explain the high use of CAM in young
A.M. Vlieger, M.D., Ph.D. infants, for example infants with regurgitation
Department of Pediatrics, St. Antonius Hospital, and reflux [4].
Nieuwegein, The Netherlands
In this chapter we will discuss the CAM treat-
M.A. Benninga, M.D., Ph.D. (*) ment options for pediatric motility and sensory
Department of Pediatrics, Emma Children’s Hospital/
disorders in which CAM is used fairly often:
MAC, H7-248, Meibergdreef 9, 1105 AZ, Amsterdam,
The Netherlands infantile colic, gastro-esophageal reflux, chronic
e-mail: [email protected] abdominal pain due to functional abdominal pain

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 481

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_44, © Springer Science+Business Media New York 2013
482 A.M. Vlieger and M.A. Benninga

and irritable bowel syndrome, and constipation. symptoms, but the significant number of children
Since CAM treatments may vary widely and who used both drugs and natural products stresses
research on safety and efficacy of these treat- the importance of studies investigating the safety
ments in children with these disorders is very of natural health products. A meta-analysis on
limited, we will focus on those treatments that adverse events associated with pediatric spinal
have been studied best and/or are being used manipulation identified 14 cases of direct adverse
most, including herbs, acupuncture, homeopathy, events involving neurologic or musculoskeletal
hypnotherapy, and manual-based therapies like events [11]. Incidence rates, however, could not be
chiropractics. The use of probiotics is not dis- inferred from these observational data. Finally,
cussed in this chapter, because this has become some words on homeopathy, which is one of the
mainstream medicine in the last decade. most commonly used CAM treatments in children
[12]. Over-the-counter homeopathic remedies are
especially popular and used often for common
General Remarks on Safety of CAM self-limiting conditions. There is little published
Therapies data on the safety of homeopathy. The few studies,
which have been performed on this subject, show
Many CAM users consider CAM therapies “natu- that adverse events to homeopathic drugs exist, but
ral” and equate this with safety. They are often are rare and not severe. CAM therapies can also
unaware of the fact that many of these therapies have indirect harmful effects due to missed diagno-
have the potential to be directly or indirectly harm- ses, delaying more effective treatments, and discon-
ful. There are several reports of severe adverse tinuation of prescribed drugs [13]. These indirect
events in children, mostly due to contamination, effects are probably not a reason for concern in
drug interactions or direct toxic effects of herbs, most motility and sensory disorders, for which
and dietary supplements (reviewed by Cuzzolin conventional treatment options are often limited.
et al. [8]). The problems of toxicity and drug inter-
actions can be extra relevant in young children and
infants whose metabolism and organ function is Infantile Colic
immature and less tolerant of even subtle changes
in comparison to the adult. To date, only scant data Infantile colic is a widespread clinical condition
on the frequency of adverse effects of CAM thera- observed in 10–30% of infants [14]. It occurs
pies in children are available. A recent review on mostly in healthy infants and is characterized by
safety and efficacy of acupuncture in children paroxysms of excessive, inconsolable crying, fre-
found a risk of adverse events of 1.55 in 100 treat- quently accompanied by flushing of the face,
ments [9]. The authors concluded that acupuncture drawing-up the legs, meteorism, and flatulence.
seems to be a safe CAM modality for pediatric These crying episodes tend to increase at the age
patients, although the risk for an individual patient of 6 weeks and usually resolve spontaneously at
may be hard to determine because certain patients, the end of 3 months. The etiology is not clear and
such as immunosuppressed patients or infants, can its limited treatment options frustrate both par-
be predisposed to an increased risk, and because ents and physicians. It is therefore not surprising
acupuncturists may differ with respect to their that many parents turn towards CAM treatments
qualifications, skills, and knowledge. Another for their infant.
study determined the frequency of concurrent use
of conventional medications and natural health
products and their potential interactions in 1,800 Acupuncture
children [10]. Concurrent use of allopathic drugs
and natural products was documented in 20% of Acupuncture has long been used for infantile
patients with potential interactions in one quarter colic, especially in China, but the published lit-
of them. The authors did not investigate whether erature is largely restricted to case studies. In
these were true interactions resulting in clinical 2008, Reinthal et al. investigated the effect of
44 Complementary and Alternative Treatments for Motility and Sensory Disorders 483

acupuncture in infantile colic in a randomized that to date there is no good evidence showing
trial [15]. Forty children with excessive crying that spinal manipulation is effective for infantile
unresponsive to conventional therapies were colic. Moreover, the recent reported fatal adverse
quasi-randomized to control or light needling reaction on a 3-month-old baby upon craniosacral
treatment. Parents were unaware of which group therapy demonstrates that spinal manipulation is
their child was assigned to. Children were given not without risks and therefore should not be rec-
light needling acupuncture on one acupoint (LI4) ommended for infantile colic [19].
on both hands for approximately 20 s on four
occasions, or received the same care except nee-
dling. Acupuncture resulted in a significant Gastro-esophageal Reflux
reduction in the rated crying intensity, and also
pain-related behavior, like facial expression, was Gastro-esophageal reflux (GER) is defined as the
significantly less pronounced in the light needling passive flow of gastric contents into the esopha-
group. The results of this study are interesting, gus. It is important to recognize that GER is a
but need to be confirmed in larger, double-blind normal physiologic phenomenon and therefore
controlled trials. occurs to some extent in all infants and children.
Symptoms, especially regurgitation, are very
common in infancy and are reported by parents to
Homeopathy occur at least regularly in 70% of 4-month-old
babies [20].
Homeopathic treatments, especially over-the- Regurgitation and vomiting are the most typi-
counter remedies, are very often used in infants cal symptoms related to GER [21]. However,
with colic [12, 16], but data on its efficacy are most of the infants experiencing those symptoms
lacking. One observational cohort study in 204 are not considered to have GER disease. A com-
children compared the effect of a standard homeo- bination of regurgitation and/or vomiting with
pathic preparation with a conventional drug (sco- excessive crying and feed-related irritability is
polamine) in the treatment of abdominal cramps. most suggestive of GER disease in infants. Other
The analysis showed comparative improvements symptoms such as hematemesis and failure to
with both treatments in spasms, pain, sleeping thrive are indicative of severe disease. Of the
disturbances, and crying. However, no double- many extraesophageal symptoms such as appar-
blind RCT has been performed with this homeo- ent life-threatening events, laryngitis, hoarseness
pathic preparation to confirm these findings, so and asthma, only dental erosions, and Sandifer’s
the effect of this homeopathic product in the syndrome are convincingly shown to be GER
treatment of infantile colic is still unknown [17]. related [22].
Parental education, guidance, and support are
usually sufficient to manage healthy, thriving
Manual-Based Treatments infants with symptoms likely to be secondary to
physiologic GER. If symptoms persist despite
One of the most frequently used treatments for these conservative measures, it can be helpful to
infantile colic is spinal manipulation, given by eliminate cow milk from the infant’s diet (or in
chiropractors, manual therapists, osteopaths, or case of breastfeeding, from the mother’s diet).
craniosacral therapists. It is often claimed by Therefore, formula-fed infants with recurrent
therapists that spinal manipulation is an effective vomiting may benefit from a 2- to 4-week trial of
treatment for colic. However, a systematic review an extensively hydrolyzed protein formula [23].
in 2009 of three randomized clinical trials showed Thickening feeds has been shown to decrease the
that the methodological quality of these trials was frequency of regurgitation, but not other symp-
low with very low sample sizes and insufficient toms and does not decrease acid exposure [24].
control of placebo effects [18]. It was concluded Many studies have been performed looking at the
484 A.M. Vlieger and M.A. Benninga

effect of posture in the postprandial position.

Although some studies suggest a beneficial effect
of lifting the head of the cot, there is not enough
evidence to support this in clinical practice [24].
Compared to supine position, prone position
significantly reduces the number of acid GER CV17
episodes, but increases the risk for sudden infant
death syndrome (SIDS) [25, 26]. The major phar- CV12
macologic agents currently used for treating
GERD in children are gastric acid-buffering
agents, mucosal surface barriers, and gastric anti-
secretory agents.
Per.6
Although many of the simple therapeutic inter-
ventions are helpful in infants and children with
GER, 40% of the parents still seek help in the com-
plementary medicine circuit. Despite this high per-
centage no well-designed trials exist which evaluate
the efficacy of the complementary treatments that Per.6 Neiguan
are used by parents for this disorder, such as oste- St.36 Zusanli
Sp.9 CV12 Zhangwan
opathy or naturopathy. Therefore, this review will
St.36 CV17 Shanzhong
only focus on acupuncture with respect to GERD.
Liv.3 Taichong
Sp.9 Yinlingquan

Acupuncture LIV3

Transient lower esophageal sphincter relaxations

(TLESR) have been shown to underlie most GER Fig. 44.1 Traditional Chinese Medicine acupuncture
episodes in healthy volunteers and healthy pre- points used in the clinical trial: acupuncture versus dou-
bling the proton pomp inhibitor dose in adults with gastro-
mature infants as well as in adult and pediatric oesophageal-related symptoms [32]
patients with GER disease [27]. Current data
indicate that transient LES relaxations are medi-
ated via a vago-vagal pathway initiated by ten- [32]. This effect appears to act on the brain stem,
sion receptors located in the proximal stomach and may be mediated through nitric oxide,
musculature [28]. CCK-A receptor, and mu-opioid receptors.
The mechanism by which acupuncture A randomized parallel-group trial studied 30
improves GERD-related symptoms remains to be adult patients (age > 18 years) with a 3-month his-
elucidated. It has been shown that electric acu- tory of GERD-related symptoms at least 2 days
puncture at zusanli (ST-36) can increase the basal per week while taking standard-dose omeprazole
LES pressure, whereas transcutaneous electric 20 mg once daily [33]. The acupuncture protocol
nerve stimulation (TENS) at Hukou acupoint consisted of five acupuncture points according to
increases the degree of LES relaxation in volun- the traditional Chinese medicine pattern diagnosis
teers (Fig. 44.1) [29]. Others have suggested that (Fig. 44.1). Treatment consisted of ten acupunc-
TENS at neiguan may inhibit the rate of TLESRs ture sessions (25 min each) over 4 weeks.
triggered by gastric distention and reduce the per- Acupuncture resulted in a significant improve-
ception to gastric distention in human beings [30, ment in daytime heartburn, night-time heartburn,
31]. A recent study in 12 healthy cats showed that and acid regurgitation when compared with dou-
electric acupoint stimulation at Neiguan bling the PPI dose. A limitation of the study was
significantly inhibits the frequency of TLESR the small sample size and the lack of a sham
44 Complementary and Alternative Treatments for Motility and Sensory Disorders 485

acupuncture arm. The authors point out, however, poor quality, included relatively small numbers
that increasing recognition in the acupuncture lit- of patients, and differed significantly in the acu-
erature exists that superficial (needling of the puncture method utilized. The review found
skin), sham (needling of non-acupuncture points), inconclusive evidence as to whether acupuncture
and placebo (needling with blunt tip that does not is superior to sham acupuncture in IBS.
penetrate the skin) acupuncture also provide an Subsequently, two studies with in total 273
active therapeutic effect [34]. No such studies patients were published comparing real acupunc-
have been performed in either infants or children ture to sham acupuncture or a waiting list. In both
with gastro-esophageal reflux disease. studies no significant difference was found
between the response rates in patients receiving
acupuncture and sham acupuncture on global
Functional Abdominal Pain and improvement of IBS, although patients in both
Irritable Bowel Syndrome groups improved significantly compared to base-
line [39, 40]. These results suggest that acupunc-
Irritable bowel syndrome (IBS) and functional ture has a potential role in the treatment of IBS,
abdominal pain (FAP) in childhood are pediatric but its effect might be non-specific. However,
functional gastrointestinal disorders, which are Schneider et al. recently showed that real acu-
characterized by chronic or recurrent abdominal puncture in comparison to sham acupuncture had
pain, and no evidence of an underlying organic dis- more specific physiological effects with a more
order. By definition, altered bowel movements and/ pronounced decrease in salivary cortisol and an
or relief of pain after defecation are seen in IBS, increased parasympathetic tone [41]. They con-
while defecation pattern is normal in patients with cluded that different mechanisms seem to be
FAP [35]. IBS and FAP are among the most com- involved in sham and real-acupuncture driven
mon pain complaints in childhood with reported improvements, but the specific mode of action of
prevalence’s between 0.3 and 19% [36]. Quality of acupuncture in IBS remains unclear and deserves
life scores of IBS and FAP children are significantly further evaluation. Whether acupuncture is also
reduced and many children also suffer from anxiety effective in the treatment of children with IBS or
and/or depression, highlighting the clinical FAP is unknown, since trials in this patient group
significance [7, 37]. Standard medical treatment is are lacking. Awaiting such trials, physicians
symptomatic and consists of dietary advice, educa- might already consider acupuncture as a potential
tion, and/or pain medication. Sometimes patients treatment option in children with refractory IBS
are referred to a child psychologist for behavioral or FAP, since acupuncture is considered a safe
therapy. All these interventions may result in CAM modality for pediatric patients [9].
reduction of symptoms, but many children con-
tinue to experience symptoms for years, even into
adulthood. It is therefore not surprising that a Herbs
significant number of patients consider alternative
treatments. Given the high placebo response shown Herbals and botanicals have been used for hundreds
in IBS studies, it is expected that many patients will of years for abdominal complaints in both adults
experience at least a short-term benefit of any of and children, but good scientific evidence of their
these treatments. effectiveness is sparse. Two of three randomized-
controlled trials (RCTs) demonstrated that (Chinese)
herbal medicine may offer improvement in some
Acupuncture adults with irritable bowel syndrome (IBS), and a
superior post-treatment effect was found with
A 2006 Cochrane Database article reviewed six individualized formulations in comparison to stan-
randomized trials using acupuncture in IBS [38]. dardized preparations [42–44]. No studies have
It was concluded that the trials were generally of been performed in children. Peppermint, which is
486 A.M. Vlieger and M.A. Benninga

commonly found in over-the-counter preparations hypnotherapy was highly superior compared to

