Neurologic Aspects of Systemic Disease Part I 1st

Edition Edition José Biller And José M. Ferro (Eds.)

updated 2025

Available at ebookfinal.com
( 4.4/5.0 ★ | 309 downloads )

https://ebookfinal.com/download/neurologic-aspects-of-systemic-
disease-part-i-1st-edition-edition-jose-biller-and-jose-m-ferro-eds/
 Neurologic Aspects of Systemic Disease Part I 1st Edition
Edition José Biller And José M. Ferro (Eds.) Pdf Download

EBOOK

Available Formats

■ PDF eBook Study Guide Ebook

EXCLUSIVE 2025 ACADEMIC EDITION – LIMITED RELEASE

Available Instantly Access Library

Here are some recommended products for you. Click the link to
download, or explore more at ebookfinal

Neurologic Aspects of Systemic Disease Part I 1st Edition

Edition José Biller And José M. Ferro (Eds.)

https://ebookfinal.com/download/neurologic-aspects-of-systemic-
disease-part-i-1st-edition-edition-jose-biller-and-jose-m-ferro-eds/

MacMillan Destination C1 C2 Grammar Vocabulary Malcolm

Mann

https://ebookfinal.com/download/macmillan-destination-c1-c2-grammar-
vocabulary-malcolm-mann/

Annual Reports on NMR Spectroscopy Volume 83 1st Edition

Webb

https://ebookfinal.com/download/annual-reports-on-nmr-spectroscopy-
volume-83-1st-edition-webb/

Neurologic Psychiatric Syndromes in Focus Part I 1st

Edition Julien Bogousslavsky

https://ebookfinal.com/download/neurologic-psychiatric-syndromes-in-
focus-part-i-1st-edition-julien-bogousslavsky/
Using the TI 83 Plus TI 84 Plus Christopher R. Mitchell

https://ebookfinal.com/download/using-the-ti-83-plus-ti-84-plus-
christopher-r-mitchell/

Justice in Oral Health Care Ethical Educational

Perspectives Marquette Studies in Philosophy 1st Edition
Jos V. M. Welie
https://ebookfinal.com/download/justice-in-oral-health-care-ethical-
educational-perspectives-marquette-studies-in-philosophy-1st-edition-
jos-v-m-welie/

Destiny Domesticated The Rebirth of Tragedy Out of the

Spirit of Technology Jos De Mul

https://ebookfinal.com/download/destiny-domesticated-the-rebirth-of-
tragedy-out-of-the-spirit-of-technology-jos-de-mul/

Learning Three js the JavaScript 3D Library for WebGL 2nd

Edition Jos Dirksen

https://ebookfinal.com/download/learning-three-js-the-
javascript-3d-library-for-webgl-2nd-edition-jos-dirksen/

Cannabinoids in Neurologic and Mental Disease 1st Edition

Liana Fattore

https://ebookfinal.com/download/cannabinoids-in-neurologic-and-mental-
disease-1st-edition-liana-fattore/
Neurologic Aspects of Systemic Disease Part I 1st Edition
Edition José Biller And José M. Ferro (Eds.) Digital
Instant Download
Author(s): José Biller and José M. Ferro (Eds.)
ISBN(s): 9780702044328, 0702044326
Edition: 1st Edition
File Details: PDF, 54.63 MB
Year: 2014
Language: english
 HANDBOOK OF CLINICAL
NEUROLOGY

Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB

VOLUME 119

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA

ST LOUIS SYDNEY TORONTO 2014
ELSEVIER B.V.
Radarweg 29, 1043 NX, Amsterdam, The Netherlands

© 2014, Elsevier B.V. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department:
phone: (þ1) 215 239 3804 (US) or (þ44) 1865 843830 (UK); fax: (þ44) 1865 853333; e-mail:
[email protected]. You may also complete your request on-line via the Elsevier website at
http://www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than
as may be noted herein).

ISBN: 9780702040863

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

Notice
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using
any information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to
verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the
responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses,
to determine dosages and the best treatment for each individual patient, and to take all appropriate safety
precautions.
To the fullest extent of the law, neither the Publisher nor the contributors or editors, assume any liability for any
injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use
or operation of any methods, products, instructions, or ideas contained in the material herein.

The Publisher

Printed in China

The
Publisher's
Commissioning Editor: Thomas E. Stone policy is to use
paper manufactured
Development Editor: Michael Parkinson from sustainable forests
Project Manager: Anitha Kittusamy Ramasamy
Designer/Design Direction: Alan Studholme
Handbook of Clinical Neurology 3rd Series

Available titles
Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571
Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905
Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016
Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941
Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009
Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933
Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104
Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996
Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965
Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972
Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989
Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958
Vol. 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081
Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036
Vol. 93, Stroke – Part II: clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043
Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050
Vol. 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081
Vol. 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159
Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392
Vol. 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067
Vol. 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074
Vol. 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142
Vol. 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315
Vol. 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039
Vol. 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927
Vol. 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385
Vol. 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023
Vol. 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029
Vol. 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988
Vol. 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995
Vol. 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378
Vol. 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015
Vol. 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919
Vol. 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107
Vol. 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652
Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds.
ISBN 9780444534903
Vol. 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022
Vol. 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972
Vol. 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910
Vol. 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016
 Foreword

Although neurology and psychiatry are closely linked specialties, many neurologists see their specialty as part of
internal medicine. Indeed, neurology departments in the United States often began as divisions within departments
of internal medicine, attesting to their special relationship. With the evolution of neurology as an independent
discipline, it has become particularly important for its practitioners to remain familiar with the neurologic aspects
of systemic diseases as well as with the systemic aspects of neurologic disorders. This has been recognized since
the Handbook of Clinical Neurology was founded by Pierre Vinken and George Bruyn, with volume 1 appearing
in December 1968. That first series concluded in 1982 and was followed by a second series, edited by them, that
concluded—in turn—in 2002. We then took over as editors of the current third series, with volume 79 appearing
in late 2003 and several volumes appearing annually since then.
Two volumes (38 and 39) were published in the first series of the Handbook, focusing on the neurologic manifes-
tations of systemic diseases. The second series included a further three volumes (63, 70, and 71) on the same topic,
published in 1993 and 1998, with one of us (MJA) serving as an editor of those volumes. Advances in the field, but
especially in immunology, genetics, imaging, pharmacotherapeutics, and intensive care, since that time have neces-
sitated a reappraisal of the field and the publication of three new volumes on the topic. We are therefore particularly
delighted at the publication of this scholarly contribution to the medical and neurologic literature and welcome it as
part of the Handbook. We believe that it will appeal not only to neurologists but to physicians in all specialties, helping
in their interactions with each other and with their patients.
Professors José Biller and José M. Ferro have together produced an authoritative, comprehensive, and up to date
account of the topic and have assembled a truly international group of authors with acknowledged expertise to con-
tribute to these important multifaceted volumes. We are grateful to them and to all the contributors for their efforts in
creating such an invaluable resource. We are confident that clinicians in many different disciplines will find much in
these volumes to appeal to them.
It is a pleasure, also, to thank Elsevier, our publishers – and in particular Tom Stone, Michael Parkinson, and Kristi
Anderson – for unfailing and expert assistance in the development and production of these volumes.

Michael J. Aminoff
François Boller
Dick F. Swaab
 Preface

Medicine has always been in a state of evolution and today, more than ever, with the accelerated growth of scientific
knowledge, patients are evaluated and treated by teams of physicians. The extensive body of knowledge and the major
scientific and clinical advances in neurology and internal medicine are again drawing both specialties closer together.
Whatever the subspecialty area of interest, the nature of modern clinical medicine calls for multidisciplinary collab-
orative efforts to better meet the needs of individual patients. The aim of these three volumes of the third series of the
Handbook of Clinical Neurology is to integrate and provide a thorough framework of the core neurologic manifes-
tations of a wide array of systemic disorders. Each chapter provides a critical appraisal and extensive background
information regarding the variety of presentations of each disorder, the characteristic clinical course, the typical neu-
rologic manifestations of each disease, and current therapeutic strategies. Comprehensive and updated references
also bring forth valuable resources for further topical reading and research. Our intended audience includes
experienced practitioners and residents in neurology, neurosurgery, and internal medicine, as well as other health care
professionals in different subspecialties caring for these challenging patients.
We have purposely divided these three volumes into chapters uniformly organized by organ system, which are
further divided by specific conditions and disease categories. Volume I is dedicated to the neurologic aspects of car-
diopulmonary diseases, renal disorders, and selective rheumatologic and musculoskeletal disorders. Volume II
encompasses core neurologic aspects of gastrointestinal and hepatobiliary disorders, endocrinologic diseases, and
a gamut of metabolic, nutritional and environmental conditions. Volume III concentrates on the neurologic aspects
of hematologic and oncologic disorders, organ transplantation, infectious diseases, and tropical neurology. It also
includes a miscellaneous group of disorders including neurodermatology, neurological complications of pregnancy,
iatrogenic neurology, neuromuscular disorders in the intensive care setting, posterior reversible leukoencephalopathy
and reversible cerebral vasoconstriction syndromes, neuro-Behcet’s, complications of neuroimaging, neuro-
traumatology, and observations pertaining to neurology in the developing world. These volumes go beyond the scope
of classic neurology and examine the neurologic manifestations of a wide range of medical conditions, spanning most
areas of medicine, that neurologists, neurosurgeons, internists, and other specialists must diagnose and treat in every-
day practice.
We are hopeful that these three volumes will contribute to the best possible care of patients with these disorders, and
that the readership will find the material informative, authoritative, reliable, and stimulating
We are extremely grateful to all the contributors from across the globe, who by sharing their knowledge and exper-
tise made these volumes possible. To bring to fruition a work of this magnitude requires a highly professional editorial
effort, and for this we thank Linda Turner for her wonderful organizational skills and administrative expertise, and
Mike Parkinson and the editorial staff at Elsevier for their unfailing dedication, professionalism, and expert assistance
in the development and production of these three volumes.
José Biller, MD
José M. Ferro, MD
 Contributors