for IBS, has also been found effective [45]. The standard medical care with complete remission
mechanism of action is thought to be from the men- of symptoms in 85% of children at 1-year follow-
thol component of peppermint that relaxes gastroin- up versus 25% in the control group [53]. In an
testinal smooth muscle by blocking calcium intriguing recent study, hypnotherapy based on
channels [46]. In children with IBS the use of pep- self-exercises at home with the help of recorded
permint oil seems to be both safe and beneficial: in scripts on CDs was used in a group of children
a small randomized, double-blind controlled 2-week with functional abdominal pain [54]. The CDs
trial, 76% of the patients receiving enteric-coated contained similar exercises as used in individual
peppermint oil capsules reported a decrease in hypnotherapy. About two thirds responded favor-
symptom severity versus only 19% in the placebo ably to this therapy compared to only 27% in the
group [47]. Another popular herb in IBS is ginger control group. Audio-recorded self-hypnosis can
(Zingiber officinale), especially used by patients become an attractive first line therapy for chil-
with nausea and dyspepsia as one of the main com- dren with FAP or IBS because of its low costs
plaints [48]. It has a prokinetic action probably and direct availability, but further studies are
mediated by spasmolytic constituents of the cal- needed to compare its effectiveness with individ-
cium antagonist type [49]. Ginger has been proven ual hypnotherapy given by a therapist.
effective for reducing postoperative nausea and
vomiting [50] and nausea in early pregnancy [51]. It
seems to be relatively safe, although abdominal dis- Manual-Based Therapies
comfort has been noted in some patients. NO RCT’s
have been performed in children with IBS, FAP, or Not many studies have been performed with
functional dyspepsia. manual-based therapies in patients with FAP or
IBS. In adults with IBS a small single-blind trial
did not show any benefit of reflexology foot mas-
Hypnotherapy sage on abdominal pain, defecation frequency,
and abdominal distension [55]. A pilot study with
Brain–gut interactions are increasingly recog- 39 adult IBS patients investigated the effect of
nized in the pathogenesis of IBS and FAP, mak- osteopathy, a manual treatment which relies on
ing body–mind medicine an appealing therapeutic mobilizing and manipulating procedures in order
approach. A body–mind technique that seems to to relieve complaints [56]. Compared to standard
be very useful in the treatment of children with medical treatment, osteopathy resulted in a
FAP and IBS is gut-directed hypnotherapy. In significantly lower disease severity index scores
this therapy a hypnotic trance is induced in which and a higher percentage of patients with definite
patients are given suggestions, directed towards overall improvement. It was concluded that
control and normalization of gut function in addi- osteopathic therapy might be a promising alter-
tion to relevant ego-strengthening interventions. native in the treatment of patients with IBS.
There is fairly strong evidence supporting the use However, more studies are needed to confirm
of this CAM modality. A Cochrane review in these findings before osteopathy can be advo-
2006 found four RCT’s in adults. The therapeutic cated as a treatment option for IBS/FAP.
effect of hypnotherapy was found to be superior
to that of a waiting list control or usual medical
management for abdominal pain and composite Constipation
primary IBS symptoms [52]. Data were not
pooled for meta-analysis due to differences in The diagnosis functional constipation in infants
outcome measures and study design. One subse- and children is based on a complex of symptoms
quent trial in children with FAP and IBS showed in the absence of an underlying organic cause.
that developmentally appropriate gut-directed These children often have infrequent, painful,
44 Complementary and Alternative Treatments for Motility and Sensory Disorders 487

large, and hard bowel movements in combination constipation. However, generalization of these
with fecal incontinence. Furthermore, many of findings is limited because of two significant
these children tend to show withholding behavior methodological flaws: (1) uncertainty in accu-
[35]. A recent systematic review reported that the rate acupoints identification and subjects’ com-
worldwide prevalence of childhood constipation pliance to instructions resulted in varied doses of
in the general population ranges from 0.7 to intervention received and (2) inconsistent inter-
29.6% [57]. As in children with functional vention protocols and therapeutic outcome crite-
abdominal pain chronic symptoms of functional ria make comparison among different studies
constipation are associated with a lower quality difficult [61, 62].
of life, as measured with generic questionnaires Acupuncture can accelerate the release of opi-
[58]. Parents reported even lower quality of life oid peptides in the central nervous system, but its
than their children which was probably impacted effect on opioid activity and constipation is not
by the duration of their child’s symptoms and by known. Investigators in one study in children
family members having similar symptoms [58]. with chronic constipation looked at the effect of
The backbone for treatment of functional consti- acupuncture on symptoms and on basal plasma
pation consists of education of the child and par- panopioid levels—the ratio of plasma binding to
ents, behavioral modifications, and laxative opioid receptors in the brain [63]. The study regi-
therapy [59]. Once disimpaction is accomplished, men consisted of five weekly placebo acupunc-
maintenance therapy is essential to prevent re- ture sessions followed by ten weekly true
accumulation of feces. Daily oral laxative therapy acupuncture sessions. A significant increase in
needs to be continued for 3 months or longer at a frequency of bowel movements occurred in both
dose that produces a daily soft stool without side boys and girls (1.5–4.4/week and 1.4–5.6/week,
effects. In many children symptoms of constipa- respectively, each P < 0.01) after treatment. The
tion will resolve within this period. However, panopioid activity was lower in the control chil-
persistence of symptoms is reported in 30–52% dren and increased only in the children who
of children in studies with at least 5 years of fol- received the true acupuncture sessions. Out of 27
low-up [60]. Not surprisingly Vlieger et al. children who started, ten did not complete the
showed that 36% of patients with constipation study due to poor compliance. In contrast to the
visiting a gastroenterology outpatient clinic used study in children, a study of acupuncture per-
a least ³CAM modality [4]. formed in adults with chronic constipation did
This review will discuss the effects of acu- not show any improvement in symptoms [64].
puncture, herbal therapies, reflexology, and
body massage in the treatment of pediatric
functional constipation. Since no well-designed Herbs
studies could be identified on the effect of hyp-
notherapy, homeopathy, chiropractic and osteo- Herbals and botanicals, and especially traditional
pathic manipulation, and energy therapies such Chinese medicine, have been used in many cul-
as Reiki and healing touch these topics will not tures over thousands of years for defecation disor-
be discussed here. ders in both children and adults. Although there
are many Chinese herbal medicine (CHM) inter-
ventions available, and some have been verified by
Acupuncture clinical trials, their efficacy and safety are still
questioned by both patients and health-care pro-
Little effort has been made to investigate the viders worldwide. A 2009 systematic review of the
efficacy of acupuncture on constipation. A literature identified a total of 62 articles of which
recently published review identified a total of 29 35 were reviewed including a total of 3,571 patients
clinical studies evaluating the complementary (ranging in age from 1 month to 93 years) [65].
effects of auriculotherapy as treatment option for Although the authors conclude that the results of
488 A.M. Vlieger and M.A. Benninga

the different studies included, favored the tested relaxation and the healing response [67]. The
CHM interventions in comparison with controls, effect of reflexology has also been studied in 50
the results of these trials should be interpreted with children, ages 3–14 years, with constipation and
caution due to the generally low methodological fecal incontinence [68]. After six weekly
quality of the included studies. First, all studies reflexology sessions of 30 min, results supported
provided insufficient information on how the ran- an increase in frequency of bowel movements and
dom allocation was generated and/or concealed, a decrease in fecal incontinence episodes with
which is necessary to avoid selection bias. Second, only 2% instead of 36% of the study children hav-
none of the studies used any blinding method. ing fewer than one bowel movement a week dur-
Third, none of the included studies addressed ing treatment. No side effects were reported, but
incomplete outcome data, such as missing data double-blind studies with longer follow-up are
due to attrition or exclusions. Fourth, none of stud- needed to exclude placebo effect and determine
ies had been registered and finally the majority of the long-term outcome of this treatment.
experimental CHM interventions were prepared
by the investigators without detailed information
describing underlying rationales on formulation, Massage
dosage, manufacturing process, etc.
A recent observational study investigated the Abdominal massage for the relief of constipation
use of a Japanese herbal medicine, Dai-Kenchu-To was a commonly practiced therapy in India,
(DKT) composed of three herbs, zanthoxylum China, Arabia, Egypt, and Greece, but its use
fruit, ginseng root, and dried ginger rhizomes, in declined over time. As for other complementary
ten children with non-defined severe constipation therapies, there is now a resurgence of interest in
over a 3- to 12-month period [66]. In this small the role that abdominal massage may play in
study the authors conclude that DKT had a favor- relieving constipation, although preliminary stud-
able clinical effect on symptoms of constipation ies have been disappointing although many
in children such as fecal incontinence. No data patients perceived the therapy as agreeable [69].
were, however, provided about the effect on def-
ecation frequency, consistency of stools, and
abdominal pain. Conclusion
Historically, the botanical agents Rhamni pur-
shiana and senna (Sannae folum) have been used Some CAM therapies and especially acupuncture
as stimulant laxatives and are approved by the and hypnotherapy show considerable promise in
Food and Drug Administration for the treatment the treatment of children with motility and sen-
of constipation in children over 2 years of age. sory disorders. Since so many patients are using
(NICE guideline), however studies evaluating CAM and because some of these modalities are
safety and efficacy of these stimulants are not always devoid of risks, it is important for
lacking. pediatricians and pediatric gastroenterologists to
be familiar with these therapies. Moreover, given
the ongoing interest in CAM by pediatric patients,
Reflexology it is in the public interest to establish more rigor-
ous evidence on efficacy and safety of these ther-
Reflexology is based on the notion that different apies. Only this way, we can head towards
areas on the hands and feet correspond to glands, integration of evidence-based CAM modalities
organs, and other parts of the body and that pres- into pediatric motility and sensory disorders.
sure on those specific areas can have therapeutic Until then, one should try to recognize both pos-
effect. The mechanism underlying this treatment is sibilities and limitations of CAM therapies in dis-
unknown, but many believe that the effect is caused cussing these treatment options with parents and
by an improvement of blood flow that encourages patients.
44 Complementary and Alternative Treatments for Motility and Sensory Disorders 489

15. Reinthal M, Andersson S, Gustafsson M, Plos K,

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 Cellular-Based Therapies for
Pediatric GI Motility Disorders 45
Ryo Hotta, Dipa Natarajan, Alan J. Burns,
and Nikhil Thapar

management and overall survival of children

Introduction suffering from severe intestinal motility disor-
ders, most of whom would otherwise not have
Currently, as has been discussed in other chap- survived beyond the neonatal period [1–3], the
ters, the therapeutic options for many gastrointes- conditions continue to be associated with high
tinal motility conditions remain inadequate. For levels of morbidity and mortality. Mortality rates
the most severe, treatments are limited to pallia- still remain in the order of 8–20%, and mostly
tive interventions such as surgery and the provi- relate to iatrogenic complications of central
sion of artificial nutrition. This highlights the fact venous catheter-related sepsis and PN-related
that current treatments aim to prevent the mortal- liver failure [1–6].
ity and limit morbidity associated with the most The poor outcome of gut motility disorders is
significant complications of the diseases but are perhaps best exemplified by Hirschsprung’s dis-
not designed to be curative. ease (HSCR) where despite substantial surgical
Although it is clear that both surgery and expertise and relatively rare use of PN, the post-
parenteral nutrition (PN) have revolutionized operative morbidity data is compelling [7–11].
A long-term follow-up study of 48 HSCR patients
with total colonic aganglionosis (TCA) by Tsuji
R. Hotta, M.D., Ph.D. et al. showed that 94% survived. Of the survivors,
Department of Anatomy and Neuroscience,
The University of Melbourne, Melbourne, Australia
fecal incontinence was present in 82% of patients
at 5 years, 57% at 10 years, and 33% at 15-year
Department of Pediatric Surgery, Keio University School
of Medicine, Tokyo, Japan
follow-up. On anthropometric follow-up, 63% of
patients with TCA were failing to thrive at 15
D. Natarajan, M.Sc., M.Phil., Ph.D. • A.J. Burns, Ph.D.
Neural Development Unit, UCL, Institute of Child
years [7]. More recent studies suggest that such
Health, London, UK problems occur irrespective of the extent of agan-
N. Thapar, B.Sc.(hon), B.M.(hon), M.R.C.P.,
glionosis [8] and persist in more than 50% of
M.R.C.P.C.H., Ph.D. (*) HSCR patients into early adulthood [9].
Gastroenterology Unit, University College London, Such data highlights the need for improved,
Institute of Child Health, Division of more curative, therapies for gut motility disor-
Neurogastroenterology and Motility ,
London, UK
ders, including those designed to definitively
restore missing components or rescue dysfunc-
Department of Paediatric Gastroenterology, Great
Ormond Street Hospital for Children,
tional ones. With particular attention to enteric
London, UK neuropathies, this chapter summarizes the prog-
e-mail: [email protected] ress that has been made and the challenges that

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 493

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_45, © Springer Science+Business Media New York 2013
494 R. Hotta et al.

remain in the development of new curative led to significant interest for their use in regener-
cellular therapies for gut motility disorders. ative medicine, especially given their potential to
generate “unlimited” quantities of cells for
replacement therapies. ES cells from both mouse
Stem Cell Therapies for ENS Disorders: (mES) and human (hES) are capable of produc-
Background and Concepts ing a range of neural cell types [22–28], includ-
ing enteric neurons [29, 30]. Kawaguchi et al.
Recent advances in molecular biology and genet- demonstrated that neural crest (NC) progenitors
ics have significantly enhanced our understand- (Sox10 expressing) derived from mES cells can
ing of the development and function of the gut colonize, and give rise to neurons (Hu- and TuJ1-
neuromusculature, especially its intrinsic inner- expressing) within explants of aneural hindgut of
vation, the enteric nervous system (ENS). This mouse embryos [30]. Neural progenitors derived
has facilitated not only our appreciation of the from hES cells also appear capable of generating
pathogenesis of gut motility disorders but also NC-like cells that migrate along normal NC
the identification of novel tools and targets for migratory pathways in quail embryos in vivo and
therapy [12, 13]. Stem cells, defined by their colonize explants of embryonic mouse gut in vitro
unique ability to self-renew, proliferate exten- where they give rise to neurons [29].
sively and differentiate into multiple lineages, Apart from neurons, mES cells also appear
provide one such tool. For the purposes of this capable of generating “gut-like” structures [31–
review the term “stem cell” has been used to 36]. These structures are 0.2–1.5 mm in diameter,
denote both progenitor cells, with limited self- and contain an endodermal epithelium, intestinal
renewal and differentiation capacities, as well as epithelial stem cells, a layer of smooth muscle
stem cells in the truest sense. cells, and interstitial cells of Cajal (ICCs); they
Successful stem cell therapy has already been also exhibit spontaneous contractions [31–36].
performed for many years in the form of bone Although they show some similarities to normal
marrow transplants, and there is currently enor- gut organogenesis [35] the requirement for brain-
mous interest in the potential of stem cell therapy derived neurotrophic factor (BDNF) for neuron
to treat diseases of both the central nervous sys- development differs from normal enteric neuron
tem (CNS) [14] and ENS [15–17]. Compared development, which does not require BDNF [37].
with other systems the use of stem cell therapy It is still unclear whether gut-like structures
for treating diseases of the ENS has some poten- derived from ES cells will be useful for cell ther-
tial advantages including accessibility to both apy or whether they are a curiosity of interest to
source and deliver cells, as well as the possibility basic ES cell researchers only.
of autologous transplantation.
CNS-derived stem cells: Although it had long been
believed that the CNS in mammals is incapable of
Sourcing Stem Cells for ENS Therapy regenerating after birth, adult neurogenesis is now
well established, including in humans [38–44].
In the quest to develop cellular therapies for ENS This neurogenesis appears to be effected by a
disorders, a number of tissue sources have been population of self-renewing, multipotent progeni-
explored to identify a cell type capable of generat- tors known as neural stem cells (NSCs) [45, 46].
ing ENS components upon transplantation. These CNS–NSCs were one of the first cell types tested
are discussed below and summarized in Table 45.1. for ENS therapy as several features were thought
to make them suitable [16]. Transplanting CNS–
Embryonic stem (ES) cells derived from the inner NSCs into the pyloric wall of an animal model of
cell mass of the blastocyst are pluripotent and gastroparesis (nNOS−/− mice) Micci et al. showed
capable of giving rise to all the cell types in the that these cells predominantly gave rise to neuronal
body [18]. Their initial discovery [19, 20] and nitric oxide synthase (nNOS) expressing neurons,
subsequent isolation from human embryos [21] which resulted in significant improvements in
Table 45.1 Possible sources of stem cells to generate a putative ENS
Differentiation in host
Source Selection/propagation Recipient or host tissue tissue Function Reference
ES
Mouse ES cells EB Mouse renal capsule N, M, ICC, and EP Regular slow wave activity and [31, 34, 35, 101]
spontaneous spike action
potentials
Mouse ES cells Sox10 Aneural hindgut explant from N ND [30]
mouse embryo in vitro
CNS
Embryonic mouse brain NS nNOS−/− mice stomach in vivo N + G Improved gastric function [47, 88]
Embryonic rat brain NS Chemically denervated rat N+G Restored rectoanal inhibitory [48]
rectum in vivo reflex
Embryonic rat neural NS Chemically denervated rat colon N + G Improved colonic motility [49]
tube in vivo
Neural crest ENS
Embryonic mouse gut Sorted Ret + cells Aganglionic gut explant from N+G ND [60, 62]
Ret−/− mouse embryo in vitro
Embryonic/postnatal NS Aganglionic gut explant from N+G ND [65]
mouse gut Ret−/− mouse embryo in vitro
45 Cellular-Based Therapies for Pediatric GI Motility Disorders

Postnatal/adult rat gut Sorted p75+/a4 Aganglionic gut explant from N ND [57, 59, 64]
integrin + cells Ednrb−/− mouse embryo grown
on chorioallantoic membrane of
chick embryos
Embryonic rat gut Sorted p75+/a4 Ednrbsl/sl rat bowel in vivo, i.p. N+G ND [100]
integrin + cells
Embryonic/postnatal NS Human gut explant in vitro N ND [70]
human gut
HSCR patient gut NS Aneural hindgut explant from N + G + ICC Restored motility patterns to [71, 72]
mouse embryo in vitro hindgut
Postnatal human gut NS Explant from aganglionic region N ND [73]
mucosa of HSCR patient in vitro
ENS cell line from Sorted p75+ cells Piebald or nNOS−/− mice colon N Improved colonic motility [102]
immortomice in vivo
(continued)
495
Table 45.1 (continued)
496

Differentiation in host
Source Selection/propagation Recipient or host tissue tissue Function Reference
embryonic mouse gut Sox2 Aneural hindgut explant from N ND [103]
mouse embryo in vitro
Other NCCs
Embryonic mouse neural Neural tube explant Dom/+ mouse colon in vivo, i.p. N + G ND [58]
tube
Embryonic rat peripheral Sorted p75+/a4 into migratory pathway of Gut; no, peripheral ND [57, 59]
nerve integrin + cells embryonic chickens in vivo nerve; N + G
CNS central nervous system, EB embryoid body, ENS enteric nervous system, EP epithelium, ES embryonic stem (cells), G glial cells, HSCR Hirschsprung’s disease, ICC inter-
stitial cells of Cajal, i.p. intraperitoneally, M myofibroblasts, N neuron, NCCs neural crest cells, ND not determined, NS neurospheres
R. Hotta et al.
45 Cellular-Based Therapies for Pediatric GI Motility Disorders 497

gastric emptying and in electric field stimulation- form the ENS when transplanted to uncolonized,
induced relaxation [47]. Although the mechanisms or aganglionic gut, are present within the gastro-
underlying such improvement of gastric function intestinal tract during development and into post-
were unclear, the study provided the first demon- natal life [59–64], including from the ganglionic
stration that NSCs transplanted into the bowel were portion of the gut from a HSCR mouse model
able to ameliorate a motility disorder [15]. More (miRet51) [65–67]. The methodology used to
recently, transplantation of fetal cerebral cortex- isolate such cells is the culture of dissociated gut
derived CNS–NSCs into the rectum of adult rats, to give rise to neurospheres or neurosphere-like
where enteric neurons had been destroyed chemi- bodies (NLBs), akin to stem cell-containing CNS
cally, resulted in the generation of neurons and glial neurospheres. In addition to differentiated neu-
cells, an increase in both the expression of nNOS rons and glia, NLBs also contain proliferating
and choline acetyltransferase (ChAT), and restora- undifferentiated cells that not only express puta-
tion of the rectoanal inhibitory reflex [48]. tive stem cell markers (e.g., Sox10), but are also
Cells isolated from the mid-embryonic rat capable of self-renewal and giving rise to both
neural tube or “neuroepithelial stem cells” have enteric neurons and glia. Grafting of postnatal
also been shown to give rise to enteric neurons NLBs into aganglionic embryonic mouse gut
in vivo in similar experimental animals to that revealed that donor cells were able to colonize
described above [49]. Transplantation of these the gut and differentiate into appropriate enteric
cells appeared to result in nNOS and ChAT phenotypes, at the appropriate locations [65].
expressing neurons and improvements in colonic Recent in vivo studies have shown that ENS
motility in recipient colons in which the ENS had stem or progenitor cells have the potential to
been chemically destroyed [49]. migrate, proliferate, and differentiate into appro-
priate phenotypes when transplanted into the
Neural crest stem cells: Perhaps the most attractive colon of postnatal mice [68]. Such cells isolated
tools for ENS therapy are derivatives of those NC from the embryonic (E14.5) mice gut survived
cells that initially gave rise to the ENS itself. This for at least 16 weeks, and formed enteric gan-
is described in detail in earlier chapters. Briefly, glion-like clusters containing neurons and glia.
during embryogenesis NC cells emigrate from the Graft-derived neurons expressed some enteric
NC, a transient structure that forms at the dorsolat- neuron subtype markers, including NOS, ChAT,
eral surface of the developing neural tube, and calbindin, and calretinin [69]. Importantly, intra-
migrate along defined pathways to give rise to cellular electrophysiological recordings from
diverse structures including the ENS [50, 51]. graft-derived neurons showed that they fired
Vagal (hindbrain) NC cells arising adjacent to action potentials and received fast excitatory
somites 1–7 [52, 53] enter the foregut and migrate postsynaptic potentials (fEPSPs) demonstrating
along the developing gastrointestinal tract to give that the graft-derived neurons had incorporated
rise to the majority of the ENS [54–56]. The capac- into the enteric circuitry [69].
ity to rescue the ENS appears to be limited to NC
cells fated to give rise to the ENS itself [57] and Human studies: A number of groups including
although there is some data to suggest that vagal ours have reported the harvesting of ENS stem
NC have some therapeutic potential [58], the most cells from postnatal human gut [70–73]. Although
promising avenue appears to be the use of NC initial studies suggested that this required full
derivatives isolated from the gut. thickness tissue, our most recent work has shown
that gut mucosal biopsies obtained by routine
endoscopic procedures can be used as a source of
Enteric Neural Crest Stem Cells (ENS stem cells [73]. Neurospheres were generated in
Stem Cells) cultures of mucosal tissue from endoscopic biop-
sies obtained from children from the neonatal
Nonhuman studies: Several studies have demon- period up to 16 years, including HSCR patients
strated that multipotent cells, with the ability to (Fig. 45.1). The neurospheres were equivalent to
498 R. Hotta et al.

Fig. 45.1 Enteric neural stem cell-containing neuro- suggests neural crest derived undifferentiated progeni-
spheres can be harvested from postnatal gut. (a) tors or stem cells. (b and c) Low power (b) and high-
Fluorescent immunostaining of day 14 cell cultures gen- power (c) bright field images of cell cultures (day 21)
erated from postnatal mouse gut showing the presence generated from dissociated human colonic mucosal
of spherical multicellular aggregates of cells, termed biopsies obtained from a 6 year old patient by conven-
neurospheres. These contain cells positive for Sox10 tional endoscopy. The cultures show numerous charac-
(red) and for S100 (green). Positivity for both markers teristic neurospheres, which have been shown to contain
(arrow) suggests the presence of glial cells, whereas the enteric neural stem cells and can be transplanted into
presence of cells positive for Sox10 only (arrowheads) recipient gut

those generated from human embryonic and full What is the ideal target disease? HSCR has
thickness postnatal gut tissue and contained puta- provided the archetypal disease for ENS stem
tive ENS stem cells. When transplanted into seg- cell therapy. The ENS deficiency (distal intestinal
ments of aganglionic gut, including human HSCR aganglionosis), however, is absolute and exten-
maintained in vitro, the neurosphere-derived cells sive, and it is unclear whether replenisment of the
colonized the recipient gut and generated neu- complex ENS circuitry is truly achievable. In
ronal phenotypes. These studies highlight a view of this, perhaps disorders with a less severe
significant advance by identifying a regenerating anatomical or functional phenotype may be more
source of tissue to generate ENS stem cells and amenable to therapy.
confirming the feasibility of autologous trans- In esophageal achalasia, in the early stages of
plantation. Although there is data that suggests disease, functional and presumably neuronal loss
that transplanted human cells are capable of appear more restricted to the lower esophagal
influencing mouse embryonic gut function [72], sphincter presenting a smaller therapeutic target.
current studies are more robustly assessing func- The underlying immunologically mediated patho-
tional rescue of recipient postnatal gut following genic processes [75], however, may need to be
ENS stem cell transplantation in vivo. controlled prior to transplantation to prevent
Most recently, the development of newer destruction of a neo-ENS. In intestinal pseudoob-
endoscopic techniques that allow the acquisition struction and slow transit constipation the overall
of full thickness gut wall biopsies may enable ENS “scaffold” appears intact but is clearly dys-
harvesting of stem cells from all the layers of functional possibly due to deficiencies of particular
ENS plexuses overcoming potential limitations elements of the neuromuscular circuitry [76–78].
of sourcing cells from any one [74]. These elements, once identified, may be easier to
replenish than the entire ENS. Generalized involve-
ment of the long gastrointestinal tract may, how-
Practical Challenges in Developing Cell ever, limit success, as would potential limitations
Therapies in migration of transplanted cells [79, 80]. It is clear
that all these potential disease targets need more
Although there has been much progress in the detailed characterization of their specific defects
sourcing of cells with potential for therapy for gut and etiology prior to the development of any tai-
motility disorders, some key challenges still need lored replensihment strategies. Recent international
addressing before effective clinical application. initiatives to address these hold promise [81].
45 Cellular-Based Therapies for Pediatric GI Motility Disorders 499

It should be noted that complete ENS restitution maintaining and repairing the tissue in which they
may not be necessary. Studies of the ageing gut, are found and restricted potential to generate only
where despite substantial neuronal loss, a scanty those cell types (e.g., neurons and glia) of the
surviving ENS functions in the absence of any required tissue (e.g., ENS), which limits the need
overt functional obstruction, suggest that partial for cell programming and reducing the risk of gen-
ENS reconstitution may be sufficient to restore erating “ectopic” cell types and malignancy. Such
some balance between inhibitory and excitatory cells, however, are present within much smaller
influences within the neuropathic gut [82, 83]. This number and appear to have a reduced potential to
suggests that delivery of smaller number of appro- proliferate. Kruger et al. reported that NC stem
priate cells may be an acceptable therapeutic goal. cells comprise only <0.2% of cells within the gut
What is the ideal cell type? It is likely that the wall of postnatal day 22 rats [64] and human stud-
therapeutic requirement for individual disorders ies have suggested that the generation of ENS stem
will determine which cell source is most suitable, cell-containing neurospheres declines with increas-
e.g., whether to use multipotent stem cells (e.g., ing postnatal age [73]. Although it is possible to
from hES, iPS) or more committed neuronal pre- enrich and expand neural stem cells obtained from
cursors (e.g., “adult stem cells” or precursors the ENS [65, 70–73], it is not known whether the
sourced from gut). Limitations exist for each source therapeutic potential is compromised with pro-
ranging from uncontrolled proliferation and tumor longed in vitro propagation. The paucity of specific
formation (ES cells) to restricted harvesting and markers for stem cells presents a further potential
differentiation potential (adult stem cells). obstacle for the field. ENS stem cell harvesting has
The production of unlimited quantities of largely been restricted to their isolation within
enteric neurons by direct induction of ES cells neurospheres, structures composed of a heteroge-
remains an exciting possibility, but there remains nous mix of cells consisting of, in addition to the
concern about their potential to form tumors stem cells, differentiated cells including neurons,
[21, 84] and unwanted cell types. Strategies have glia, and smooth muscle cells [65, 73]. Although it
been proposed to prevent this including partially may be argued that pure isolation of stem cells is
differentiating ES cells, enriching for appropriate perhaps not necessary as neurospheres exist as
cell types and then screening for undifferentiated potential readymade stem cells niches and com-
cells [84–86]. Certainly it would be advantageous plete therapeutic packages capable of colonizing
to differentiate them into specific neuronal sub- aganglionic gut [65, 71, 73], unless specific isola-
types before transplantation. Protocols for such tion is possible the manipulation within, and gen-
specific differentiation from each stem cell type eration of targeted cell types from, this heterogenous
have yet to be established although some prog- pool is likely to be a major problem.
ress has been made. Stem cells from fetal brain One of the most exciting developments in stem
(CNS–NSCs) also have the ability to divide, form cell science has been the generation of induced
neurospheres and differentiate into neurons, and pluripotent stem (iPS) cells by the reprogramming
non-neuronal cells [45, 87]. Micci et al. have of mouse embryonic or adult fibroblasts back to a
reported that CNS–NSCs preferentially differen- pluripotent state by introducing four transcrip-
tiate into nNOS neurons [47, 88], which may be tional factors—Oct4, Sox2, Klf4, and c-Myc [89].
promising for conditions such as esophageal Successful reprogramming of differentiated human
achalasia. For many patients, clinical practitio- somatic cells into a pluripotent state raised the
ners and the general public at large, however, possibility of creating patient-derived stem cells
there are ethical problems associated with the use [90], which would bypass both immunological
of hES cells and CNS–NSCs from fertilized problems and bioethical issues associated with
human eggs and aborted fetal brain tissues, hES cells or those obtained from fetal brains. In
respectively. terms of the gastrointestinal tract, iPS cells can
Much focus has therefore shifted onto “adult” produce intestinal tissue and gut-like structures
stem cells, especially given their presumed role in in vitro. Three-dimensional intestinal organoids
500 R. Hotta et al.