H.P. Adams Jr. M.W. Baumgaertel

Division of Cerebrovascular Diseases, Department of St. Franziskus Hospital Muenster, Department of
Neurology, Carver College of Medicine, University of Nephrology, M€ unster, Germany
Iowa Health Care Stroke Center, University of Iowa,
Iowa City, IA, USA J.B. Bodensteiner
Department of Neurology, Mayo Clinic, Rochester,
J.L. Antunes MN, USA
Department of Neurosurgery, Hospital de Santa Maria,
University of Lisbon, Lisbon, Portugal I.J. Butler
Division of Child and Adolescent Neurology,
J.J. Asconapé Department of Pediatrics, University of Texas Medical
Department of Neurology, Stritch School of Medicine, School, Houston, TX, USA
Loyola University Chicago, Maywood, IL, USA
P. Camacho
H. Attarian Loyola University Osteoporosis and Metabolic Bone
Circadian Rhythms and Sleep Research Laboratory, Disease Center, Loyola University Chicago, Stritch
Department of Neurology, Northwestern University School of Medicine, Maywood, IL, USA
Feinberg School of Medicine, Chicago, IL, USA
L.R. Caplan
E. Auriel
Division of Stroke and Cerebrovascular Disease,
Department of Neurology, Tel-Aviv University,
Beth Israel Deaconess Medical Center, Boston,
Ramat-Aviv, Israel
MA, USA
S. Bansal
Pediatric Neurology, National Children’s Medical J.S. Cho
Center, Washington, DC, USA Division of Vascular Surgery and Endovascular
Therapy, Loyola University Chicago, Stritch School of
V.K. Bansal Medicine, Maywood, IL, USA
Division of Nephrology and Hypertension, Loyola
University Medical Center, Maywood, IL, USA S. Cruz-Flores
Department of Neurology, Paul L. Foster School of
C.L. Bassetti Medicine, Texas Tech University Health Sciences
Department of Neurology, University Hospital of Bern Center, El Paso, TX, USA
(Inselspital), Bern, Switzerland
M. de Carvalho
P. Berlit Department of Neurosciences, St Maria Hospital,
Department of Neurology and Clinical Neurophysiology, and Institute of Molecular Medicine, Lisbon,
Alfried-Krupp-Hospital, Essen, Germany Portugal

J. Biller E. de los Reyes

Department of Neurology, Loyola University Medical Division of Child Neurology, Ohio State University,
Center, Maywood, IL, USA Columbus, OH, USA
xii CONTRIBUTORS
M. de Visser M.N. Haque
Department of Neurology, Academic Medical Centre, Division of Cardiology, Department of Medicine,
Amsterdam, The Netherlands Loyola University Chicago, Stritch School of Medicine,
Chicago, IL, USA
S. Debette
Department of Epidemiology and Public Health, J.T. Hecht
Raymond Poincaré Hospital, Garches; INSERM Unit Department of Pediatrics and Pediatric Research
U708, Pitié-Salpêtrière Hospital, Paris and University of Center, University of Texas Medical School, Houston,
Versailles – St Quentin en Yvelines, Versailles, France TX, USA

R.S. Dieter R. Hershberger

Division of Cardiology, Department of Medicine, Division of Vascular Surgery and Endovascular
Loyola University Chicago, Stritch School of Medicine, Therapy, Loyola University Chicago, Stritch School of
Chicago, IL, USA Medicine, Maywood, IL, USA

K. Dombrowski S. Hocker
Department of Medicine (Neurology), Duke University Division of Critical Care Neurology, Mayo Clinic,
Medical Center, Durham, NC, USA Rochester, MN, USA

E.J. Dropcho S.E. Kasner

Department of Neurology, Indiana University Medical Department of Neurology, University of Pennsylvania,
Center, Indianapolis, IN, USA Philadelphia, PA, USA

A.J. Espay C.S. Kidwell

James J. and Joan A. Gardner Center for Parkinson’s Department of Neurology, Georgetown University
Disease and Movement Disorders, Department of Medical Center, Washington, DC, USA
Neurology, UC Neuroscience Institute, University of
Cincinnati, Cincinnati, OH, USA A.D. Korczyn
Department of Neurology, Tel-Aviv University,
J.M. Ferro Ramat-Aviv, Israel
Department of Neurosciences, Serviço de Neurologia,
Hospital de Santa Maria, University of Lisbon, Lisbon, M. Kraemer
Portugal Department of Neurology and Clinical Neurophysiology,
Alfried-Krupp-Hospital, Essen, Germany
A.C. Fonseca
Department of Neurosciences, Serviço de Neurologia, A. Krumholz
Hospital de Santa Maria, University of Lisbon, Lisbon, Department of Neurology, University of Maryland
Portugal School of Medicine, Baltimore, MD, USA

A.F. Francisco D. Laskowitz

Department of Neurosurgery, Hospital de Santa Maria, Departments of Medicine (Neurology), and
University of Lisbon, Lisbon, Portugal Anesthesiology, Duke University Medical Center,
Durham, NC, USA
D.P. Germain
Division of Medical Genetics, National Referral Center M.C. Leary
for Fabry disease and Inherited Disorders of Connective Department of Neurology, Harvard Clinical Research
Tissue, CHU Raymond Poincaré, Garches and Institute, Boston, MA, USA
University of Versailles – St Quentin en Yvelines,
Versailles, France D.S. Liebeskind
UCLA Stroke Center, Los Angeles, CA, USA
G. Gruener
Leischner Institute of Medical Education and M. McCoyd
Department of Neurology, Loyola University Chicago, Department of Neurology, Loyola University Healthcare
Stritch School of Medicine, Maywood, IL, USA Center, Maywood, IL, USA
 CONTRIBUTORS xiii
T. McKiernan E.S. Roach
Center for Heart and Vascular Medicine, Loyola Division of Child Neurology, Ohio State University,
University Healthcare Center, Maywood, IL, USA Columbus, OH, USA

J.L. Melancia D. Roeltgen

Department of Neurosurgery, Hospital de Santa Maria, Cape Physicians Associates, Cape May Court House,
University of Lisbon, Lisbon, Portugal NJ, USA

Y. Molad M.J. Schneck

Sackler Faculty of Medicine, Tel Aviv University, Tel Departments of Neurology and Neurosurgery, Loyola
Aviv and Rheumatology Unit, Beilinson Hospital, Rabin University Chicago, Stritch School of Medicine,
Medical Center, Petah Tikva, Israel Maywood, IL, USA

J.F. Moran C. Sila

Division of Cardiology, Loyola University Medical Department of Neurology, Case Western
Center, Maywood, IL, USA Reserve University School of Medicine and
Stroke and Cerebrovascular Center, University
D.E. Moulin Hospitals–Case Medical Center, Cleveland,
Departments of Clinical Neurological Sciences and OH, USA
Oncology, University of Western Ontario, London,
Ontario B.J. Stern
Department of Neurology, University of Maryland
J. Mukherji School of Medicine, Baltimore, MD, USA
Department of Anesthesiology, Loyola University
Medical Center, Maywood, IL, USA J.Y. Streifler
Department of Neurology, Sackler Faculty of Medicine,
S. Oana Tel Aviv University, Tel Aviv and Neurology Unit,
Department of Anesthesiology, Loyola University Hasharon Hospital, Rabin Medical Center, Petah Tikva,
Medical Center, Maywood, IL, USA Israel

R.A. Ostrowski J.I. Suarez

Division of Rheumatology, Department of Medicine, Department of Neurology, Baylor College of Medicine,
Loyola University Medical Center, Maywood, IL, USA Houston, TX, USA

T. Paiva J.E. Sumpton

Sleep Medicine Centre, Medical Faculty of Lisbon, Department of Pharmacy, Victoria Hospital, London
Lisbon, Portugal Health Sciences Centre, London, Ontario, Canada

R.S. Price M. Swash

Department of Neurology, University of Pennsylvania, Department of Neurology, Royal London Hospital,
Philadelphia, PA, USA Queen Mary School of Medicine, University of London,
London, UK
A.A. Rabinstein
Department of Neurology, Mayo Clinic, Rochester, MN, T. Takagishi
USA Division of Rheumatology, Department of Medicine,
Loyola University Medical Center, Maywood, IL, USA
K. Regev
Department of Neurology, Tel-Aviv University, M.Z. Urfy
Ramat-Aviv, Israel Department of Neurology, Baylor College of Medicine,
Houston, TX, USA
J. Robinson
Division of Rheumatology, Department of Medicine, A.J. van der Kooi
Loyola University Medical Center, Maywood, Department of Neurology, Academic Medical Centre,
IL, USA Amsterdam, The Netherlands
xiv CONTRIBUTORS
S.C. Vasaiwala E.F.M. Wijdicks
Cardiovascular Institute, Loyola University Medical Division of Critical Care Neurology, Mayo Clinic,
Center, Maywood, IL, USA Rochester, MN, USA

J.S. Veluz D.J. Wilber

Cardiothoracic Surgery, St. Luke’s Hospital and Health Cardiovascular Institute, Loyola University Medical
Network, Bethlehem, PA, USA Center, Maywood, IL, USA
Handbook of Clinical Neurology, Vol. 119 (3rd series)
Neurologic Aspects of Systemic Disease Part I
Jose Biller and Jose M. Ferro, Editors
© 2014 Elsevier B.V. All rights reserved

Chapter 1

Cardiovascular manifestations of neurologic disease

KEITH DOMBROWSKI1* AND DANIEL LASKOWITZ1,2
1
Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, USA
2
Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA

CARDIOLOGY IN VASCULAR AND 2006). Decreased heart rate variability, suggestive of