were derived from human iPS cells using activin A of Endothelin 3 significantly increased the prolif-
treatment to induce endoderm formation, followed eration of ENS progenitors as well as increasing
by FGF4 and WNT3A manipulations to develop neurite outgrowth [65, 95]. Such findings and
hindgut and intestinal specification [91]. Gut-like studies have enormous implications for pre-trans-
structures can also be derived from mouse iPS plantation priming of ENS stem cells as well as
cells that contain a lumen with three distinct layers the creation of receptive environments within
(epithelium, connective tissue, and muscle layer), recipient aganglionic gut.
neuronal networks, and ICCs, which exhibited Is the gut environment suitable for cell replen-
spontaneous contractions [92]. It is unknown ishment? In HSCR the average aganglionic seg-
whether iPS cell-derived gut-like structures or ment measures almost 10 cm. Yet data from
neurons will have any therapeutic relevance for the several groups including ours suggest that longi-
treatment of enteric neuropathies. Studies will be tudinal migration of transplanted cells within
required to elucidate the mechanisms of repro- recipient embryonic gut maintained in organ cul-
gramming of somatic cells into enteric neurons ture may be limited to a few millimeters at best
using exogeneously delivered transcription fac- [73]. Limited migratory ability of grafted stem
tors, and to establish a method of purifying desired cells appears special important in adolescent or
cells with 100% frequency in vitro. older patients, where the mesenchyme is already
Is cell manipulation prior to transplantation well differentiated [47, 79, 80]. It is possible that
likley to be necessary? The finding that stem cells the local gut environment of patients with con-
can be generated from innervated or ganglionic genital gut motility disorders might be defective
portions of diseased gut makes it likely that in and/or not be permissive for the grafts to survive
some cases, especially with autologous trans- or differentiate into appropriate cell types. For
plantation, that genetic modification of the cells example, there are reports of decreased expres-
may be necessary and possible before transplan- sion of GDNF in the aganglionic region of
tation. Stem cells derived from the normo-gangli- patients even with no mutation of GDNF [96].
onic part of HSCR gut are likely to have defective GDNF has consistently been implicated in the
biological function, underlining the inability of process of directed migration of NC-derived ENS
their predecessors to form a complete or func- progenitors to facilitate colonization of the devel-
tional ENS [93]. Indeed, enteric progenitors iso- oping gut during embryogenesis [97, 98].
lated from the monoisoformic Ret51 (miRet51) Therefore, similar to donor cells, the recipient
HSCR mouse model show delayed differentia- gut may also require pre-treatment to optimize
tion compared to controls [66]. These defective transplant success. More work needs to be done
cells appear to be rescued by genetic manipula- to confirm that pre-treatment of cells, the recipi-
tion, given that re-introducing the Ret9 isoform ent gut or patients themselves does not have any
within the miRet51 ENS progenitor cells reverses adverse effects in other aspects of the health of
the differentiation deficits (Natarajan and Pachnis, patients.
personal communication). Finally, immunological rejection of trans-
Injection of stem cells supplied with some planted cells within the gut is also likely to be a
missing neurotrophic factors might also be problem [99] (Hotta, personal communication).
needed for their survival, migration, and differen- This may well be overcome with improving pro-
tiation [17]. Recent data suggests this may be tocols of immunosupression already in use with
possible. Endothelin 3, for example, inhibits solid organ and cellular transplatation and use of
reversibly the commitment and differentiation of autologous transplantation.
ENS progenitor cells along the neurogenic and What is the most effective route to deliver cell
gliogenic lineages, suggesting a role for this fac- therapy to the gut? The gut is easier to access
tor in the maintenance of multilineage ENS pro- compared to the brain or spinal cord and cells
genitors [94]. Glial cell line-derived neurotrophic have been introduced into the gut wall of animals
factor (GDNF) acting in the presence or absence through the serosa via laparotomy [47–49, 58].
45 Cellular-Based Therapies for Pediatric GI Motility Disorders 501

Stems cells have also been injected intraperitone-

ally into animals to replace enteric neurons, but Summary and Future Directions
further work is needed to identify all the sites
colonized by using this method [58, 100]. A Cell therapy for gastrointestinal motility disor-
recent study has revealed the potential of NC ders is an exciting and promising prospect. The
stem cells to give rise to a small number of neu- ENS has many potential advantages that favor the
rons and glial cells when injected into the perito- success of transplantation therapies. These
neal cavity of Ednrbsl/sl rat, but none of the injected include accessibility to both source and deliver
cells were found in the aganglionic colon [100]. cells, as well as the possibility of minimizing
Injecting cells intravenously can allow cells to be immunological rejection by expanding neural
delivered to a broader area which would be an stem cells, obtained from unaffected regions of
advantage over mulitple injections. However, the the intestine, for autologous transplantation.
vasculature has not yet been explored extensively The evidence to date suggests that cells with
as a delivery route for cells to gut. the potential of generating components of the ENS
Endoscopy is routinely practised to deliver can be harvested from a range of allogeneic and
drugs into the gut wall. This may be a better way autologous sources, have their biological proper-
for not only harvesting cells but also for their ties manipulated, and ultimately be transplanted
delivery into recipient guts especially when com- into diseased or dysmotile gut to replenish compo-
bined with imaging techniques for better preci- nents of the ENS and rescue function. Although a
sion (e.g., ultrasound, confocal). Disadvantages number of significant hurdles remain, which will
include the need to intubate entire segments of all need to be addressed, all is perhaps not so bleak.
diseased gastrointestinal tract, some of which, Aging-related neuronal loss is not associated with
e.g., mid-small intestine remain relatively inac- functional failure giving hope that restitution of a
cessible, and would require more complicated full normal ENS is perhaps not needed. Gene ther-
enteroscopy techniques. apy is already established in clinical therapies and
What is the best measure of the success of cell rescue of defective ENS stem cells derived from
therapy? The main aim of replacement cell ther- murine models of HSCR possible. Tissue trans-
apy is to restore some function to the diseased plantation and management of immunological
gut. Grafted human ENS stem cells have been aspects is well studied and potentially overcome
reported to differentiate into glia and neuronal with use of autologous transplantation. Recent
subtypes reminiscent of a functional ENS within work has shown that minimally invasive proce-
explants of aneural hindgut from chick and mouse dures such as endoscopy can be used to isolate
embryos [72, 73]. Lindley et al. further reported ENS stem cells from a regenerating source of
that the newly generated neurons formed syn- intestinal tissue and ultimately to deliver them
apses and were able to regulate the rate of con- back into gut. Transplantation of such cells into
traction of the recipient guts [72]. models of aganglionic gut suggests they are capa-
Although it is clear that further studies are ble of colonization, generating components of the
required to determine whether introduced stem ENS, and effecting functional change. Although
cells integrate into the circuitry of a preexisting pleasing progress has been seen with enteric neu-
ENS when introduced into a ganglionic region, ropathies, other motility disorders such as myopa-
or form an ENS with the appropriate circuitry to thies and mesenchymopathies will need to see
produce functional recovery when introduced similar initiatives in terms of understanding dis-
into aganglionic regions, it is likely that func- ease pathogenesis, pathology and ultimately cel-
tional data will only truly be understood within lular therapies.
the context of in vivo studies, studying parame- There is no doubt that children and adults
ters ranging from simple gut transit to definitive with gut motility disorders represent a significant
measurements of peristaltic activity and sphinc- challenge in management. Significant strides
ter function. have been made in teasing away at the processes
502 R. Hotta et al.

that underlie the complex workings of the gut 14. Lindvall O, Kokaia Z, Martinez-Serrano A. Stem cell
neuromusculature, especially the ENS, and have therapy for human neurodegenerative disorders-how
to make it work. Nat Med. 2004;10(Suppl):S42–50.
given us tremendous insight into pathogenesis 15. Young HM. Neural stem cell therapy and gastrointes-
and the identification of putative treatments. tinal biology. Gastroenterology. 2005;129:2092–5.
Cellular therapies should now be considered 16. Micci MA, Pasricha PJ. Neural stem cells for the
alongside these and perhaps herald a shift treatment of disorders of the enteric nervous system:
strategies and challenges. Dev Dyn. 2007;236:33–43.
towards definitive cures for gut motility 17. Schafer KH, Micci MA, Pasricha PJ. Neural stem cell
disorders. transplantation in the enteric nervous system: road-
maps and roadblocks. Neurogastroenterol Motil.
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18. Wobus AM, Boheler KR. Embryonic stem cells: pros-
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 Chronic Intestinal Pseudo-
obstruction Syndrome: Surgical 46
Approach and Intestinal
Transplantation

Olivier Goulet and Sabine Irtan

Chronic intestinal pseudo-obstruction syndrome or recessive autosomal inheritance have been

(CIPO) is a severe, often unrecognized cause of described. Based on histological features intestinal
neonatal or post-natal progressive intestinal fail- pseudo-obstruction is classified into three main
ure (IF). This rare syndrome represents one of the groups: neuropathies, and myopathies or “mesen-
main causes of IF and is characterized by impair- chymopathies,” according to the predominant
ment of physical growth and development as well involvement of enteric neurones, smooth muscle
as by a high rate of morbidity and mortality. cells, and interstitial cells of Cajal, respectively
The diagnosis of CIPO is based on typical [6–14]. Mitochondrial disorders have been
clinical manifestations, radiological evidence of reported [15, 16]. Regardless of the histologic
distended bowel loops with air-fluid levels, and type, CIPO always involves alterations of smooth
the exclusion of any organic obstruction of the muscle contractile function, leading to abnormal
gut lumen [1–5]. CIPO is often unrecognized, intestinal tract peristalsis and nutritional disorders.
and the diagnosis, therefore, delayed by several Manometry can play a supportive role in defining
years with useless and potentially dangerous the diagnosis, as well as by showing differences in
surgeries. the manometric pattern of CIPO [17].
CIPO can occur in patients with underlying dis- Accompanying uropathies must be sought in
eases associated with gastrointestinal manifesta- patients with CIPO [6, 18]. The clinical impact of
tions (scleroderma, amyloidosis, hypothyroidism, these uropathies may be important and require
etc.) or be secondary to water-electrolyte disorders specific management by using daily drainage and,
(e.g., hypokalemia), and toxic, viral, and parasitic sometimes, vesicostomy.
causes. Most cases are idiopathic and sporadic, Longitudinal surveys have been published,
even though familial forms with either dominant including a large multicenter French pediatric
study [19–23]. Long-term outcomes are gener-
ally poor despite surgical and medical therapies
and characterized by disabling and potentially
O. Goulet, M.D., Ph.D. (*)
Department of Pediatric, Gastroenterology Hepatology life-threatening complications. Treatment of
and Nutrition, National Reference Center for Rare CIPO involves nutritional, pharmacological, and
Digestive Diseases, Hospital Necker-Enfants Malades, surgical therapies but is often frustrating and does
University of Paris Descartes,
not change the natural course in the majority of
149 rue de Sèvres 75015, Paris, France
e-mail: [email protected] cases [24–27]. Nutritional management is of cru-
cial importance in the pediatric age group and
S. Irtan, M.D.
Pediatric Surgery, Hôpital Necker-Enfants Malades, involves enteral delivery of special formulae, by
University of Paris, Paris, France nasogastric tube, percutaneous gastrostomy, or

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 507

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9_46, © Springer Science+Business Media New York 2013
508 O. Goulet and S. Irtan

jejunostomy [26]. In the most severe cases, should have intestinal full-thickness biopsies for
parenteral nutrition becomes mandatory in order specific diagnosis. This should be done regard-
to satisfy nutritional requirements and appropri- less of the patient’s age.
ately manage obstructive episodes.
Surgery is one of the mainstays of CIPO ther-
apeutic management. Surgery is performed in a Gastrostomy Tubing
variety of situations in pediatric patients but sur-
gical options must be evaluated carefully. There Bowel decompression by a gastrostomy and/or
is no consensus regarding indications and pro- jejunostomy is often required. Repeated acute
cedures. This short chapter aims to review the episodes of bowel obstruction as well as chronic
main situations in which surgery may be intestinal distension require bowel decompres-
required. sion by using nasogastric suction. The placement
of a venting gastrostomy is of great benefit in
avoiding the recurrent placement of nasogastric
Surgery for Diagnosis tubes. When surgery is required, a gastrostomy
may be performed during the same surgical pro-
Variable clinical presentation and lack of other cedure. If a gastrostomy is not surgically placed,
specific diagnostic tests often leads to surgery percutaneous endoscopic gastrostomy tube (GT)
being required for diagnosis. Nevertheless, placement is easily achieved in these children.
unnecessary laparotomy could be avoided since Since enteral feeding should always be preferred
diagnosis is mostly based on clinical and radio- to using parenteral nutrition (PN), intragastric
logical symptoms of intestinal obstruction. It is administration of feeding may be achieved by the
not unusual, however, for some patients, espe- GT as continuous or bolus enteral tube feeding.
cially children and adolescents with an acute pre-
sentation, to undergo an exploratory laparotomy.
In the absence of organic obstruction observed at Enterostomy
this laparotomy, we suggest that a medico-surgi-
cal discussion be undertaken to consider: In neonates and young infants, intestinal obstruc-
– Performing intestinal full-thickness biopsies tion may last several weeks requiring total paren-
at different levels for histopathologic analysis teral nutrition (TPN) with subsequent
– Performing an enterostomy according to the complications including catheter-related sepsis
level of intestinal distension and liver disease [4]. Enterostomy may offer the
In reality, in most cases, the acute presentation chance to restart intestinal transit allowing feed-
and subsequent surgical procedure do not occur at ing and reducing the need for PN.
a specialized center, and these suggested interven- In some patients, attacks of intestinal obstruc-
tions are not done. Such issues are controversial tion are frequent and/or life threatening. Chronic
but we do propose that if the diagnosis of CIPO is bowel dilatation impairs intestinal motility creat-
strongly suggested from the surgical exploration, ing a vicious circle which increases intraluminal
careful biopsies should be performed. Regarding bacterial overgrowth with the subsequent risk of
enterostomy, our experience tends to suggest that intestinal translocation, enterotoxin release, and
if it is not performed at first laparotomy, it will liver disease [28, 29]. Enterostomy should be
need to be done later but with subsequent increased performed to bypass the functional obstruction
risk of peritoneal adhesions. and obtain digestive decompression.
In summary, patients with evidence of CIPO The location of the enterostomy is a matter of
from clinical and radiological presentation should debate. In cases of obvious megacystis microco-
not be operated on to make the diagnosis. Patients lon syndrome, a terminal ileostomy is certainly
who undergo laparotomy for enterostomy because required. Otherwise, we do recommend perform-
of permanent or recurrent intestinal obstruction ing a terminal ileostomy and avoiding a colostomy
46 Chronic Intestinal Pseudo-obstruction Syndrome: Surgical Approach and Intestinal Transplantation 509