INTENSIVE CARE NEUROLOGY impaired autonomic regulation, is seen in stroke patients
with right insular cortex involvement, and is associ-
The relationship between the nervous and cardiovascular
ated with arrhythmias and an elevated risk of sudden
systems has been well recognized since the mid-19th
cardiac death (Tokgozoglu et al., 1999; Colivicchi
century (Coote, 2007), and cardiac complications are
et al., 2004).
common during the care of hospitalized neurology
Outflow from the insular cortex feeds back to subcor-
patients. In recent years, an increasing body of experi-
tical and diencephalic structures such as the amygdala
mental work has further defined the role of neurologic
and hypothalamus. The amygdala is believed to play
disease in mediating arrhythmias, subendocardial injury,
an important role in mediating cardiovascular responses
neurogenic cardiomyopathy, and neurogenic shock
to emotional stimuli, particularly negative stress
(Oppenheimer, 1993; Cheung et al., 1997; Coote, 2007).
responses. In a rat model of right middle cerebral artery
stroke, increased concentrations of adrenergic precur-
Pathophysiology
sors have been observed in the amygdala (Cheung
Although the relationship between the heart and the et al., 1997). Extreme stress responses have been associ-
brain has been explored for the better part of a century, ated with the rare occurrence of neurogenic stunned
more recent work has localized discrete neuroanatomic cardiomyopathy (takotsubo disease). The hypothalamus,
sites that influence heart rhythm and rate, myocardial particularly dorsomedial and paraventricular nuclei,
function, and vascular tone (Oppenheimer, 1993; integrates input from higher neural centers and trans-
Tokgozoglu et al., 1999; Coote, 2007). These locations mits autonomic information to sites within the brainstem
include the insular cortex, amygdala, paraventricular and spinal cord (Furlan and Fehlings, 2008). There is a
and caudal hypothalamus, and various sites in the known correlation between damage to the hypothalamus
brainstem and spinal cord including rostral ventro- and necrosis of myocardial tissue in subarachnoid hem-
lateral medulla, solitary tract nucleus, and interme- orrhage (Doshi and Neil-Dwyer, 1977). The brainstem
diolateral cell column (Fig. 1.1). (Aminoff, 1995; Coote, also plays an important role in mediating autonomic
2007). The insular cortex can influence the generation tone, and preclinical studies have implicated lower brain-
of arrhythmias and release of cardiac enzymes when stem structures such as the rostral ventrolateral medulla
irritated by vascular disease or epileptic phenomena, and solitary tract nucleus (Coote, 2007). Clinically, the
and several preclinical and clinical studies have demon- importance of brainstem structures in mediating cardio-
strated laterality of insular responses. The right insula vascular responses is evident during neurosurgical pro-
is associated with tachyarrhythmias and a pressor cedures of the skull base and rostrocaudal herniation in
response, while stimulation of the left insular the setting of intracranial hypertension. Changes in vas-
cortex is more commonly associated with bradycardia cular tone may also be clinically important in the setting
and a depressor response (Oppenheimer et al., 1992; of trauma. Cases of spinal cord injury, particularly
Oppenheimer, 1993; Tokgozoglu et al., 1999; Ay et al., above the level of T6, may result in vasomotor paralysis

*Correspondence to: Keith Dombrowski, M.D., Fellow, Neurocritical Care, Department of Medicine (Neurology), Duke University
Medical Center, Box 2905, Durham, NC 27710, USA. Tel: þ1-919-684-5650, Fax: þ1-919-684-6514, E-mail: keith.dombrowski@
duke.edu
4 K. DOMBROWSKI AND D. LASKOWITZ

Fig. 1.1. Sympathetic and parasympathetic outflow tracts of the central nervous system.
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 5
and neurogenic shock. Thus, cervical and high thoracic insular cortex and parietal lobe appear to correlate with
spinal cord injury may impair sympathetic outflow with the presence of myocardial damage and poor cardiac
resultant autonomic dysreflexia, arrhythmias, and outcome (Ay et al., 2006; Rincon et al., 2008). The phe-
orthostatic hypotension (Furlan and Fehlings, 2008). nomenon of neurogenic stunned cardiomyopathy is less
frequent in acute ischemic stroke, but is well described
(Yoshimura et al., 2008).
Acute ischemic stroke
Cardiac complications from ischemic stroke are
Intraparenchymal hemorrhage
extremely common and may complicate clinical manage-
ment. Such complications may be the result of concur- ECG changes following intraparenchymal hemorrhage
rent cardiovascular disease or be caused by focal are similar to those of ischemic stroke and subarachnoid
cerebral injury (Touze et al., 2005; Dhamoon et al., hemorrhage. Retrospective studies of patients with lobar
2007; Lee et al., 2008). For example, the incidence of and basal ganglia hemorrhages demonstrate ECG
comorbid coronary artery disease in patients with ische- changes in 64–95% of cases (Goldstein, 1979; Hays
mic cerebrovascular disease may be as high as 65% and Diringer, 2006; Maramattom et al., 2006; van
(Rokey et al., 1984). In the acute setting, it may be diffi- Bree et al., 2010). Repolarization changes are most char-
cult to differentiate the influence of pre-existing coro- acteristic and include QTc prolongation, nonspecific ST-
nary disease from cardiac dysfunction mediated by T changes, and deeply inverted T waves. Prolonged QTc
acute neurologic injury. is frequently associated with hydrocephalus and insular
Electrocardiographic changes are extremely preva- cortex involvement (van Bree et al., 2010). Sinus brady-
lent in the setting of acute ischemic stroke, with some cardia is a common arrhythmia found in patients with
studies reporting EEG changes in up to 90% of patients. supratentorial intracerebral hemorrhage (ICH), while
T wave inversion, ST-T changes, and premature ventric- atrial fibrillation has been associated with brainstem
ular beats are the most common (Dimant and Grob, hemorrhage (Talman, 1985). Although a common find-
1977; Goldstein, 1979). In many circumstances, these ing after ICH, ECG changes also do not consistently indi-
ECG changes are transient and of little clinical conse- cate that myocardial injury has taken place, and there is
quence. However, more malignant arrhythmias, includ- no clear association between mortality and the appear-
ing third-degree atrioventricular block and asystole, may ance or severity of ECG changes (Maramattom et al.,
also occur (Christensen et al., 2005), and ventricular 2006). Myocardial injury is observed in a small propor-
ectopy and QTc prolongation directly correlate with tion of patients with intracerebral hemorrhage, likely as a
mortality. This may be related to elevated rates of ische- result of an increase in sympathetic tone. The finding of
mic cardiac disease in the ischemic stroke population troponin elevations may serve as an independent predic-
(Stead et al., 2009). Arrhythmias are also common with tor of in-hospital mortality (Hays and Diringer, 2006;
stroke and include atrial fibrillation and sinus bradycar- Sandhu et al., 2008; Chung et al., 2009).
dia. Although it is often difficult to discern whether
newly documented atrial fibrillation is the cause or the
Subarachnoid hemorrhage
consequence of stroke, ECG and cardiac monitoring
of all acute ischemic stroke patients is recommended ECG changes in subarachnoid hemorrhage (SAH) were
(Adams et al., 2007). first described by Byer in 1947 (Byer et al., 1947), and
Ischemic changes on ECG and elevation of serum car- may occur in up to 90% of patients, especially those
diac enzymes (CK-MB and troponin I) are also com- of poor clinical grade (Andreoli et al., 1987). ECG
monly observed in the setting of acute ischemic changes in SAH are similar to those in intraparenchymal
stroke. Because ischemic stroke and myocardial infarc- hemorrhage. T wave changes (22%) are the most fre-
tion (MI) share similar risk factors, the occurrence of quent ECG abnormality reported, followed by U waves,
acute MI in the setting of large-artery cerebral athero- presence of left ventricular hypertrophy (LVH), and pro-
thrombosis is not surprising. However, myocardial dam- longed QT (Di Pasquale et al., 1987; Kawahara et al.,
age is frequently seen in the absence of cardiac 2003; van der Bilt et al., 2009). The most common
symptomatology such as chest pain or echocardio- rhythm changes are sinus arrhythmias and atrial fibrilla-
graphic change (Chalela et al., 2004; Lee et al., 2008). tion, which typically occur in the first 24–48 hours after
In circumstances such as this, myocardial injury is likely ictus. More ominous arrhythmias such as ventricular
the result of dysautonomia with excess sympathetic tachycardia, torsades de pointes, ventricular fibrillation,
tone. This may be produced by an increase in circulating and asystole have also been described, and are more
catecholamines or norepinephrine release at endocardial likely to occur in the setting of prolonged QT and hypo-
nerve terminals. Stroke severity and localization to the kalemia (Di Pasquale et al., 1987, 1988).
6 K. DOMBROWSKI AND D. LASKOWITZ
Myocardial injury is a common event in SAH and is been documented with increasing frequency in SAH.
probably of greater clinical significance than in intrapar- Left ventricular apical ballooning similar in appearance
enchymal or ischemic stroke. The presence of ECG abnor- to stress cardiomyopathy (takotsubo disease) and severe
malities, particularly repolarization changes and sinus global hypokinesis has been documented (Jain et al.,
arrhythmias, is significantly associated with an increase 2004; Lee et al., 2006). Neurogenic stunned cardiomyop-
in poor outcome and death (van der Bilt et al., 2009). athy appears to be most common in young women who
The frequency of cardiac biomarker elevation in SAH use sympathomimetic drugs (Kothavale et al., 2006).
is approximately 33% (van der Bilt et al., 2009), with a Although such phenomena are typically transient, these
direct correlation between clinical severity of the sub- cardiac abnormalities are associated with a poor progno-
arachnoid hemorrhage and the presence of myocardial sis in SAH as well as increased frequency of vasospasm
injury (Tung et al., 2004; Kothavale et al., 2006). Eleva- and delayed cerebral ischemia (Kothavale et al., 2006;
tions of serum brain natriuretic peptide may be secondary van der Bilt et al., 2009). The clinical significance of
to direct brain injury or neurogenic cardiac injury, and impaired systolic or diastolic dysfunction is most evident
may be correlated with delayed cerebral ischemia during the treatment of vasospasm and delayed cerebral
(Wijdicks et al., 1997; McGirt et al., 2004). Histologic evi- ischemia where augmentation of blood pressure with
dence of myocardial injury changes consists of contrac- inotropic agents may be initiated to optimize cerebral
tion band necrosis and myofibrillar degeneration with perfusion.
an inflammatory infiltrate (Doshi and Neil-Dwyer,
1977). In addition to cardiac enzyme elevations, transient
Head trauma
wall motion abnormalities (WMA) on echocardiography
have been reported in 22–31% of patients (van der Bilt Cardiac abnormalities in traumatic brain injury (TBI) are
et al., 2009). Myocardial WMAs are outside of normal likely common, although less well characterized than in
coronary vascular distribution and can vary from segmen- other neurologic diseases (Hersch, 1961; Wittebole et al.,
tal changes to global hypokinesis. It is likely that the 2005). In the largest series of 164 TBI patients, QT pro-
changes correspond to the localization of cardiac sympa- longation, increased P wave amplitudes, and T-wave
thetic nerve terminals. inversions were found (Hersch, 1961; Wittebole et al.,
In recent years, severe left ventricular systolic func- 2005). Additional reports have shown ischemic ECG
tion (neurogenic stunned cardiomyopathy) (Fig. 1.2) has changes in patients with TBI with no evidence of