whatever the clinical presentation or histopatho- reports are available both in children and adults
logic pattern. It is important to consider the so- describing the indications, complications, and
called ileo-caecal brake as the segment that outcomes. A retrospective, single-center study
should be short-circuited. In our experience, all involving eight adults was reported by Lynch
patients who first underwent a colostomy went et al. [33]. Six patients had CIPO and two had
on to have formation of a terminal ileostomy or chronic constipation. Use in seven of eight cases
jejunostomy. resulted in clinical improvement with reduction
The outcome after ileostomy or jejunostomy of intestinal obstruction episodes and improved
varies according to the location of the enteros- feed tolerance. One patient suffering chronic
tomy and to the disease itself. The literature does constipation required surgical removal of the per-
not provide any evidence of a histopathology- cutaneous endoscopic cecostomy tube at 4 days
related prognosis even if the survey reported by for fecal spillage resulting in peritonitis despite
Henyeke et al. suggested worse prognosis of successful tube placement. Removal of the cecos-
myopathies and that they all need ileostomies tomy tube occurred in three of six cases of
[22]. However, much fewer than 50% of patients pseudo-obstruction (the other three remain in
improve after ileostomy by being weaned from place). In the other patient with chronic constipa-
PN. In our opinion, enterostomy, as distal as pos- tion, clinical improvement occurred, but the
sible is the most logical approach. Terminal ileo- patient died of underlying illness 21 days after
stomy usually enables transit to resume and leads placement. A case of acute stercoral peritonitis
to a major long-term reduction in obstructive epi- was reported [34]. At laparotomy, the colostomy
sodes. We currently perform an ileostomy to flange was embedded in the abdominal wall but
obtain durable intestinal autonomy and PN wean- no pressure necrosis was found at the level of the
ing, with the future plan to do a total or subtotal colonic wall. This complication was likely related
colectomy with ileorectal or ileosigmoid pull- to inadvertent traction of the colostomy tube.
through [23]. Percutaneous endoscopic cecostomy is consid-
Irtan et al. have reported stomal prolapse in ered by some authors as a viable alternative to
children with chronic intestinal pseudo-obstruc- surgically or fluoroscopically placed cecostomy
tion as a frequent complication [30]. Twenty-two in a select group of patients with recurrent colonic
out of 34 (65%) CIPO children referred to their pseudo-obstruction or chronic intractable
center between 1988 and 2008 had a stoma and constipation.
were compared with 22 other children referred
for another pathology necessitating a stoma. The
incidence of stomal prolapse in CIPO children Closure of the Stoma
was 45% vs. 9% in non-CIPO children (p = 0.01).
Prolapse occurred between the first postoperative In children whom a decompression ileostomy has
day and the tenth postoperative month, with a produced relief, but there is diffuse disease, the
median of 2 months. Surgical management was urge to re-establish connection with the defunc-
required in 60%, with an intestinal necrosis rate tioned limb of the bowel should be resisted as this
of 20% leading to intestinal resection. The authors will only result in further episodes of obstruction.
did not identify particular risk factors favoring In other words, performing an ileostomy and
stomal prolapse. closing it because of clinical improvement results
Percutaneous endoscopic cecostomy or colos- in the patient undergoing two surgical procedures
tomy (PEC) is increasingly proposed as an alter- without resolution of the primary issues. This
native to surgery to treat CIPO and relapsing should be avoided. Conversely, in patients in
sigmoid volvulus [31–34]. Cecostomies or even which clear improvement from ileostomy is
sigmoidostomies have been used to administer observed, with PN weaning and at least 2 years
antegrade enemas when intractable constipation follow up on enteral tube feeding or oral feeding
appears to be the prominent symptom. A few without exacerbations, total colectomy and
510 O. Goulet and S. Irtan

ileorectal anastomosis with the Duhamel proce- distension and pain. The mean duration of symp-
dure may be considered. In our experience, two- toms of colonic volvulus before seeking medical
third of the patients who underwent this procedure help was 4.2 days (range 1–7 days). Water-soluble
remain off PN for a long period of time [23]. contrast enema was the single most useful inves-
tigation for confirming the diagnosis. All patients
required surgery. There was no mortality associ-
Recurrent Laparotomies ated with colonic volvulus. Clinicians should be
and Enterectomy vigilant and include volvulus in the differential
diagnosis of the acute onset of abdominal disten-
In the past, many patients underwent multiple sion and pain in patients with CIPO and CIC.
surgical procedures. Unnecessary abdominal sur- Delay in diagnosis can result in bowel ischemia
gery in children with CIPO should be avoided and perforation.
because they bear the risk of prolonged postop- Some patients, in whom there is segmental
erative ileus and developing adhesions, creating a bowel dilatation but no evidence of mechanical
diagnostic problem each time there is a new obstruction, have been reported to benefit from
obstructive episode. Mechanical obstruction segmental resections or to have improved follow-
should be considered in patients with an enteros- ing placement of a jejunostomy tube within the
tomy who continue to present with exacerbations dilated loop [36, 37]. In our experience, the use
of bowel obstruction. In an earlier study involv- of this jejunostomy button device for daily inter-
ing only seven patients, surgery was performed mittent bowel decompression can effectively
as a treatment 21 times with a mean of three pro- improve bowel function allowing decreased PN
cedures per patient [20]. This is similar to other intake. However, one should consider the quality
data reported. In one study, 67 surgical proce- of life (QOL) of a child with three tubes and, for
dures were performed in 22 patients [8], and in most of the time, a central line.
another study involving 105 pediatric infants and Patients suffering from CIPO clearly benefit
children, 71 patients underwent surgery during from home parenteral nutrition (HPN) to main-
their illness, with 217 surgical procedures [21]. tain adequate nutritional status and general
An ostomy was the most performed procedure. health [38]. However, permanent and severe
Surgery may cause adhesions, so interpretations intestinal dysmotility can seriously disturb the
of postoperative obstructive episodes are difficult. QOL to the point of making it intolerable.
Exploratory laparotomy for obstruction should Subtotal enterectomy [39, 40] or bilateral thora-
be performed only when a clear mechanical coscopic splanchnicectomy have been proposed
obstruction has been demonstrated which remains in severe CIPO [41]. A retrospective study of
very difficult to assess. Signs of peritonitis, eight patients with end-stage CIPO maintained
extreme dilatation and pain in association with on HPN and suffering from chronic occlusive
specific episodes of obstruction point more symptoms refractory to medical treatment under-
towards mechanical rather than functional went extensive small bowel resection preserving
obstruction, and a laparotomy may be required to less than 70 cm of total small bowel and less than
relieve it. 20 cm of ileum [40]. The jejunum was anasto-
Patients with CIPO or chronic intractable con- mosed either to the ileum or to the colon. Six
stipation (CIC) may develop anatomical obstruc- patients were completely relieved from obstruc-
tion such as colonic volvulus, with presenting tive symptoms. Two patients needed a second
symptoms mimicking those of underlying operation to remove the residual ileum because
pseudo-obstruction. Patient records of 8 children of recurrent symptoms. Both were significantly
with colonic volvulus were retrospectively improved and there was no postoperative death.
reviewed [35]. The mean age at presentation with All patients experienced a significant improve-
colonic volvulus was 13.2 ± 5.05 years. All ment in their QOL. Near total small bowel resec-
patients presented with worsening of abdominal tion appears to be a safe and effective procedure
46 Chronic Intestinal Pseudo-obstruction Syndrome: Surgical Approach and Intestinal Transplantation 511

in end-stage CIPO patients, refractory to optimal antithymocyte antibody and alemtuzumab).

medical treatment. Experience at centers of excellence demonstrate
The implantation of gastric or intestinal pace- 1- and 5-year patient survival rates of 95% and
makers aimed at improving motility constitutes a 77%, respectively, with ongoing investigations
promising investigational approach in patients focusing on lowering long-term causes of graft
with severe motility disorders. The use of gastric loss such as chronic rejection [45].
electrical stimulation has been shown to In many cases of CIPO, outcome is poor, with a
significantly improve nausea and vomiting not constant risk of sepsis from intestinal bacterial
only in patients with diabetic gastroparesis, but overgrowth, and water-electrolytic disorders
more recently also in three adult patients with related to intraluminal fluid retention. ITx is the
familial and one with postsurgical CIPO with dis- only definitive curative treatment especially when
abling nausea and vomiting [42]. The weekly many medical and surgical attempts have failed.
vomiting frequency decreased from 24 before ITx with or without liver transplantation is required
implantation of the gastric pacemaker to 6.9 after in patients with primary neuro-muscular disease
12 months. The clinical response was unrelated and PN-related complications such as progressive
to the presence of, or improvement in, delayed or end-stage liver disease or for those whose intra-
gastric emptying in these patients. Although venous access has become unreliable and precari-
placements of the electrodes along the anterolat- ous because of repeated sepsis and extensive
eral surface of the stomach was successful in thrombosis. Transplant procedures vary according
most patients by laparoscopic implantation, the to indication for liver transplant and based on the
procedure was not without risk since the elec- experience of the transplant surgical team [47–49].
trodes caused ileus necessitating explantation Combined small bowel–liver transplantations or
and short intestinal resection [42]. multivisceral transplantations including the stom-
ach have been performed in refractory forms of
CIPO associated with end-stage liver disease [47–
Intestinal Transplantation 49]. Multivisceral transplantation (MVTx) was
reported in 16 children with a median age of 4
Intestinal transplantation (ITx) has become a life- years [47]. Indications for MVTx were liver fail-
saving procedure for patients with irreversible ure (n = 10), loss of venous access (n = 3), or sepsis
intestinal failure (IF) [43–45]. Indications for ITx (n = 3). Modified MVTx without the liver was per-
include not only extreme short bowel syndromes formed in six patients. Reported actuarial patient
but also all situations in which the small intestine survival for 1 year/2 years were 57.1% to
is unable to achieve nutritional requirements; these 88.9%/42.9% to 77.8% according to immunosup-
include inborn errors of intestinal mucosa devel- pressive regimens. Currently, none of the long-
opment (intestinal epithelial dysplasia, microvillus term survivors are on PN and all tolerate enteral
inclusion disease) or severe motility disorders such feeding. Gastric emptying was substantially
as CIPO [46–50]. Approved indications for ITx affected in one case. Bladder function did not
include liver dysfunction, loss of major venous improve in those with urinary retention problems.
access, frequent central line-related sepsis, and MVTx for CIPO offers a lifesaving option with
recurrent episodes of severe dehydration despite excellent function of the transplanted pancreas and
intravenous fluid management. Surgical options stomach among survivors.
include transplantation of the isolated intestine, ITx may represent the only definitive cure for
combined liver–intestine transplantation, or multi- patients with permanent intestinal failure due to
visceral transplantation of the stomach, duode- CIPO. However, graft rejection, and immuno-
num, pancreas, and small bowel (with or without suppression-related lymphoproliferative disor-
the liver). Immunosuppression for ITx is based on ders are more common than other organ
tacrolimus therapy, often with induction immuno- transplants. It is not yet established whether the
suppression using antilymphocyte antibodies (e.g., results of ITx achieved in CIPO patients are
512 O. Goulet and S. Irtan

equivalent to those experienced with other causes and transplant surgery. For many reasons (nutri-
of IF such as short gut syndrome, total agangli- tion, prevention of infectious complications,
onosis, microvillous inclusion disease, or epithe- etc.), an enterostomy (preferably an ileostomy) is
lial dysplasia [51]. Complications seem to be often performed as one of the first therapeutic
more common due to multiple previous abdomi- measures. The “permanent” surgical reconstruc-
nal surgeries, dysmotility of the stomach and tion, designed to be minimally obstructive, is
esophagus, and extra-intestinal manifestations only envisaged after a long period of stability and
including associated anomalies of the urological, if possible when the child is weaned from long-
immune, and neurological systems. An extensive term PN. Intestinal transplantation may be the
workup including a search for mitochondrial dis- last therapeutic option when all medical and sur-
orders should be performed before any discus- gical approaches have failed.
sion of ITx and careful consideration is required
before transplantation is undertaken. Determining
the extent of the disease process (which may References
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 Index

A Aerophagia
Abdominal bloating, 361 morbus ructuosus, 401
Abdominal distension, 273, 401, 402 pathophysiology, 402
Achalasia Rome III diagnostic criteria, 401, 402
clinical presentation, 231 treatment
differential diagnosis, 231 anxiolytic therapy, 403
endoscopy, 232 diagnosis, 402
epidemiology and incidence, 230 pharmacologic therapy, 403
etiology, 230–231 Aganglionosis
manometry, 232–234 genetic/congenital neuropathies, 188
outcome, 236–237 Hirschsprung disease (HSCR), 271, 272
pathophysiology, 230 Air swallowing, 401–403
radiography, 231–232 ALADIN protein, 206
treatment Alginate-antacids and mucosaprotectors, 342–343
endoscopic therapy, 234, 236 Allgrove syndrome, 206, 231
pharmacologic, 232, 234 Altered gut motility, 51
surgical, 236 Anal achalasia, 124–126
Acid reflux, 129, 130, 134 Anal canal length, ARM, 122
Acid suppression, 238, 239, 343 Anal stenosis, 304
Adolescent rumination syndrome Anorectal agenesis without fistula, 304
clinical presentation, 406 Anorectal malformations
diagnosis classification
antroduodenal tracing, 407, 408 anal stenosis, 304
differential, 407 anorectal agenesis without fistula, 304
manometry, 407 perineal (cutaneous) fistula, 302, 303
medical, 405 persistent cloaca, 302–303
Rome III criteria, 406, 407 rectourethral fistula, 302, 303
epidemiology, 405–406 rectovaginal fistula, 303, 304
pathophysiology, 406 rectum-bladder neck fistula, 302, 303
treatment vestibular fistula, 302, 303
biofeedback uses, 409 embryology and genetics, 301, 302
drugs, 409 long-term outcomes, 304–305
education and reassurance, 407–408 Anorectal manometry (ARM)
functional gastrointestinal disorder, 409 anatomy/physiology, 119–120
gradual refeeding, 409 diseases, anorectal canal
HRT, 408 anal achalasia, 124–126
intensive, 410 dyssynergic defecation, 126–127
psychological factor, 410 Hirschsprung disease, 124, 275
Adolescents, 369, 394 neuromuscular disease, 126
Adult stem cells, 499 fecal continence and defecation, 119

C. Faure et al. (eds.), Pediatric Neurogastroenterology: Gastrointestinal Motility 515

and Functional Disorders in Children, Clinical Gastroenterology,
DOI 10.1007/978-1-60761-709-9, © Springer Science+Business Media New York 2013
516 Index