Fig. 1.2. Diagnostic images in a single patient with neurogenic stunned myocardium. (A) Coronary angiogram without significant
disease (left coronary artery). (B) Transthoracic echocardiogram showing systole with left apical ballooning (solid arrow) and
hypercontractile base (dashed arrow). (C) Left ventriculogram in diastole showing apex (solid arrow) and base (dashed arrow).
(D) Left ventriculogram in systole showing left apical ballooning (solid arrow) and hypercontractile base (dashed arrow).
(Illustration graciously provided by David Adams, M.D., Duke University Medical Center Echocardiography Laboratory.)
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 7
coronary vascular disease (Syverud, 1991). There are In the care of patients with intracranial hyperten-
rare reports of myocardial injury and regional wall sion, optimizing cerebral perfusion pressure (CPP) may
motion abnormalities (RWMA), as well (Riera et al., require augmentation of blood pressure with intravenous
2010). Studies of dysautonomia in TBI have demon- inotropic agents as well as peripheral vasoconstrictors.
strated a correlation between decreased heart rate vari- Mean arterial pressure goals are often maintained at
ability and poor prognosis in this patient population supraphysiologic levels in order to obtain a desired CPP.
(Lowensohn et al., 1977). However, the use of pressors to induce hypertension must
be carefully considered in patients with neurogenic cardiac
injury, as this may exacerbate sympathetic-mediated car-
diac injury. One study has found a univariate association
Management of neurogenic cardiac events
of increasing phenylephrine dose and regional wall motion
Although it is important to identify and monitor patients abnormalities in subarachnoid hemorrhage, although this
at risk for neurogenic cardiac injury, the optimal man- may have been related either to the adrenergic effect of
agement of cardiac changes associated with acute brain phenylephrine or the poor neurologic condition of the
injury has not been studied rigorously. This is particu- patient (Tung et al., 2004). Induced hypertension may also
larly important, as ECG and echocardiographic findings be associated with acute lung injury in those with acute
consistent with ischemia or infarction may occur in brain injury (Contant et al., 2001). Thus, the development
patients without coronary artery disease, and these of optimal strategies for the treatment of cardiac dysfunc-
abnormalities are often self-limited and may be associ- tion in the setting of neurologic catastrophe has not been
ated with focal wall motion abnormalities. An appropri- fully defined and remains an active area of research.
ate history and diagnostic workup should be performed,
as the consequences of inappropriate thrombolytic, CARDIOLOGY OF PAROXYSMAL
antithrombotic, and anticoagulant therapy in the setting NEUROLOGIC EVENTS
of acute brain injury may be deleterious.
Migraine
For many patients, especially those with large intrapar-
enchymal and subarachnoid hemorrhage, intensive care Migraine headaches are a common cause of neurologic
monitoring is required, though prospective data demon- referral and may be associated with prominent autonomic
strating the effect of dedicated neurointensive care units symptoms such as flushing, piloerection, diaphoresis, and
on patient outcomes remains an active area of research. lacrimation. In migraine variants such as cluster head-
The treatment of arrhythmias for patients with neuro- aches, focal sympathetic dysfunction can take the form
genic cardiac abnormalities should include standard phar- of a Horner’s syndrome (ipsilateral ptosis, meiosis, and
macologic therapy and pacing. As overstimulation of the anhidrosis). Cardiovascular dysfunction has been studied
sympathetic nervous system is implicated in many forms extensively in migraine headache. Abnormalities that
of cardiac dysfunction following catastrophic brain occur in migraineurs include mild orthostasis, arrhyth-
injury, adrenergic blockade has been studied as a means mias, and repolarization changes on ECG (Aygun et al.,
of preventing myocardial injury and possibly improving 2003; Thijs et al., 2006). Cardiovascular changes are noted
survival in acute brain injury (Neil-Dwyer et al., 1978). during, as well as in between, attacks. During headaches,
In patients with decreased heart rate variability (cardiac benign, transient sinus arrhythmias, premature ventricu-
uncoupling) and severe TBI, b-blockers may be associ- lar contractions, and repolarization changes may occur
ated with a survival benefit (Riordan et al., 2007). How- on ECG (Aygun et al., 2003). Reversible disturbances
ever, at the present time, there is no recommendation of autonomic regulation with sympathetic hyperfunction
for the use of adrenergic blockade following TBI in the or hypofunction are likely responsible for these cardiovas-
US (Carney and Ghajar, 2007). Several randomized clini- cular changes (Duru et al., 2006).
cal trials of atenolol, propranolol, and phentolamine have Migraineurs also appear to have a unique pattern of
also suggested a reduction of myocardial necrosis and cardiac structural changes. Mitral valve prolapse, patent
improved outcome in patients with subarachnoid hemor- foramen ovale (PFO), atrial septal defect (ASD), and
rhage (Neil-Dwyer et al., 1985, 1986). Although several right-to-left shunting are more common in patients with
observational studies have explored the use of b-blockade migraine headache than in the general population
in patients with ischemic stroke and suggested benefit (Schwedt, 2009). Although PFO is prevalent in the general
(Dziedzic et al., 2007), its use was not as promising when population (25–30%), as many as 50% of patients with
explored prospectively. The current recommendations by migraine with aura may have this defect (Schwedt,
the American Heart Association do not recommend the 2009). The degree of right-to-left shunting appears to cor-
use of antihypertensives in most cases of acute stroke relate with the presence of migraine headaches (Post and
(Barer et al., 1988; Adams et al., 2007). Budts, 2006; Woods et al., 2010). Intracardiac or
8 K. DOMBROWSKI AND D. LASKOWITZ
intrapulmonary shunting may allow paradoxical emboli to causing cardiovascular dysregulation is the likely cause
reach the cerebral microcirculation and produce cortical for these changes in children and adults with a possible pre-
spreading depression with subsequent aura or migraine dominance in symptomatic mesial temporal lobe epilepsy
headache. PFO closure has been explored as a possible (Opherk et al., 2002; Mayer et al., 2004).
therapy for intractable migraines. Small noncontrolled Although malignant ventricular arrhythmia due to
studies have reported significant benefit but larger trials autonomic dysfunction is relatively rare, it is postulated
such as the Migraine Intervention with STARflex Tech- that neurogenic cardiac events are responsible for an
nology (MIST-1) study using a percutaneous inserted increased risk of sudden death in epileptics. At present,
device found only minimal benefits (Anzola et al., the mechanisms for sudden death in epilepsy (SUDEP)
2006; Carroll, 2008; Jesurum et al., 2008). have not been fully defined, although there is a strong
“Triptan” medicines, which target the serotonin 5-HT1D association with medically refractory epilepsy in young
receptor, are increasingly used to treat migraine head- adults. It has been proposed that fatal arrhythmias are
aches in migraineurs with and without aura. Although the immediate cause of death with bradycardia and ictal
the use of triptans has evolved as a first-line abortive asystole as one possible mechanism (Fig. 1.3) (So, 2008).
therapy for many migraineurs, triptans may induce As neurogenic cardiac events may result from an imbal-
peripheral vasoconstriction associated with hypertension, ance in the tone of the autonomic nervous system, victims
chest pain syndromes, and, rarely, coronary vasospasm of SUDEP have been demonstrated to exhibit increased
(Sumatriptan, 2010). Thus, triptans should be used with autonomic activity with seizures. This increased activity
caution in patients with suspected coronary artery disease, was noted particularly during sleep–wake transitions This
angina, or significant cerebrovascular disease, although in is consistent with the observation that SUDEP victims are
those without known cardiovascular disease, there does frequently found in bed (Nei et al., 2004).
not appear to be a significantly elevated risk of cardiac The occurrence of cardiac changes in cases of convul-
complications (Hall et al., 2004). sive status epilepticus (SE) is also common, and may be
exacerbated by extreme metabolic demands. Ischemic
Epilepsy changes on ECG are most common followed by bundle
branch block and axis changes. Although the majority of
Heart rate and rhythm alterations are common in patients arrhythmias are not symptomatic, potentially life-
with epilepsy (Opherk et al., 2002; Mayer et al., 2004), and threatening arrhythmias, including ventricular fibrilla-
this is often the most recognizable non-neurologic symp- tion, may occur. As with neurovascular events, ECG
tom associated with seizures. The prevalence of ictal abnormalities and myocardial injury in SE may portend
tachycardia (IT) is as high as 80–100% (Zijlmans et al., a poor prognosis, and the presence of ECG changes other
2002). In rare cases, sinus tachycardia will degenerate to than sinus tachycardia more than doubled the mortality
a more concerning rhythm such as atrial fibrillation or flut- of patients in SE (Boggs et al., 1993).
ter (Nei et al., 2004). It is important to recognize that tachy-
cardia is not always a response to increased physiologic
demand as it may occur in partial seizures without second- CARDIOLOGY OF MOVEMENT
ary generalization (Mayer et al., 2004; Surges et al., 2010). DISORDERS AND
Ictal bradycardia (IB) is also a common pattern, and has NEURODEGENERATIVE DISEASES
been reported in as many as 20% of epileptic patients
Parkinson disease and parkinsonian
(Rugg-Gunn et al., 2004). Typically, the decrease in heart
disorders
rate is asymptomatic but bradycardia can progress to asys-
tole. Ischemic ECG changes and conduction block are also Autonomic disturbances and cardiovascular changes are
common findings during epileptic seizures (Opherk et al., common in patients with Parkinson disease and related
2002; Zijlmans et al., 2002; Nei et al., 2004). Dysautonomia syndromes including multiple system atrophy (MSA)