Anorectal manometry (ARM) (cont.) deep breathing, 179

methods/technique gut motility and sensitivity, 7
anal canal length, 122 head up tilt, 179–180
balloon expulsion/defecatory dynamics, 124 preparation steps, 182
basal/resting anal sphincter pressure, 122 quantitative sudomotor reflex test (QSART), 177, 182
conscious rectal sensation, 124 sustained (static) handgrip, 181
HRM, 120, 121 tests of cardiovascular autonomic function, 177, 178
initial urge to defecate, 124 tests of sudomotor autonomic function (sweating),
maximal squeeze pressure, 122 177, 179
RAIR, 121, 122, 124 thermoregulatory sweat test (TST), 177, 182
references, 124, 125 tilt table test
water-perfusion manometry (WPM), 120, 121 different blood pressure and heart rate changes,
Antegrade enemas, 111, 112 180, 181
Antidepressants, 371 normal response, 180
Antimotility orthostatic hypotension (OH), 181
agents, 441, 448 postural tachycardia syndrome (POTS), 180
diphenoxylate, 448 reflex syncope, 180–181
loperamide, 448 utility, FGID, 182–183
Antimuscarinics, 448, 450 Valsalva maneuver (VM), 179, 180
Antispasmodics Autonomic testing, 177, 182, 183
antimuscarinics, 448, 450 Axial transformations, HRM, 82
calcium channel blocker, 452
direct smooth muscle relaxers, 450
dosages, 453 B
onabotulinumtoxin A, 450–451 Balloon expulsion/defecatory dynamics, 124
oral nitrate, 452 Bardet-Biedl syndrome, 209
topical nitrates, 451–452 Barostat test
Antispsmodics, 441–456 compliance, 145–146
Antral motility, 168 functional gastrointestinal disorders
Antroduodenal manometry (ADM) constipation, 147
HRM, 97 gastric sensitivity measurement, 146
indications, 101–103 rectal sensitivity measurement, 146
low compliance perfused manometric system, 95–97 somatic projections and reproducibility, 147
methodological aspects principle, 143, 144
analysis, manometric recording, 99–102 procedure, 143–145
patient preparation, 97–98 qualitative and quantitative assessment, 146
reference values, 100–101 sensory thresholds, 145
study procedure, 98–99 tone and accommodation, 146
normal motility visceral sensitivity, 143, 147
amplitude, single contractions, 92 Basal/resting anal sphincter pressure, 122
bursts of contractions, 94, 96 Bianchi intestinal lengthening, 308–309
discrete clustered contractions (DCCs), 93–95 Bidirectional signaling, 50
gastrointestinal housekeeper, 93 Biomedical model, psychological issues, 60
giant migrating contractions, 94 Biopsychosocial model, psychological issues, 60
migrating motor complex (MMC), 91–93 Bisacodyl, 455
postprandial/fed pattern, 93, 94 Bolus transit, 228, 236, 238
solid-state manometric system, 97 Bradycardia, 335
technical aspects, 94–95 Bradygastria, 163, 164
Antroduodenal motility and gastric myoelectrical Brain-gut axis, psychological issues, 61–62
activity, 318–319 Brain-gut-enteric microbiota axis, 52
Apnea, 335 Brain imaging, 42, 368, 380
Apparent life-threatening events (ALTE), 335 Breath testing (BT)
Aspiration and GER, 152–153 advantages, 167
Autism spectrum disorders (ASD), 223–224 gastric emptying, 166
Autoimmune ganglionitis, 196, 197 gastroparesis, 166
Autoimmune gastrointestinal dysmotility, 250, 251 indications, 165
Autoimmune myositis, 196 limitations, 167
Autoimmune neuropathy, 250–251 whole gastrointestinal transit (WGT), 166
Automated impedance manometry (AIM) analysis, 220 Brendenoord, 137
Autonomic nervous system testing Burping, 403
clinical tests, 177 Bursts of contractions, 94, 96
Index 517

C treatment
CAM. See Complementary and alternative medicine drugs, 263–265
(CAM) nutrition support, 263
Cannabionoid, 253 outcomes, 266–267
Catheter-based esophageal pH-monitoring surgery, 265–266
definitions and criteria, 130 Chronic nonspecific diarrhea (CNSD)
diagnostic accuracy and reproducibility, 131 clinical presentation, 355–356
electrode placement, 130 definition, 355
normal ranges, 131 diagnosis, 356–357
recording conditions, 130 epidemiology, 355
symptom correlation, 131–132 pathophysiology, 356
Caustic ingestion, 240, 253 treatment, 357
CBT. See Cognitive behavioral therapy (CBT) Chronic severe constipation, 273
CD56 (N-CAM) immunostaining, 199–200 Cisapride, 444–445
Celiac disease and inflammatory bowel Clearance, 228
diseases, 252 Cluster of contractions (CCs), 93–94
Cellular-based therapy CNSD. See Chronic nonspecific diarrhea
CNS-NSC, 499 (CNSD)
disadvantages, 501 Cognitive behavioral therapy (CBT), 382–383
endoscopy, 501 abdominal pain, 474
ENS benefits, 473–474
CNS-derived stem cell, 494, 497 chronic pain, 474
gut-like structure, 494 components of, 472–473
human studies, 497–498 mechanism of
neural crest, 497 active ingredients, 476
nonhuman studies, 497 coping, 477
putative, 495–496, 498 coping responses, 477
stem cell therapy, 494 parental solicitousness, 477
esophageal achalasia, 498 physiological changes, 477
HSCR, 493, 500 psychological distress, 478
ideal cell type, 499 motivation of, 472
immunological rejection, 500 psychosocial intervention, 471
iPS cell, 499–500 therapeutic delivery techniques, 472
parenteral nutrition, 493 community-school based intervention, 475
transcriptional factors, 499–500 computerization, 476
translantation, 501 family intervention, 474–475
Central mechanisms, visceral hypersensitivity, 43–44 home-based intervention, 475
Central nervous system disorders, 251 internet, 476
Central pathway, visceral sensitivity treatment, 475–476
central processing, 41 Colectomy and partial colonic resection, 312–314
descending modulatory, 41 Collagen vascular disorders, 239–240
spinal, 41 Colonic inertia, 109
vagal, 40–41 Colonic manometry
Central sensitization, 44 chronic intestinal pseudo-obstruction
Cerebral palsy (CP) (CIPO), 112
developmental disorders, motility problems, Hirschsprung’s disease and anorectal malformations,
285–287 112–114
feeding and swallowing disorders, 222–223 identifiable motility patterns, 110–111
Chicago Classification 2009, 230 indications, 111
Chiropractics, 481, 482 intractable constipation, 112
Chronic abdominal pain, 367, 378, 416, 474 normal physiology, 107–108
Chronic diarrhea, 355, 357 study performance
Chronic intestinal pseudo-obstruction (CIPO) catheter placement, 108–110
classification, 507 study protocol, 109
clinical features, 257, 258 variations
clinical presentation, 260–261 ambulatory 24 h, 114
definition, 112 high resolution colonic manometry, 115
diagnosis, 261–263 wireless motility capsule, 114–115
etiology, 257–259 Colonic transit scintigraphy, 156–159
pathology, 259–260 Colonic transit time (CTT), 433
518 Index

Colon transit, 169 diagnosis of, 399

Complementary and alternative medicine (CAM) etiopathogenesis, 392
allopathic medication, 481 evaluation, 395–396
constipation HPA axis activation, 393
acupuncture, 487 lifestyle modifiiation, 397
complementary therapies, 488 mitochondrial dysfunction, 392–393
diagnosis, 486–487 mitochondrial supplement, 398–399
herbals, 487–488 penultimate defect, 393–394
reflexology, 488 phenotypes, 395
GER, 483–485 prophylactic therapy, 397–398
IBS and FAP rescue therapy, 396–397
acupuncture, 485 treatment, 396
herbals, 485–486 Cystic fibrosis, 197–198
hypnotherapy, 486
osteopathic therapy, 486
infantile colic D
acupuncture, 482–483 Deep breathing, 179
clinical presentation, 482 Deglutition, 217
homeopathy, 483 Delayed passage of meconium, 272–273
treatment, 483 Dental erosions, 335
prevalence of, 481 Descending modulatory pathways, 41
safety of, 482 Developmental disorders, motility problems
Congenital central hypoventilation syndrome, cerebral palsy (CP), 285–287
209, 210 Down syndrome (DS), 287
Congenital diaphragmatic hernia (CDH), 311 familial dysautonomia, 288
Conscious rectal sensation, 124 mitochondrial disorders (MD), 289
Constipation mitochondrial neurogastrointestinal
classification, 413 encephalomyopathy
complications, 415–416 (MNGIE), 289
diagnosis, 416–418 Williams syndrome (WS), 288
outcome, 423–425 Diabetes mellitus, 249–250
pathophysiology Diaphragmatic breathing, 408, 409
children and adolescents, 415 Diffuse and segmental acquired diseases
infants and toddlers, 413–415 autoimmune ganglionitis, 196, 197
treatment autoimmune myositis, 196
children and adolescents, 419–420 eosinophilic ganglionitis, 196
infants and toddlers, 418–419 immune modulation
maintenance therapy, 420–423 nerves, 197
Contour plots, HRM, 82 smooth muscle, 196–197
Contractile protein isoforms, 199 Diffuse esophageal spasm (DES), 237–238
Contractility, 170, 433 Diphenoxylate, 448
Contraction segments, HRM, 86 Discrete clustered contractions
Contrast enema, 275 (DCCs), 93–95
Corticosteroids, 239 Disembaeva, 163
Corticotrophin releasing factor, 62 Domperidone, 441–442
Cotrophin-releasing factor (CRF), 62–63 Down syndrome (DS), 287
Cow’s milk protein allergy (CMPA), Drug action
249, 334 antimotility agent, 448
CTT. See Colonic transit time (CTT) antispasmodics (see Antispasmodics)
Cutaneous fistula, 302, 303 laxatives (see Laxatives)
Cyclic vomiting syndrome (CVS) prokinetic agent (see Prokinetics)
abdominal migraine, 391–392 Dumping syndrome
epidemiology and demographics, 391, 392 esophageal atresia (EA), 296
functional gastrointestinal disorder, 391 gastric motor disorders, 253–254
medical morbidity, 392 Dysphagia
pathophysiology esophageal atresia (EA), 296
abortive therapy, 397, 398 esophageal dysmotility, 229
autonomic dysfunction, 393 feeding and swallowing disorders, 217
clinical presentation, 394–395 Dysregulation, pain processing, 44
comorbidity, 395 Dyssynergic defecation, 126–127
Index 519

E Esophageal atresia (EA)

Eating disorders, 165 clinical symptoms
Electrogastrography (EGG) dumping syndrome, 296
chronic intestinal pseudo-obstruction, 165 dysphagia, 296
clinical applications, 164–165 GER, 295
developmental aspects, 163 esophageal motility
eating disorders, 165 esophageal body dysfunction, 296, 297
functional gastrointestinal disorders, 165 lower esophageal sphincter (LES), 296–297
GER, 165 postsurgical dysmotility, 297–298
medications, gastric myoelectrical activity, 165 primary motility disorder, 297
normal values, 163–164 upper esophageal sphincter (UES), 296
surgery, 165 Nissen fundoplication, 298
tachygastria and bradygastria, 163, 164 Esophageal body dysfunction, 296, 297
Elemental diet, 235, 239 Esophageal dilation, 234, 235, 239
Elimination diet, 235, 239, 357, 372–373 Esophageal dysmotility
Encopresis, 415, 429 chest pain, 229
Endoscopic therapies, 234 dysphagia, 229
Endothelin, 188, 207 foreign body impaction, 229–230
Endothelin receptor-B (EDNRB) pathway, 13 prevalence, 229
Enteric muscle coats, 5–6 Esophageal function testing (EFT), 228
Enteric myopathy, 99, 102. See also Genetic/congenital Esophageal impedance and pH monitoring, 228
myopathies Esophageal impedance recording
Enteric neural crest-derived cells (ENCCs) impedance studies, 338–339
development, 15 studies in children, 340–341
fluorescently labeled, 12 studies in infants, 339–340
glial cell line-derived neurotrophic factor Esophageal manometry
(GDNF), 13 equipment, 80–81
migration, 16 high-resolution manometry (HRM)
proliferation, 13 adults study, 85
RET signaling, 13 advantages, 82–83
Enteric neuromuscular system (ENS) axial transformations, 82
components, 4 contour plots, 82
development, 5 contraction segments, 86
developmental interactions, 17–18 conventional investigation, 84–85
differentiation, 13–15 gastro-esophageal junction (GEJ), 84
ganglia formation and connectivity, 15–16 gastroesophageal reflux (GER), 86–87
gut embryogenesis, 9 limitations, 86
interstitial cells of Cajal (ICC) neonate study, 85–86
different forms and functions, 16 perfused and solid-state systems, 81–82
embryological origin, 16–17 protocol, 86–87
human gastrointestinal motility disorders, 17 requirements, 81
multiple transmitters, neurons, 4, 6 surface plots, 82
organization, human and medium-large theoretical level, 82
mammals, 4, 5 transient LES relaxation, 87
precursors migration, 12–14 lower esophageal sphincter (LES), 79–80
proliferation, 13 test performance, 81
smooth muscle development upper esophageal sphincter (UES), 79–80
defects, motility disorders, 10–12 Esophageal motility
stages, 9–10 esophageal body dysfunction, 296, 297
Enteric neuropathies, 99, 188. See also Genetic/ lower esophageal sphincter (LES), 296–297
congenital neuropathies postsurgical dysmotility, 297–298
Enterocolitis, 273, 277–278 primary motility disorder, 297
Enteroendocrine cells, 39 upper esophageal sphincter (UES), 296
ENT manifestations, 335 Esophageal motor disorders
Eosinophilic esophagitis (EoE), 238–239 achalasia (see Achalasia)
Eosinophilic ganglionitis, 196 background physiology, 227
Eosinophils, 227–241 caustic ingestion, 240
Epigastric impedance, 168 Chicago Classification 2009, 230
Epigastric pain and nausea, 359 chronic idiopathic intestinal pseudo-obstruction
Epigastric pain syndrome. See Functional dyspepsia (CIIP), 240
520 Index

Esophageal motor disorders (cont.) definition, 429

collagen vascular disorders, 239–240 diagnosis
diffuse esophageal spasm (DES) and nutcracker abdominal radiography, 432–433
esophagus (NE), 237–238 barostat and manometry, 433
eosinophilic esophagitis (EoE), 238–239 CTT, 433
esophageal dysmotility MRI, 433
chest pain, 229 pelvic ultrasound, 433–434
dysphagia, 229 FNRFI (see Functional non-retentive fecal
foreign body impaction, 229–230 incontinence (FNRFI))
prevalence, 229 functional constipation, 430, 434
esophageal function testing (EFT), 228 groups of, 430
esophageal impedance and pH monitoring, 228 organic and functional, 431
Hirschsprung’s disease, 240 physical examination, 432
ineffective esophageal motility (IEM), 240–241 prevalence of, 429–430
manometry, 227 quality of life, 431
nonspecific esophageal motility disorders symptoms, 432
(NEMDs), 241 treatment, 434
videocineroentgenography/video fluorography Feeding and swallowing disorders
(VFG), 228 assessment, oropharyngeal dysphagia, 218–220
Esophageal pH and impedance monitoring autism spectrum disorders (ASD), 223–224
catheter-based definition, 217
definitions and criteria, 130 dysphagia, 217
diagnostic accuracy and reproducibility, 131 GERD, 221–222
electrode placement, 130 manometry and impedance, 220
normal ranges, 131 neurological disability, 222–223
recording conditions, 130 oropharyngeal physiology, 218
symptom correlation, 131–132 problems, 220–221
gastroesophageal reflux disease (GERD), 129 velo-cardio-facial syndrome (VCFS), 223
multichannel intraluminal impedance (MII-pH) FNRFI. See Functional non-retentive fecal incontinence
catheter, 134, 136 (FNRFI)
definitions, 134–136 Food impaction, 238, 239, 241
future, 139 Foregut function, 103
impedance and clinical outcome, 138–139 Fructose, 356, 361
interpretation, 136 Full thickness rectal biopsy, 275
normal values, 137 Functional abdominal pain (FAP)
proximal reflux, 138 CAM, 485–486
reproducibility, 137 clinical presentation
retrograde bolus movement, 134, 135 differential diagnosis, 381
sensitivity, 136–137 symptoms identification, 382
symptom association, 137–138 definition, 377–378
pharyngeal, 132–133 diet, 383
proximal, 133–134 epidemiology, 378
wireless, 133 functional nature of, 377
Esophageal transit, 150–152 management, 382
Esophagitis, 334 meta-analysis, 386
External anal sphincter (EAS), 119–120 pathophysiology
Extraesophageal manifestations central sensitization, 380
apnea, 335 gastrointestinal symptoms, 380–381
apparent life-threatening events (ALTE), 335 peripheral sensitization, 380
bradycardia, 335 spinal neurons, 379–380
dental erosions, 335 spinothalamic pathway, 379
ENT manifestations, 335 symptoms, 378
reactive airway disease, 334–335 pharmacotherapy
recurrent pneumonia, 335 antisecretory drug, 383
Sandifer syndrome, 335 citalopram, 386
inflammation and immune alteration, 386
tricyclic antidepressant, 383, 386
F psychological therapy
Familial dysautonomia, 288 CBT, 382–383
Fecal incontinence evaluation studies, 384–385
clinical presentation, 432 relaxation treatment, 383
Index 521

Functional diarrhea. See Chronic nonspecific diarrhea Gastric emptying

(CNSD) breath testing (BT), 166
Functional dyspepsia gastric function after fundoplication, 318
clinical presentation, 361 gastroparesis, 247, 248
definition, 359 radionuclide transit tests, 153–156
diagnostic evaluation SmartPill, 170
laboratory analysis, 361–362 transit studies, 168
NSAIDs, 362 ultrasonography (US), 167
epidemiology, 359–360 Gastric emptying time, 140, 156
management Gastric function after fundoplication
acupuncture, 364 antroduodenal motility and gastric myoelectrical
antidepressant, 363–364 activity, 318–319
clinical evaluation, 362 gastric emptying, 318
complementary therapies, 362–363 gastric sensorimotor function, 317–318
duodenal eosinophilia, 364 postoperative symptoms, 319–320
PPI, 363 Gastric motor disorders
pathogenesis dumping syndrome, 253–254
altered visceral sensation, 361 gastroparesis
differential diagnosis, 360 autoimmune neuropathy, 250–251
dyspeptic symptom, 360 cannabionoid, 253
etiology, 360 caustic ingestion, 253
mucosal inflammation, 361 celiac disease and inflammatory bowel
prognosis, 362 diseases, 252
Functional gastrointestinal disorders (FGIDs). See also central nervous system disorders, 251
Functional abdominal pain (FAP) diabetes mellitus, 249–250
anthropological approach and method, 72–73 etiology, 247, 249
barostat test gastric emptying, 247, 248
constipation, 147 gastroesophageal reflux and functional
gastric sensitivity measurement, 146 dyspepsia, 252
rectal sensitivity measurement, 146 Hirschsprung’s disease, 251
somatic projections and reproducibility, 147 immaturity, 248–249
definition, 71 immune and inflammatory food allergy, 252
EGG, 165 myopathies, 251
epidemiology, 71–72 peripheral neuropathies, 249
patient-physician relationship, 73–75 post-infectious, 249
Functional non-retentive fecal incontinence (FNRFI) postsurgical, 251–252
definition, 430 treatment, 253
mechanism of, 431 Gastric pacemaker, 163, 511
treatment, 434–435 Gastric sensorimotor function, 317–318
Functional pain, 377–387 Gastro-esophageal junction (GEJ), HRM, 84
Fundoplication. See Gastric function after Gastroesophageal reflux (GER)
fundoplication acupuncture, 484–485
aspiration and, 152–153
electrogastrography (EGG), 165
G esophageal atresia (EA), 295
Ganglioneuromatosis, 189, 190 functional dyspepsia, 252
Gastric accommodation, 317, 318 herapeutic interventions, 484
Gastric dysmotility, 251, 252 HRM, 86–87
Gastric electrical stimulation (GES) symptoms, 483
gastroparesis, 465 Gastroesophageal reflux disease (GERD). See also
mechanism, 465 Functional dyspepsia
permanent case studies, 203–204
laparoscopy, 467 COL3A1 gene, 205
placement of, 467 C825T, 205
surgical placement, 467–469 esophageal pH and impedance monitoring, 129
temporary familial clustering, 204
placement of, 466–467 hiatal hernia, 204
standard pediatric endoscope, 466 IL-1B and IL-1RN, 205
therapy, 469–470 pathophysiologic determinants, 203, 204
treatment, 468 twin studies, 204
522 Index

Gastrointestinal functioning intestinal inflammation, 52–53

immune, 64–65 modulation, visceral hypersensitivity, 53
motor, 62–63 potential therapeutic applications,
sensory, 63–64 53–54
Gastrointestinal housekeeper, 93 published pediatric reports, 55
Gastrointestinal (GI) tract, 3 small-bowel bacterial overgrowth, 51
Gastroparesis, 465 mucosal-gut microbial interaction, 49–50
autoimmune neuropathy, 250–251 Gut motility and sensitivity
cannabionoid, 253 autonomic nervous system, 7
caustic ingestion, 253 central processing, visceral sensitivity, 4
celiac disease and inflammatory bowel enteric muscle coats, 5–6
diseases, 252 enteric nervous system (ENS)
central nervous system disorders, 251 components, 4
diabetes mellitus, 249–250 development, 5
etiology, 247, 249 multiple transmitters, neurons, 4, 6
gastric emptying, 247, 248 organization, human and medium-large
gastroesophageal reflux and functional mammals, 4, 5
dyspepsia, 252 gastrointestinal (GI) tract, 3
Hirschsprung’s disease, 251 interstitial cells of Cajal (ICC), 7
immaturity, 248–249 neuronal cells, myenteric and submucosal
immune and inflammatory food allergy, 252 plexuses, 3, 4
myopathies, 251 sensory functions, 3
peripheral neuropathies, 249 Gut motility development
post-infectious, 249 human neonates and children
postsurgical, 251–252 colonic, 31
treatment, 253 control mechanisms, 31–32
Gastroschisis, 311–312 gastric, 30
Genetic/congenital myopathies pharyngo-esophageal, 29–30
abnormalities in contractile proteins, 195–196 small intestinal, 30–31
diffuse extra muscle coat, 193, 194 patterns and control mechanisms
fibrosis, myocyte vacuolation and atrophy, 194 developing gut, 25
masson trichrome, 191, 193 enteric neurons, 25–27
myopathy with autophagic activity, 194–195 environmental influences, 29
pink blush and nuclear crowding, 194, 195 ICC, 27–28
segmental absence, muscle layer, 192 mature gut, 23–25
segmental extra muscle coat, 192 myogenic mechanisms, 28
smooth muscle actin immunostained section,
191, 193
Genetic/congenital neuropathies H
aganglionosis, 188 Habit reversal training (HRT), 408
diagnosis and genetic defect, 188 Head up tilt, 179–180
ganglioneuromatosis, 189, 190 Heartburn, 334
glial cell hyperplasia, 190–192 Heller myotomy, 232, 236, 237
hyperganglionosis, 190, 191 High amplitude propagated contractions (HAPC),
hypoganglionosis, 190 110–111
neuronal degeneration, 191 High-resolution and pediatrics, 121
neuronal immaturity, 191 High resolution colonic manometry, 115
GES. See Gastric electrical stimulation (GES) High-resolution esophageal pressure topography
Giant migrating contractions, 94 (HROPT), 230
Glial cell hyperplasia, 190–192 High-resolution manometry (HRM)
Goldberg-Shprintzen syndrome, 209, 210 adults study, 85
Guided Imagery, 472, 473, 475 advantages, 82–83
Gut embryogenesis, 9 antroduodenal manometry (ADM), 97
Gut microflora and neurogastrointestinal system ARM, 120, 121
altered gut motility, 51 axial transformations, 82
bidirectional signaling, 50 contour plots, 82
brain communication, 49, 50 contraction segments, 86
irritable bowel syndrome (IBS) conventional investigation, 84–85
gut microbiome, 51–52 esophageal body dysfunction, 296
incidence, 50 gastro-esophageal junction (GEJ), 84
Index 523

gastroesophageal reflux (GER), 86–87 I

limitations, 86 IBS. See Irritable bowel syndrome (IBS)
neonate study, 85–86 Immune and inflammatory food allergy, 252
perfused and solid-state systems, 81–82 Immune modulation
protocol, 86–87 nerves, 197
requirements, 81 smooth muscle, 196–197
surface plots, 82 Immunological factors, 64, 65
theoretical level, 82 Imperforate anus. See Anorectal malformations
transient LES relaxation, 87 Induced pluripotent stem (iPS) cells, 499–500
Hirschsprung disease (HSCR) Ineffective esophageal motility (IEM), 240–241
aganglionosis, 271, 272 Infant colic
anorectal manometry, 124 definition, 347
associated medical problems, 276, 277 differential diagnosis
classification, 207 neurodevelopmental hypothesis, 348
clinical presentation normal crying curve, 349
abdominal distension, 273 physiologic differences, 348
chronic severe constipation, 273 epidemiology, 347–348
delayed passage of meconium, 272–273 management
enterocolitis, 273 caregiver, 351
neonatal bowel perforation, 272 clinician suggestions, 350
neonatal intestinal obstruction, 272 elements of, 349
symptoms, 271, 272 goal of, 349
colonic manometry, 112–114 guaranteed sleep, 352
definition, 271 infant-parent system, 352
diagnostic strategies on-off-on-off pattern, 352
anorectal manometry, 275 pain theory, 350
contrast enema, 275 prognosis, 350
full thickness rectal biopsy, 275 rescue mechanism, 351–352
rectal suction biopsy, 274–275 state-transition-associated crying patterns, 352
enteric neuromuscular system (ENS), 10, 12 temperament characteristics, 350
enterocolitis, 277–278 subside, 349
epidemiology/genetics overview, 275–276 Infant dyschezia, 415
esophageal motor disorders, 240 Infant regurgitation and pediatric GERD
gastric motor disorders, 251 (alginate-)antacids and mucosaprotectors,
initial management cost, 276–277 342–343
isolated, 207–208 complications, 336
long term outcome, 278 definitions, 331
mouse models, 278 diagnosis, 336–337
nomenclature, 271 distressed behavior, 333–334
problems and opportunities, 278–279 esophageal impedance recording
rectal biopsy, 273–274 impedance studies, 338–339
red flags, 274 studies in children, 340–341
surgical management, 276 studies in infants, 339–340
syndromic, 208–210 esophagitis, 334
Histopathology, 188, 199 extraesophageal manifestations
H2-receptor antagonists (H2RAs), 343 apnea, 335
HRT. See Habit reversal training (HRT) apparent life-threatening events (ALTE), 335
Human gastrointestinal motility disorders, 17 bradycardia, 335
Human neonates and children dental erosions, 335
colonic, 31 ENT manifestations, 335
control mechanisms, 31–32 reactive airway disease, 334–335
gastric, 30 recurrent pneumonia, 335
pharyngo-esophageal, 29–30 Sandifer syndrome, 335
small intestinal, 30–31 heartburn, 334
Hyperalgesia, 42 H2-receptor antagonists (H2RAs) and proton pump
Hyperganglionosis, 190, 191 inhibitors (PPI), 343
Hypersensitivity, 41–42 neurologic impairment, 336
Hypoganglionosis, 190 nonintervention complications, 341
Hypothalamic-pituitary-adrenal axis, 61, 62, non-pharmacologic and nonsurgical therapies,
379, 392 341–342
524 Index

Infant regurgitation and pediatric GERD (cont.) gastrointestinal microbiota, 368

prokinetics and other nonacid-reducing/blocking genetic determination, 368
medication, 342 psychiatric disorders, 368
recurrent regurgitation/vomiting and poor weight risk factor, 367
gain, 333 visceral hypersensitivity, 368
risk groups, 336 potential therapeutic applications, 53–54
surgery and therapeutic endoscopic procedures, 343 published pediatric reports, 55
symptoms, 331–332 small-bowel bacterial overgrowth, 51
treatment, 341, 342 treatment
uncomplicated regurgitation, 332–333 antibiotics, 371
Inflammation, visceral hypersensitivity, 42 antidepressants, 371
Inflammatory myopathy, 251 antispasmodics, 370–371
Insulin-dependent diabetes mellitus (IDDM), 250 dietary supplementation, 372–373
Integration, biomedical and psychosocial issues 5-hydroxytryptamine, 372
case history, 59 linaclotide, 372
psychological issues lubiprostone, 371–372
biomedical model, 60 melatonin, 371
biopsychosocial model, 60 pharmaceutical and non-pharmaceutical, 370
brain-gut axis, 61–62 physical therapy, 373
system theory, 60–61 probiotics, 371
psychosocial influences, stress and psychological therapy, 373
definition, 62 Isolated HSCR, 207–208
gastrointestinal immune functioning, 64–65
gastrointestinal motor functioning, 62–63
gastrointestinal sensory functioning, 63–64 K
Integrative, 475 Kit-positive ICC, 17
Interdisciplinarity, 75, 410
Internal anal sphincter (IAS), 119–120
Interstitial cells of Cajal (ICC) L
enteric neuromuscular system (ENS) Laxatives
different forms and functions, 16 dosages, 454
embryological origin, 16–17 osmotic and lubricant
human gastrointestinal motility disorders, 17 lactulose, 452, 454
enteric neuromusculature, 199 magnesium salts, 454
gut motility and sensitivity, 7 mineral oil, 455
gut motility development, 27–28 polyethylene glycol, 454–455
Intestinal failure, 507, 511 sorbitol, 455
Intestinal lengthening, 308–310 stimulant
Intestinal microbiota, 3 bisacodyl, 455
Intestinal neuronal dysplasia, 15, 251, 260 linaclotide, 456
Intestinal resection, 509, 511 lubiprostone, 456
Intestinal transit, 168–169 senna, 455–456
Intestinal transmural ganglioneuromatosis. Levator ani complex, 119
See Ganglioneuromatosis Linaclotide, 456
Intestinal transplantation, 309 Loperamide, 448
Intractable constipation, 112 Low compliance perfused manometric system, 95–97
Intraganglionic endings (IGLE), 39 Lower esophageal sphincter (LES)
Irritable bowel syndrome (IBS) esophageal manometry, 79–80
CAM, 485–486 esophageal motility, 296–297
clinical presentation Low fat diet, 356
abdominal pain and abnormal stool pattern, 369 Lubiprostone, 456
Rome III diagnostic criterion, 369
symptoms, 368–369
epidemiology, 368 M
gut microbiome, 51–52 Malrotation and intestinal atresia, 312
incidence, 50 Manometry
intestinal inflammation, 52–53 esophageal motor disorders, 227
modulation, visceral hypersensitivity, 53 impedance and, 220
pathophysiology Mast cell hyperplasia and mucosal innervation, 42
altered motility, 367 Maximal squeeze pressure, 122
Index 525