Fig. 1.3. Electroencephalogram showing a sinus pause (line with arrow) during a seizure. (Reproduced from Nei et al., 2000, with
permission.)
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 9
and dementia with Lewy bodies. Orthostatic hypotension upper motor neuron findings. FA is caused by an abnor-
is the most frequent symptomatic cardiovascular abnor- mal expansion of GAA trinucleotide repeats in the fra-
mality, and may be extremely challenging to manage. taxin gene with resultant mitochondrial respiratory
In Parkinson disease (PD), orthostasis is caused by chain dysfunction. ECG and echocardiographic abnor-
baroreflex failure and postganglionic cardiac sympa- malities are common in this disorder and may include
thetic denervation, which has been demonstrated using repolarization changes and hypertrophic cardiomyopa-
123
iodine-metaiodobenzylguanidine (MIBG) scintigraphy. thy. In unusual circumstances, asymmetric septal hyper-
In MSA, symptoms of autonomic failure are more severe trophy and dilated cardiomyopathy may also occur.
and appear earlier than in PD. Autonomic function tests Arrhythmias, including atrial flutter, are common and
and MIBG studies can help diagnose MSA (Courbon become clinically apparent as the disease progresses
et al., 2003; Goldstein et al., 2003). Prolongation of the (Alboliras et al., 1986). The cause of death of most
QT is known to occur in patients with Parkinson disease patients with FA is congestive heart failure as a result
and multiple system atrophy (MSA) and may be related of cardiomyopathy. Therapies aimed at reducing oxida-
to the increased incidence of sudden cardiac death in this tive stress such as idebenone, a synthetic analog of coen-
population (Deguchi et al., 2002). In 2007, ergotamine- zyme Q10, have achieved marginal success in preventing
based dopamine agonists such as cabergoline and pergo- the progression of structural cardiac disease and neuro-
lide received national attention and were removed from logic dysfunction (Trujillo-Martin et al., 2009).
the market due to an increased rate of fibrotic valvulopa-
thies associated with clinically significant valvular in- NEUROMUSCULAR DISORDERS WITH
sufficiency (Zanettini et al., 2007). CARDIAC MANIFESTATIONS
Dementia Disorders of peripheral nerves
Selective impairment of parasympathetic and sympa- Acquired disorders of peripheral nerves, such as
thetic nervous systems resulting orthostatic hypotension Guillain-Barré syndrome and diabetes mellitus, are fre-
have been described in vascular (VaD) and Alzheimer’s quently associated with an autonomic neuropathy that
dementia (AD) (Allan et al., 2007). Decreased heart rate produces sinus arrhythmias and orthostatic hypotension.
variability, increased QT dispersion, and other auto- Sympathetic nerve axons traverse the spinal cord and
nomic nervous system involvement in patients with exit through white rami at the level of T1 and L2–L4.
dementia may correlate with the degree of cognitive These fibers synapse in paravertebral ganglia and merge
impairment as well as mortality, particularly in those with anterior spinal roots before traveling to innervate
with low blood pressure (Guo et al., 1998; Zulli et al., organs. Preganglionic parasympathetic fibers travel in
2005; Royall et al., 2006). VaD and AD are difficult cranial nerves III, VII, IX, and X and S2–S4 spinal roots.
to differentiate clinically and share many similar risk These myelinated axons synapse within small ganglia
factors with cardiovascular disease, including hyperten- near their target organ. Dysautonomia results from
sion, diabetes, and presence of the APOE4 polymor- demyelination or degeneration of these small myelinated
phism. Risk factor modification for atherosclerosis and unmyelinated sympathetic and parasympathetic
may play a role in the prevention of dementia and has nerve fibers. Most frequently, involvement of the
garnered significant interest in recent years. Trials of carotid sinus, glossopharyngeal, and vagus nerves
antihypertensive agents, including calcium channel- results in dysautonomia.
blockers, ACE inhibitors, and diuretics, have found a
reduced incidence of dementia with treatment (Forette GUILLAIN–BARRÉ SYNDROME
et al., 2002; Tzourio et al., 2003). Cholesterol-lowering
Cardiovascular abnormalities are common and may be
agents, including statins, have used similar endpoints
life-threatening in Guillain–Barré syndrome (GBS), an
in studies and found potentially protective effect (Jick
inflammatory disease that results in demyelination of
et al., 2000). However, a recent prospective trial failed
peripheral nerves. Although most often sporadic, GBS
to demonstrate a significant difference in cognitive test-
occurs with increased frequency after upper respiratory
ing in patients with established dementia taking atorva-
and Campylobacter jejuni infections, as well as some
statin after 72 weeks (Feldman et al., 2010).
vaccinations. Autonomic dysregulation is often clini-
cally significant and the presence of cardiovascular com-
Degenerative ataxias: Friedreich’s ataxia
plications is a predictor of mortality in GBS (Alshekhlee
Friedreich’s ataxia (FA) is an autosomal recessive spino- et al., 2008). The most common cardiovascular changes
cerebellar neurodegenerative disease characterized by include labile blood pressure, arrhythmias, ECG
progressive ataxia, areflexia, proprioceptive loss, and changes, and, less frequently, myocardial dysfunction
10 K. DOMBROWSKI AND D. LASKOWITZ
(Durocher et al., 1980; Pfeiffer et al., 1999; Yoshii et al., by the duration and severity of diabetes. CAN is diag-
2000). Cardiovascular changes tend to be more prominent nosed after demonstrating a decrease in heart rate vari-
in those with significant motor involvement requiring ability and resting tachycardia, likely as a result of vagal
mechanical ventilation (Winer and Hughes, 1988). Like- neuropathy (Pop-Busui, 2010). I-MIBG scintigraphy
wise, the resolution of dysautonomia parallels neurologic is also helpful in the diagnosis of CAN and may be
improvement (Lyu et al., 2002). Pathologically, autonomic more sensitive than HRV studies (Scholte et al., 2010)
neuropathy is likely the result of inflammatory demyelin- Although there is no specific intervention for CAN,
ation of the vagus, glossopharyngeal nerves, and pregan- treatment focuses on improving glycemic control
glionic sympathetic fibers (Matsuyama and Haymaker, (Pop-Busui et al., 2010).
1967; Tuck and McLeod, 1981). Fluctuations of greater
than 85 mmHg systolic blood pressure are an important
Disorders of neuromuscular junction
indicator of dysautonomia and may correlate with the
occurrence of significant arrhythmias (Winer and Cardiovascular changes may also be associated with dis-
Hughes, 1988; Pfeiffer et al., 1999). Although sinus tachy- orders of the neuromuscular junction including myasthe-
cardia is the most frequent arrhythmia observed in GBS, nia gravis (MG) and Lambert–Eaton myasthenic
sinus bradycardia may occur in a third of patients and is syndrome (LEMS). Giant cell myocarditis has been seen
more clinically significant (Flachenecker et al., 2000). in association with MG in a significant number of patients
When bradycardia is severe or occurs with periods of asys- (58%), particularly those with thymomas (Gibson, 1975).
tole, implantation of a pacemaker may be necessary. Auto- One study found that antistriational autoantibodies may
nomic neuropathy in GBS may result in a profound be directed against myocardial tissue in some patients
increase in sympathetic tone and the occurrence of neuro- with MG-associated myocarditis (Suzuki et al., 2009).
genic stunned cardiomyopathy, hypertensive encephalop- ECG changes are also noted in a earlier studies, including
athy, and posterior reversible encephalopathy syndrome ischemic-appearing ST-T changes and prolonged QT
(PRES) (Durocher et al., 1980; Elahi et al., 2004). ECG (Gibson, 1975; Chiavistelli et al., 2009). Interestingly,
repolarization changes and cardiac enzyme elevations ECG changes and myocardial dysfunction occurring with
should prompt echocardiographic investigation MG may be pyridostigmine-responsive in some patients
(Bernstein et al., 2000). I-MIBG scintigraphy may show (Gibson, 1975; Furlund Owe et al., 2008).
defects similar to those patients with neurogenic stunned Lambert–Eaton myasthenic syndrome is a paraneo-
cardiomyopathy following subarachnoid hemorrhage plastic neuromuscular junction disorder that affects pre-
(Yoshii et al., 2000). synaptic voltage-gated Caþ channel and produces
Because of the potential for significant dysautono- subacute, progressive muscle weakness that improves
mia, most GBS patients with severe motor deficits with exercise. In LEMS, cardiovagal abnormalities are
should be monitored in an intensive care setting with common and may occur in 75% of patients. Cardiovascu-
continuous heart rate and blood pressure monitoring. lar and other autonomic signs may occur as the result of
As a practical consideration, vigilance is required when deficient presynaptic neurotransmitter release as symp-
turning the patient and during tracheal suctioning, as toms respond to treatment with 3,4-diaminopyridine
vagal stimulation may precipitate profound bradycardia (McEvoy et al., 1989; O’Suilleabhain et al., 1998).
and asystolic episodes. When treating the hypertension
associated with GBS, b-blockers should be avoided,
Disorders of muscle
and short-acting agents should be utilized in case of
an exaggerated response to vasoactive drugs. (Table 1.1)

DIABETIC CARDIAC AUTONOMIC NEUROPATHY DYSTROPHINOPATHIES

Peripheral and cardiac autonomic neuropathy (CAN) is Dystrophinopathies, including Duchenne and Becker
common in diabetic patients and is associated with an muscular dystrophy (MD), are X-linked recessive inher-
increase in mortality. Recent glucose control trials have ited diseases that result from mutations on the dystro-
found an independent association between all-cause phin gene. Symptoms are characterized by progressive
mortality and CAN, regardless of the duration of diabe- weakness of skeletal muscle, beginning in the pelvic
tes and presence of other cardiovascular risk factors girdle with eventual involvement of appendicular and
(Gerritsen et al., 2001; Pop-Busui et al., 2010). CAN is respiratory musculature. Duchenne MD (DMD) results
also associated with silent myocardial ischemia and sud- from severely reduced or absent normal dystrophin. It
den death (Maser et al., 2003; Young et al., 2009). The results in an earlier and more severe phenotype than
development of CAN is multifactorial and is influenced Becker MD (BMD). Cardiac involvement is prominent
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 11
Table 1.1
Cardiac manifestations of muscle disorders: myopathies with significant cardiac involvement with respective abnormal
genetic or gene product abnormality