Meanings, 73 spinal terminals, 39

Medical anthropology, 72 vagal innervation, 37–38
Megacystis-microcolon-intestinal-hypoperistalsis vagal terminals, 39
syndrome (MMIHS), 212–213 visceral innervation, 37, 38
Mesenchymopathic CIPO, 212 Neurofibromatosis, 211, 260
Mesenchymopathy, 259 Neurologic impairment, 336
Methodological aspects, ADM Neuromuscular disease, 126
analysis, manometric recording, 99–102 Neuronal cells, 3, 4
patient preparation, 97–98 Neuronal degeneration, 191
reference values, 100–101 Neuronal immaturity, 191
study procedure, 98–99 Neuropathy, 99, 258, 493, 500, 507. See also Specific
Metoclopramide, 442–443 Neuropathies
Migrating motor complex (MMC) Nissen fundoplication, 298
ADM, 91–93 Non-acid reflux, 129, 134, 136, 340
gut motility development, 24–25 Non-specific diarrhea, 355–357
small bowel and colonic dysfunction after Nonspecific esophageal motility disorders
surgery, 308 (NEMDs), 241
SmartPill, 170 Nonspecific motor disorder, 227–241
Mitochondrial cytopathy, 197–198 Nonsteroidal anti-inflammatory drugs (NSAIDs), 362
Mitochondrial disorders (MD), 289 Normal motility, ADM
Mitochondrial myopathy-Epilepsy-Lactic acidosis and amplitude, single contractions, 92
Stroke-like episodes (MELAS), 213 bursts of contractions, 94, 96
Mitochondrial neurogastrointestinal encephalomyopathy discrete clustered contractions (DCCs), 93–95
(MNGIE), 289 gastrointestinal housekeeper, 93
Mitochondriopathy, 258 giant migrating contractions, 94
Morphological phenotypes of enteric neuromuscular migrating motor complex (MMC), 91–93
disease, 187 postprandial/fed pattern, 93, 94
Motility and visceral sensitivity, 49–55 NSAIDs. See Nonsteroidal anti-inflammatory drugs
Motility patterns, colonic manometry, 110–111 (NSAIDs)
Mowat-Wilson syndrome, 209, 210, 277 Nuclear pore complex, 206
Mucosal-gut microbial interaction, 49–50 Nucleus of the solitary tract (NTS), 40–41
Multichannel intraluminal impedance (MII-pH) Nutcracker esophagus (NE), 237–238
catheter, 134, 136
definitions, 134–136
future, 139 O
impedance and clinical outcome, 138–139 Onabotulinumtoxin A, 450–451
interpretation, 136 Oropharyngeal dysphagia, 218–220
normal values, 137 Orthostatic hypotension (OH), 181
proximal reflux, 138
reproducibility, 137
retrograde bolus movement, 134, 135 P
sensitivity, 136–137 Paracetamol absorption test, 168
symptom association, 137–138 Parasympathetic, 177, 179, 181, 207
Multiple endocrine neoplasia, 207, 208 Pathology, enteric neuromusculature
Muscle membrane proteins, 199 CD56 (N-CAM) immunostaining, 199–200
Myenteric cells, 3, 4 contractile protein isoforms, 199
Myopathic CIPO, 212–213 diffuse and segmental acquired diseases
autoimmune ganglionitis, 196, 197
autoimmune myositis, 196
N eosinophilic ganglionitis, 196
Nausea, 465, 467, 469 immune modulation, 196–197
Neonatal bowel perforation, 272 genetic/congenital myopathies
Neonatal intestinal obstruction, 272 abnormalities in contractile proteins, 195–196
Neural crest cells (NCC), 12–13 diffuse extra muscle coat, 193, 194
Neuroanatomy and processing, visceral sensitivity fibrosis, myocyte vacuolation and atrophy, 194
enteroendocrine cells, 39 masson trichrome, 191, 193
receptors, visceral afferents, 39–40 myopathy with autophagic activity, 194–195
sacral innervation, 39 pink blush and nuclear crowding, 194, 195
sensory terminals, 39 segmental absence, muscle layer, 192
spinal innervation, 38–39 segmental extra muscle coat, 192
526 Index

Pathology, enteric neuromusculature (cont.) prucalopride, 446

smooth muscle actin immunostained section, tegaserod, 445–446
191, 193 velusetrag, 446–447
genetic/congenital neuropathies methylnaltrexone, 447–448
aganglionosis, 188 motilin
diagnosis and genetic defect, 188 bethanechol, 444
ganglioneuromatosis, 189, 190 erythromycin, 443–444
glial cell hyperplasia, 190–192 neostigmine, 444
hyperganglionosis, 190, 191 octreotide, 447
hypoganglionosis, 190 Prolonged intestinal contractions, 94
neuronal degeneration, 191 Pro-motility agents. See Prokinetics
neuronal immaturity, 191 Protease-activated receptors (PAR), 43
histological changes, 187 Proton pump inhibitors (PPIs), 333, 343, 362
ICC, 199 Proximal esophageal pH monitoring, 133–134
muscle membrane proteins, 199 Prucalopride, 446
optimal diagnostic specimen, 187–188 Pseudo-Hirschsprung’s disease, 187
pseudo-Hirschsprung’s disease, 187 Psychological issues, health and disease
secondary to a systemic disease, 197–198 biomedical model, 60
Patterns and control mechanisms biopsychosocial model, 60
developing gut, 25 brain-gut axis, 61–62
enteric neurons, 25–27 system theory, 60–61
environmental influences, 29 Psychosocial factors, 59, 65
ICC, 27–28 Psychosocial influences, stress
mature gut, 23–25 definition, 62
PEC. See Percutaneous endoscopic cecostomy (PEC) gastrointestinal immune functioning, 64–65
Pediatric functional gastrointestinal disorders, 177, 327 gastrointestinal motor functioning, 62–63
Pediatric Rome II criteria, 327 gastrointestinal sensory functioning, 63–64
Perceptual sensitivity, 43
Percutaneous endoscopic cecostomy (PEC), 509
Perineal fistula, 302, 303 Q
Peripheral mechanisms, visceral hypersensitivity Quantitative sudomotor reflex test (QSART), 177, 182
central mechanisms, 43–44
central sensitization, 44
dysregulation, pain processing, 44 R
inflammation, 42 Radioisotope, 153, 156
mast cell hyperplasia and mucosal innervation, 42 Radionuclide transit tests
PAR2 and PAR4, 43 colonic transit scintigraphy, 156–159
potential mechanisms, 43 esophageal transit, 150–152
serotonin (5HT), 43 gastric emptying study, 153–156
TRPV1 and TRPV4, 43 gastroesophageal reflux (GER) and aspiration,
Peripheral neuropathies, 249 152–153
Peristalsis, 7, 24, 25 radiopharmaceuticals, 150
Persistent cloaca, 302–303 small intestine transit scintigraphy, 156
Pharyngeal pH monitoring, 132–133 RAIR, 121, 122, 124
Post-infectious gastroparesis, 249 Reactive airway disease, 334–335
Postprandial distress syndrome. See Functional dyspepsia Rearranged after transfection (RET) gene, 207–208
Postprandial/fed pattern, 93, 94 Receptors, visceral afferents, 39–40
Postsurgical dysmotility, 297–298 Rectal biopsy, 273–275
Postsurgical gastroparesis, 251–252 Rectourethral fistula, 302, 303
Post-surgical gastroparesis, 251 Rectovaginal fistula, 303, 304
Postural orthostatic tachycardia syndrome (POTS), 180, Rectum-bladder neck fistula, 302, 303
393, 395 Recurrent pneumonia, 335
PPI. See Proton pump inhibitors (PPI) Recurrent regurgitation/vomiting and poor weight
Prokinetics gain, 333
dopamine-2 (D2) receptor antagonist Reflex syncope, 180–181
domperidone, 441–442 Regurgitation, 332–333
metoclopramide, 442–443 Retching, 317, 319, 320
dosage, 449 Riley-Day syndrome, 288
5-hydroxytryptamine-4 receptor agonist Rome criteria
cisapride, 444–445 history, 325
Index 527

international pediatric working team, 326 nonhuman studies, 497

publications, 327 putative, 495–496
Rome III diagnostic criterion, 369 Stress and psychosocial influences
Roux-en-Y Jejunostomy and bariatric surgery, 311 definition, 62
Rumination, 405–410 gastrointestinal immune functioning, 64–65
gastrointestinal motor functioning, 62–63
gastrointestinal sensory functioning, 63–64
S Submucosal plexuses, 3, 4
Sacral innervation, 39 Sudden infant death syndrome (SIDS), 484
Sandifer syndrome, 335 Surface plots, HRM, 82
Satiety drinking tests, 147 Sustained (static) handgrip, 181
Scintigraphy, 149, 228 Syndromic CIPO, 211–212
Sensory terminals, 39 Syndromic HSCR, 208–210
Sensory thresholds, 145 System theory, psychological issues, 60–61
Serial transverse enteroplasty (STEP), 308–309
Serotonin (5HT), 43
SIDS. See Sudden infant death syndrome (SIDS) T
Small bowel and colonic dysfunction after surgery Tachygastria, 163, 164
classification, 307–308 Tegaserod, 445–446
colectomy and partial colonic resection, 312–314 Tests of cardiovascular autonomic function,
congenital diaphragmatic hernia (CDH), 311 177, 178
gastroschisis, 311–312 Tests of sudomotor autonomic function (sweating),
intestinal lengthening, 308–310 177, 179
intestinal transplantation, 309 Therapeutic alliance, 74, 75
malrotation and intestinal atresia, 312 Thermoregulatory sweat test (TST), 177, 182
migrating motor complex (MMC), 308 Tilt table test
Roux-en-Y Jejunostomy and bariatric surgery, 311 different blood pressure and heart rate changes,
Small-bowel bacterial overgrowth, 51 180, 181
Small bowel transit, 150, 156 normal response, 180
Small intestine transit scintigraphy, 156 orthostatic hypotension (OH), 181
SmartPill postural tachycardia syndrome
advantages, 171 (POTS), 180
constipation, 170–171 reflex syncope, 180–181
gastric emptying, 170 Total parenteral nutrition (TPN), 508
limitations, 171 TPN. See Total parenteral nutrition (TPN)
migrating motor complex (MMC), 170 Tracheo-esophageal fistula, 295, 297
Smith-Lemli-Opitz syndrome, 210 Transient LES relaxation, 87
Smooth muscle development, ENS Transit studies
defects, motility disorders, 10–12 advantages, 169
stages, 9–10 colon transit, 169
Socio-cultural diversity, 74 epigastric impedance, 168
Soiling, 429 gastric emptying, 168
Solid-state manometric system, 97 intestinal transit, 168–169
Sonic hedgehog (Shh), 9–10 limitations, 169
Spinal afferents, 38–39 radiopaque markers, 168, 169
Spinal central pathway, 41 Transplantation, 497, 498, 500, 501
Spinal innervation, 38–39 Triple A syndrome, 206
Spinal terminals, 39 Trisomy 21, 209, 231, 274
State transitions, 348, 349 TRPV1 and TRPV4, 43
Stem cell therapy
advantages, 494
CNS-derived, 494, 497 U
CNS-NSCs, 499 Ultrasonography (US)
embryonic, 494 advantages, 168
endoscopy, 501 antral motility, 168
human studies, 497–498 developmental aspects, 167
immunological rejection, 500 gastric emptying, 167
injection of, 500 gastric receptive accommodation, 168
iPS cells, 499–500 limitations, 168
neural crest, 497 Uncomplicated regurgitation, 332–333
528 Index

Upper esophageal sphincter (UES) Visceral sensitivity

esophageal manometry, 79–80 barostat test, 143, 147
esophageal motility, 296 central pathways
Upper gastrointestinal disorders, 251 central processing, 41
descending modulatory, 41
spinal, 41
V vagal, 40–41
Vagal afferents, 37, 40 central processing, 4
Vagal central pathway, 40–41 neuroanatomy and processing, GI tract
Vagal innervation, 37–38 enteroendocrine cells, 39
Vagal terminals, 39 receptors, visceral afferents, 39–40
Valsalva maneuver (VM), 179, 180 sacral innervation, 39
Velo-cardio-facial syndrome (VCFS), 223 sensory terminals, 39
Velusetrag, 446–447 spinal innervation, 38–39
Vestibular fistula, 302, 303 spinal terminals, 39
Videocineroentgenography/video fluorography vagal innervation, 37–38
(VFG), 228 vagal terminals, 39
Visceral hypersensitivity visceral innervation, 37, 38
definitions, 41–42
pediatrics, 42
peripheral mechanisms W
central mechanisms, 43–44 Waardenburg syndrome, 208, 209
central sensitization, 44 Water-perfusion manometry (WPM), 120, 121
dysregulation, pain processing, 44 Whole gastrointestinal transit (WGT), 166
inflammation, 42 Whole gut transit, 165, 170, 171
mast cell hyperplasia and mucosal innervation, 42 Williams-Beuren syndrome, 288
PAR2 and PAR4, 43 Williams syndrome (WS), 288
potential mechanisms, 43 Wireless motility capsule (WMC), 114–115. See also
serotonin (5HT), 43 SmartPill
TRPV1 and TRPV4, 43 Wireless pH monitoring, 133
Visceral innervation, 37, 38