Genetic/protein
Disease Mode of inheritance abnormality Cardiac manifestations

Dystrophinopathies Xr Dystrophin ECG – large R waves in lead 1, AV block, atrial

Duchenne fibrillation, and ventricular arrhythmias
Becker Dilated cardiomyopathy and heart failure
Emery–Dreyfus Xr Emerin ECG – bradycardia, AV block, and sudden death
disease
Myotonic dystrophy AD Abnormal CTG ECG – AV block, prolonged QT and torsades de
repeats pointes
Dilated cardiomyopathy and heart failure
Laminopathies AR Lamin A/C ECG – supraventricular arrythmias and AV block
Cardiac dilatation and dilated cardiomypathy
Limb girdle AD or AR Sarcoglycans ECG – conduction abnormalities and ST elevation
muscular Dilated cardiomyopathy
dystrophies
Congenital
myopathies
Nemaline rod AD or AR a-Actin Myocardial dilatation and heart failure
myopathy
Desmin myopathy AD, AR, or Desmin ECG – AV block and ventricular tachycardia
sporadic Systolic and diastolic heart failure
Central core AD Ryanodine receptor Myocardial dilatation and heart failure
myopathy gene
Myofibrillar AD and unknown Various Z-disk Dilated cardiomyopathy and LVHT
myopathy proteins
Glycogenoses X-linked and AR Various enzyme Myocardial thickening, heart failure, and sudden
deficiencies cardiac death
Andersen–Tawil AD periodic Kþ channelopathy Prolonged QT and bidirectional ventricular
disease paralysis tachycardia
Mitochondrial Mitochondrial Mitochondrial DNA ECG – ventricular ectopy and WPW
cytopathies point mutations Dilated and hypertrophic cardiomyopathy
(MELAS, MERFF, ECG – atrivoventricular block and BBB
LHON)
Kearns–Sayre
syndrome
Barth syndrome Xr Taffazine ECG — ventricular arrhythmias
Endocardial fibroelastosis and cardiomyopathy

MELAS, metabolic encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; LHON, Leber’s
hereditary optic neuropathy; Xr, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive; CTG, cytosine-thymine-
guaninenucleotide sequence; AV, atrioventricular; LVHT, left ventricular hypertrabeculation; WPW, Wolf–Parkinson–White syndrome; BBB,
bundle branch block.

in dystrophinopathies and significantly contributes to DMD (Connuck et al., 2008). Typical ECG changes in
the morbidity and mortality of these conditions. these muscular dystrophies include atrioventricular con-
Cardiac conduction abnormalities have been found in duction block, a marked increase in the R wave of lead
48% of DMD patients with pathologic evidence of multi- V1, and deep Q waves in the precordial leads (Perloff
focal fibrosis in the cardiac conduction system (Sanyal et al., 1967). Fibrotic change and fatty infiltration of
and Johnson, 1982). Rhythm abnormalities are common the myocardium result in dilated cardiomyopathy with
and include sinus tachycardia, atrial fibrillation, and systolic and diastolic dysfunction in most DMD patients
atrial flutter (Perloff et al., 1967; Finsterer and (Brockmeier et al., 1998). Although, historically, death
Stollberger, 2008b). Ventricular arrhythmias are also com- typically occurred by the third decade in patients with
mon and are an important cause of death for those with DMD as a result of respiratory failure, advances in the
12 K. DOMBROWSKI AND D. LASKOWITZ
supportive treatment of DMD patients have led to a lon- manifest with progressive proximal weakness in the pel-
ger life expectancy and a resulting increase in cardiac vic girdle and early onset contractures at the elbows. X-
symptoms (Cripe, 2005; Bushby et al., 2010). Thus, car- linked EDMD is more frequently associated with
diac dysfunction represents a serious source of morbidity conduction abnormalities than structural heart disease.
in this patient population, with approximately two-thirds Supraventricular and His–Purkinje conduction system
of DMD patients dying as a result of congestive heart disease is evident with numerous and dangerous
failure (Connuck et al., 2008). arrhythmias including atrial fibrillation and flutter, atrial
In BMD, the incidence of cardiac abnormalities may standstill, and ventricular tachycardia. Ventricular
approach 90%, although symptoms rarely present early arrhythmias may be responsible for the occurrence of
in the disease course (Finsterer and Stollberger, 2008a; sudden death in patients with EDMD. Permanent
Yilmaz et al., 2008). Cardiac involvement typically pacemaker implantation is indicated in many patients
becomes clinically apparent in the third decade of life, with Emery–Dreyfus disease. An autosomal dominant
and is associated with ECG abnormalities, arrhythmias, variant of EDMD that results from a defect in lamin
and myocardial abnormalities that are similar to, but less A/C manifests with cardiomyopathy in addition to con-
severe than, those seen with DMD (Yilmaz et al., 2008). duction defects (Finsterer and Stollberger, 2000, 2008b).
In a rare subset of patients, cardiac disease may be more
severe than skeletal muscle weakness, or even the pre- Myotonic dystrophy
senting symptom of BMD (Finsterer et al., 1999;
Myotonic muscular dystrophy type 1 (MMD) is the most
Yokota et al., 2004). In pediatric patients, the occurrence
common inherited muscular dystrophy presenting in
of cardiomyopathy is less frequent than those with DMD
adulthood. This disease is caused by an expansion of
but may be more severe. Cardiac transplantation for car-
CTG repeats at the 30 -UTR of the serine/threonine myo-
diomyopathy in BMD is a viable option due to a favor-
tonic dystrophy protein kinase (DMPK). Multiple organ
able neurologic prognosis (Finsterer et al., 1999; Yokota
systems are involved in MMD, including vision, endo-
et al., 2004; Connuck et al., 2008).
crine, and cardiovascular. Cardiac involvement is very
The cardiac management of patients with muscular
common in MMD and includes conduction abnormali-
dystrophy is multifaceted and includes early evaluation
ties and structural heart disease as a result of interstitial
and involvement of a cardiologist in the care of the
myocardial fibrosis and myofibrillar degeneration
patient. Cardiac symptoms may be masked my mus-
(Motta et al., 1979). Electrocardiographic abnormalities
culoskeletal limitations, and guidelines devised by the
are reported in 65–80% of patients, who most commonly
American Academy of Pediatrics Section on Cardiology
experience PVCs, QRS prolongation, PR interval prolon-
and Cardiac Surgery recommend a baseline exam,
gation with atrioventricular block, and left fascicular
ECG, and echocardiography at the time of diagnosis or
block (Perloff et al., 1984; Groh et al., 2002). Atrial fibril-
by age 6 for DMD (Cripe, 2005). Cardiac MRI may also
lation and flutter are also commonly reported (Finsterer
be considered as it may be more sensitive than echocardi-
and Stollberger, 2008a). The presence of ECG abnormal-
ography in evaluating myocardial disease in DMD
ities correlates with skeletal muscle disability, age, and,
(Yilmaz et al., 2008). Pharmacologic intervention should
possibly, CTG repeat length (Groh et al., 2002). Signifi-
begin when ventricular function abnormalities are first
cant cardiomyopathy can occur but it is less common
noted. The management of heart failure in patients with
than conduction abnormalities. Management of patients
DMD involves b-blockers, diuretics, and ACE inhibitors.
with MMD should include an annual ECG from the time
ACE inhibitors have beneficial effects on cardiac remo-
of diagnosis, Holter monitoring if PR interval increases
deling, endothelial function, and when in combination
or bradycardia is noted, and pacemaker implantation
with b-blockers may delay progression of LV systolic dys-
with evidence of a progressing arrhythmia or atrioven-
function in DMD (Duboc et al., 2005; Ogata et al., 2009).
tricular block (Gregoratos et al., 1998).
For patients with BMD, screening cardiologic evaluations
should begin at age 10 or at the onset of symptoms, and be
MITOCHONDRIAL CYTOPATHIES
continued every 2 years. Treatments for the cardiac man-
ifestations are similar to those of DMD. Carriers for The mitochondrial cytopathies include a large number of
DMD and BMD are susceptible to cardiac disease and disorders with diverse clinical presentations that occur as
should be referred to a cardiologist (Cripe, 2005). a result of abnormalities within the respiratory chain and
lipid b-oxidation. Disorders of the respiratory chain typi-
cally result from point mutations in the mitochondrial
EMERY–DREYFUS MUSCULAR DYSTROPHY
DNA. Mutant DNA is present in variable proportions in
Emery–Dreyfus muscular dystrophy (EDMD) is an muscle and cardiac tissues, accounting for significant
X-linked muscular dystrophy caused by an abnormality phenotypic heterogeneity. The more common signs and
in the nuclear membrane protein emerin. The disorder is symptoms include lactic acidosis, myopathy, external
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 13
ophthalmoplegia, and central and peripheral nervous sys- Association Stroke Council, Clinical Cardiology Council,
tem disease, such as encephalopathy, dementia, seizures, Cardiovascular Radiology and Intervention Council, and
and neuropathy. Cardiac involvement is common in the Atherosclerotic Peripheral Vascular Disease and
mitochondrial respiratory chain disorders and includes Quality of Care Outcomes in Research Interdisciplinary
Working Groups. The American Academy of Neurology
conduction disturbances, myocardial thickening, hyper-
affirms the value of this guideline as an educational tool
trophic and dilated cardiomyopathy. In mitochondrial dis-
for neurologists. Circulation 115: e478–e534.
orders of b-oxidation of long chain fatty acids, Alboliras ET, Shub C, Gomez MR et al. (1986). Spectrum of
hypertrophic cardiomyopathy with lipid deposition is cardiac involvement in Friedreich’s ataxia: clinical, elec-
often present. Some of these disorders are the result of trocardiographic and echocardiographic observations.
primary carnitine deficiency and respond well to supple- Am J Cardiol 58: 518–524.
mentation (Finsterer and Stollberger, 2008a). Allan LM, Ballard CG, Allen J et al. (2007). Autonomic
Kearns–Sayre syndrome (KSS) is a sporadic dysfunction in dementia. J Neurol Neurosurg Psychiatry 78:
mitochrondrial cytopathy that exists along a spectrum 671–677.
of diseases, although external opthalmoplegia is an Alshekhlee A, Hussain Z, Sultan B et al. (2008). Guillain–
invariant feature. In addition to ocular muscle weakness, Barre syndrome: incidence and mortality rates in US hos-
pitals. Neurology 70: 1608–1613.
the most prominent features of the syndrome include
Aminoff MJ (1995). Neurology and General Medicine: The
cardiac arrhythmias, retinopathy, and proximal muscle
Neurological Aspects of Medical Disorders. 2nd edn.
weakness. Prolonged intraventricular conduction Churchill Livingstone, New York.
time, atrioventricular block, and bundle branch block Anan R, Nakagawa M, Miyata M et al. (1995). Cardiac
are the most frequent cardiac findings (Berenberg involvement in mitochondrial diseases. A study on 17
et al., 1977; Anan et al., 1995). Fibrous and adipose tissue patients with documented mitochondrial DNA defects.
deposition in the bundle of His and distal bundle Circulation 91: 955–961.
branches are found on pathologic analysis (Clark Andreoli A, di Pasquale G, Pinelli G et al. (1987).
et al., 1975). Prior studies have shown a high prevalence Subarachnoid hemorrhage: frequency and severity of car-
of serious cardiac events in those with KSS, necessitat- diac arrhythmias. A survey of 70 cases studied in the acute
ing close cardiac follow-up and permanent pacemaker phase. Stroke 18: 558–564.
Anzola GP, Frisoni GB, Morandi E et al. (2006). Shunt-
implantation in many patients (Berenberg et al., 1977;
associated migraine responds favorably to atrial septal
Gregoratos et al., 1998). Cardiomyopathy is much less
repair: a case-control study. Stroke 37: 430–434.
common but it has been reported in pediatric patients Ay H, Koroshetz WJ, Benner T et al. (2006). Neuroanatomic
with KSS. correlates of stroke-related myocardial injury. Neurology
66: 1325–1329.
Aygun D, Altintop L, Doganay Z et al. (2003).
CONCLUSION Electrocardiographic changes during migraine attacks.
Cardiac manifestations of neurologic disorders are com- Headache 43: 861–866.
mon, and there is a growing understanding of the impor- Barer DH, Cruickshank JM, Ebrahim SB et al. (1988). Low
dose beta blockade in acute stroke (“BEST” trial): an eval-
tant interaction between the heart and brain. This has
uation. Br Med J (Clin Res Ed) 296: 737–741.
become increasingly evident in the setting of vascular dis- Berenberg RA, Pellock JM, DiMauro S et al. (1977). Lumping
ease, in which cardiovascular and cerebrovascular pathol- or splitting? “Ophthalmoplegia-plus” or Kearns–Sayre
ogy is often comorbid. The increased sympathetic tone syndrome? Ann Neurol 1: 37–54.
that occurs in the setting of acute neurologic disease Bernstein R, Mayer SA, Magnano A (2000). Neurogenic
may also exacerbate cardiac dysfunction. Characteristic stunned myocardium in Guillain–Barre syndrome.
patterns of cardiac dysfunction have been identified in Neurology 54: 759–762.
neuromuscular disease, neurodegenerative disease, and Boggs JG, Painter JA, DeLorenzo RJ (1993). Analysis of elec-
in the setting of paroxysmal neurologic events, such as trocardiographic changes in status epilepticus. Epilepsy
epilepsy. Thus, a thorough understanding of the cardiac Res 14: 87–94.
complications associated with neurologic disease will Brockmeier K, Schmitz L, Moers A et al. (1998).
X-chromosomal (p21) muscular dystrophy and left ventric-
facilitate the prompt recognition and management of car-
ular diastolic and systolic function. Pediatr Cardiol 19:
diac dysfunction, and will play an increasingly important 139–144.
role in optimizing clinical management. Bushby K, Finkel R, Birnkrant DJ et al. (2010). Diagnosis and
management of Duchenne muscular dystrophy. Part 2.
REFERENCES Implementation of multidisciplinary care. Lancet Neurol
9: 177–189.
Adams HP Jr, Alberts MJ, Bhatt DL et al. (2007). Guidelines for Byer E, Ashman R, Toth LA (1947). Electrocardiograms with
the early management of adults with ischemic stroke: a guide- large, upright T waves and long Q-T intervals. Am Heart J
line from the American Heart Association/American Stroke 33: 796–806.
14 K. DOMBROWSKI AND D. LASKOWITZ
Carney NA, Ghajar J (2007). Guidelines for the manage- Di Pasquale G, Pinelli G, Andreoli A et al. (1988). Torsade de
ment of severe traumatic brain injury. Introduction. pointes and ventricular flutter-fibrillation following spon-
J Neurotrauma 24 (Suppl 1): S1–S2. taneous cerebral subarachnoid hemorrhage. Int J Cardiol
Carroll JD (2008). Migraine Intervention With STARFlex 18: 163–172.
Technology trial: a controversial trial of migraine and pat- Dimant J, Grob D (1977). Electrocardiographic changes and
ent foramen ovale closure. Circulation 117: 1358–1360. myocardial damage in patients with acute cerebrovascular
Chalela JA, Ezzeddine MA, Davis L et al. (2004). Myocardial accidents. Stroke 8: 448–455.
injury in acute stroke: a troponin I study. Neurocrit Care 1: Doshi R, Neil-Dwyer G (1977). Hypothalamic and myocardial
343–346. lesions after subarachnoid haemorrhage. J Neurol
Cheung RT, Hachinski VC, Cechetto DF (1997). Neurosurg Psychiatry 40: 821–826.
Cardiovascular response to stress after middle cerebral Duboc D, Meune C, Lerebours G et al. (2005). Effect of peri-
artery occlusion in rats. Brain Res 747: 181–188. ndopril on the onset and progression of left ventricular dys-
Chiavistelli P, Cei M, Carmignani G et al. (2009). function in Duchenne muscular dystrophy. J Am Coll
Pseudoischemic electrocardiogram in myasthenia gravis Cardiol 45: 855–857.
with thymoma: reversibility after thymectomy. Clin Durocher A, Servais B, Caridroix M et al. (1980). Autonomic dys-
Cardiol 32: E75–E78. function in the Guillain–Barre syndrome. Hemodynamic and
Christensen H, Boysen G, Christensen AF et al. (2005). Insular neurobiochemical studies. Intensive Care Med 6: 3–6.
lesions, ECG abnormalities, and outcome in acute stroke. J Duru M, Melek I, Seyfeli E et al. (2006). QTc dispersion and P-
Neurol Neurosurg Psychiatry 76: 269–271. wave dispersion during migraine attacks. Cephalalgia 26:
Chung PW, Won YS, Kwon YJ et al. (2009). Initial troponin 672–677.
level as a predictor of prognosis in patients with intracere- Dziedzic T, Pera J, Szczudlik A (2007). Beta-blockers reduce
bral hemorrhage. J Korean Neurosurg Soc 45: 355–359. the risk of early death in ischemic stroke. J Neurol Sci 252:
Clark DS, Myerburg RJ, Morales AR et al. (1975). Heart block 53–56.
in Kearns–Sayre syndrome: electrophysiologic-pathologic Elahi A, Kelkar P, St Louis EK (2004). Posterior reversible
correlation. Chest 68: 727–730. encephalopathy syndrome as the initial manifestation of
Colivicchi F, Bassi A, Santini M et al. (2004). Cardiac auto- Guillain–Barre syndrome. Neurocrit Care 1: 465–468.
nomic derangement and arrhythmias in right-sided stroke Feldman HH, Doody RS, Kivipelto M et al. (2010).
with insular involvement. Stroke 35: 2094–2098. Randomized controlled trial of atorvastatin in mild to mod-
Connuck DM, Sleeper LA, Colan SD et al. (2008). erate Alzheimer disease: LEADe. Neurology 74: 956–964.
Characteristics and outcomes of cardiomyopathy in chil- Finsterer J, Stollberger C (2000). Cardiac involvement in pri-
dren with Duchenne or Becker muscular dystrophy: a com- mary myopathies. Cardiology 94: 1–11.
parative study from the Pediatric Cardiomyopathy Finsterer J, Stollberger C (2008a). Atrial fibrillation/flutter in
Registry. Am Heart J 155: 998–1005. myopathies. Int J Cardiol 128: 304–310.
Contant CF, Valadka AB, Gopinath SP et al. (2001). Adult Finsterer J, Stollberger C (2008b). Primary myopathies and the
respiratory distress syndrome: a complication of induced heart. Scand Cardiovasc J 42: 9–24.
hypertension after severe head injury. J Neurosurg 95: Finsterer J, Bittner RE, Grimm M (1999). Cardiac involvement
560–568. in Becker’s muscular dystrophy, necessitating heart trans-
Coote JH (2007). Landmarks in understanding the central ner- plantation, 6 years before apparent skeletal muscle involve-
vous control of the cardiovascular system. Exp Physiol 92: ment. Neuromuscul Disord 9: 598–600.
3–18. Flachenecker P, Lem K, Mullges W et al. (2000). Detection of
Courbon F, Brefel-Courbon C, Thalamas C et al. (2003). serious bradyarrhythmias in Guillain–Barre syndrome:
Cardiac MIBG scintigraphy is a sensitive tool for detecting sensitivity and specificity of the 24-hour heart rate power
cardiac sympathetic denervation in Parkinson’s disease. spectrum. Clin Auton Res 10: 185–191.
Mov Disord 18: 890–897. Forette F, Seux ML, Staessen JA et al. (2002). The prevention
Cripe L (2005). Cardiovascular health supervision for individ- of dementia with antihypertensive treatment: new evidence
uals affected by Duchenne or Becker muscular dystrophy. from the Systolic Hypertension in Europe (Syst-Eur) study.
Pediatrics 116: 1569–1573. Arch Intern Med 162: 2046–2052.
Deguchi K, Sasaki I, Tsukaguchi M et al. (2002). Abnormalities Furlan JC, Fehlings MG (2008). Cardiovascular complications
of rate-corrected QT intervals in Parkinson’s disease – a after acute spinal cord injury: pathophysiology, diagnosis,
comparison with multiple system atrophy and progressive and management. Neurosurg Focus 25: E13.
supranuclear palsy. J Neurol Sci 199: 31–37. Furlund Owe J, Skulstad Davidsen E, Eide GE et al. (2008).
Dhamoon MS, Tai W, Boden-Albala B et al. (2007). Risk of Left ventricular long-axis function in myasthenia gravis.
myocardial infarction or vascular death after first ischemic J Neurol 255: 1777–1784.
stroke: the Northern Manhattan Study. Stroke 38: Gerritsen J, Dekker JM, TenVoorde BJ et al. (2001). Impaired
1752–1758. autonomic function is associated with increased mortality,
Di Pasquale G, Pinelli G, Andreoli A et al. (1987). Holter especially in subjects with diabetes, hypertension, or a his-
detection of cardiac arrhythmias in intracranial subarach- tory of cardiovascular disease: the Hoorn Study. Diabetes
noid hemorrhage. Am J Cardiol 59: 596–600. Care 24: 1793–1798.
 CARDIOVASCULAR MANIFESTATIONS OF NEUROLOGIC DISEASE 15
Gibson TC (1975). The heart in myasthenia gravis. Am Heart J Maramattom BV, Manno EM, Fulgham JR et al. (2006).
90: 389–396. Clinical importance of cardiac troponin release and cardiac
Goldstein DS (1979). The electrocardiogram in stroke: rela- abnormalities in patients with supratentorial cerebral hem-
tionship to pathophysiological type and comparison with orrhages. Mayo Clin Proc 81: 192–196.
prior tracings. Stroke 10: 253–259. Maser RE, Mitchell BD, Vinik AI et al. (2003). The association
Goldstein DS, Pechnik S, Holmes C et al. (2003). Association between cardiovascular autonomic neuropathy and mortal-
between supine hypertension and orthostatic hypotension ity in individuals with diabetes: a meta-analysis. Diabetes
in autonomic failure. Hypertension 42: 136–142. Care 26: 1895–1901.
Gregoratos G, Cheitlin MD, Conill A et al. (1998). ACC/AHA Matsuyama H, Haymaker W (1967). Distribution of lesions in
Guidelines for Implantation of cardiac pacemakers and the Landry–Guillain–Barre syndrome, with emphasis on
antiarrhythmia devices: executive summary – a report of involvement of the sympathetic system. Acta
the American College of Cardiology/American Heart Neuropathol 8: 230–241.
Association Task Force on Practice Guidelines (Committee Mayer H, Benninger F, Urak L et al. (2004). EKG abnormal-
on Pacemaker Implantation). Circulation 97: 1325–1335. ities in children and adolescents with symptomatic tempo-
Groh WJ, Lowe MR, Zipes DP (2002). Severity of cardiac con- ral lobe epilepsy. Neurology 63: 324–328.
duction involvement and arrhythmias in myotonic dystro- McEvoy KM, Windebank AJ, Daube JR et al. (1989). 3,4-
phy type 1 correlates with age and CTG repeat length. J Diaminopyridine in the treatment of Lambert–Eaton myas-
Cardiovasc Electrophysiol 13: 444–448. thenic syndrome. N Engl J Med 321: 1567–1571.
Guo Z, Viitanen M, Fratiglioni L et al. (1998). Low blood pres- McGirt MJ, Blessing R, Nimjee SM et al. (2004). Correlation
sure and early death of elderly people with dementia. of serum brain natriuretic peptide with hyponatremia and
Lancet 352: 1035–1036. delayed ischemic neurological deficits after subarachnoid
Hall GC, Brown MM, Mo J et al. (2004). Triptans in migraine: hemorrhage. Neurosurgery 54: 1369–1373, discussion
the risks of stroke, cardiovascular disease, and death in 1373–1374.
practice. Neurology 62: 563–568. Motta J, Guilleminault C, Billingham M et al. (1979). Cardiac
Hays A, Diringer MN (2006). Elevated troponin levels are abnormalities in myotonic dystrophy. Electrophysiologic
associated with higher mortality following intracerebral and histopathologic studies. Am J Med 67: 467–473.
hemorrhage. Neurology 66: 1330–1334. Nei M, Ho RT, Sperling MR (2000). EKG abnormalities dur-
Hersch C (1961). Electrocardiographic changes in head inju- ing partial seizures in refractory epilepsy. Epilepsia 41:
ries. Circulation 23: 853–860. 542–548.
Jain R, Deveikis J, Thompson BG (2004). Management of Nei M, Ho RT, Abou-Khalil BW et al. (2004). EEG and ECG in
patients with stunned myocardium associated with sub- sudden unexplained death in epilepsy. Epilepsia 45: 338–345.
arachnoid hemorrhage. AJNR Am J Neuroradiol 25: Neil-Dwyer G, Walter P, Cruickshank JM et al. (1978).
126–129. Effect of propranolol and phentolamine on myocardial
Jesurum JT, Fuller CJ, Kim CJ et al. (2008). Frequency of necrosis after subarachnoid haemorrhage. Br Med J 2:
migraine headache relief following patent foramen ovale 990–992.
“closure” despite residual right-to-left shunt. Am J Neil-Dwyer G, Walter P, Cruickshank JM (1985). Beta-
Cardiol 102: 916–920. blockade benefits patients following a subarachnoid hae-
Jick H, Zornberg GL, Jick SS et al. (2000). Statins and the risk morrhage. Eur J Clin Pharmacol 28 (Suppl): 25–29.
of dementia. Lancet 356: 1627–1631. Neil-Dwyer G, Cruickshank J, Stratton C (1986). Beta-
Kawahara E, Ikeda S, Miyahara Y et al. (2003). Role of auto- blockers, plasma total creatine kinase and creatine kinase
nomic nervous dysfunction in electrocardio-graphic abnor- myocardial isoenzyme, and the prognosis of subarachnoid
malities and cardiac injury in patients with acute hemorrhage. Surg Neurol 25: 163–168.
subarachnoid hemorrhage. Circ J 67: 753–756. O’Suilleabhain P, Low PA, Lennon VA (1998). Autonomic
Kothavale A, Banki NM, Kopelnik A et al. (2006). Predictors dysfunction in the Lambert–Eaton myasthenic syndrome:
of left ventricular regional wall motion abnormalities serologic and clinical correlates. Neurology 50: 88–93.
after subarachnoid hemorrhage. Neurocrit Care 4: 199–205. Ogata H, Ishikawa Y, Ishikawa Y et al. (2009). Beneficial
Lee VH, Oh JK, Mulvagh SL et al. (2006). Mechanisms in effects of beta-blockers and angiotensin-converting
neurogenic stress cardiomyopathy after aneurysmal sub- enzyme inhibitors in Duchenne muscular dystrophy.
arachnoid hemorrhage. Neurocrit Care 5: 243–249. J Cardiol 53: 72–78.
Lee SJ, Lee KS, Kim YI et al. (2008). Clinical features of Opherk C, Coromilas J, Hirsch LJ (2002). Heart rate and EKG
patients with a myocardial infarction during acute changes in 102 seizures: analysis of influencing factors.
management of an ischemic stroke. Neurocrit Care 9: Epilepsy Res 52: 117–127.
332–337. Oppenheimer S (1993). The anatomy and physiology of corti-
Lowensohn RI, Weiss M, Hon EH (1977). Heart-rate variabil- cal mechanisms of cardiac control. Stroke 24 (12 Suppl):
ity in brain-damaged adults. Lancet 1: 626–628. I3–I5.
Lyu RK, Tang LM, Hsu WC et al. (2002). A longitudinal car- Oppenheimer SM, Gelb A, Girvin JP et al. (1992).
diovascular autonomic function study in mild Guillain– Cardiovascular effects of human insular cortex stimulation.
Barre syndrome. Eur Neurol 47: 79–84. Neurology 42: 1727–1732.
Another Random Scribd Document
with Unrelated Content
 Business - Case Study
Spring 2023 - Institute

Prepared by: Teaching Assistant Garcia

Date: August 12, 2025

Methodology 1: Ethical considerations and implications

Learning Objective 1: Research findings and conclusions
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 1: Diagram/Chart/Graph]
Learning Objective 2: Fundamental concepts and principles
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 3: Problem-solving strategies and techniques
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 4: Practical applications and examples
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Learning Objective 5: Ethical considerations and implications
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Current trends and future directions
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 6: Diagram/Chart/Graph]
Note: Best practices and recommendations
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Fundamental concepts and principles
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Example 8: Practical applications and examples
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 9: Diagram/Chart/Graph]
Example 9: Fundamental concepts and principles
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
References 2: Best practices and recommendations
Important: Comparative analysis and synthesis
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Interdisciplinary approaches
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Example 12: Key terms and definitions
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Fundamental concepts and principles
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Key terms and definitions
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 15: Comparative analysis and synthesis
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Experimental procedures and results
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 17: Diagram/Chart/Graph]
Key Concept: Ethical considerations and implications
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Interdisciplinary approaches
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 19: Diagram/Chart/Graph]
Remember: Experimental procedures and results
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Lesson 3: Fundamental concepts and principles
Important: Fundamental concepts and principles
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Interdisciplinary approaches
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Case studies and real-world applications
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 23: Diagram/Chart/Graph]
Important: Critical analysis and evaluation
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Key Concept: Statistical analysis and interpretation
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Comparative analysis and synthesis
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 26: Diagram/Chart/Graph]
Practice Problem 26: Study tips and learning strategies
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Fundamental concepts and principles
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Problem-solving strategies and techniques
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Problem-solving strategies and techniques
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 30: Diagram/Chart/Graph]
Lesson 4: Literature review and discussion
Remember: Fundamental concepts and principles
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 31: Diagram/Chart/Graph]
Example 31: Key terms and definitions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Theoretical framework and methodology
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Research findings and conclusions
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 34: Diagram/Chart/Graph]
Example 34: Literature review and discussion
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 35: Practical applications and examples
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Experimental procedures and results
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 37: Diagram/Chart/Graph]
Definition: Research findings and conclusions
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Critical analysis and evaluation
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Historical development and evolution
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
References 5: Statistical analysis and interpretation
Note: Research findings and conclusions
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 41: Practical applications and examples
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Research findings and conclusions
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 43: Diagram/Chart/Graph]
Example 43: Problem-solving strategies and techniques
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Study tips and learning strategies
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Practical applications and examples
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 46: Best practices and recommendations
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Theoretical framework and methodology
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 48: Ethical considerations and implications
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Historical development and evolution
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Review 6: Problem-solving strategies and techniques
Example 50: Case studies and real-world applications
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 51: Theoretical framework and methodology
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Fundamental concepts and principles
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Learning outcomes and objectives
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 54: Comparative analysis and synthesis
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 55: Assessment criteria and rubrics
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 56: Diagram/Chart/Graph]
Important: Current trends and future directions
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Learning outcomes and objectives
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 58: Problem-solving strategies and techniques
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Experimental procedures and results
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Lesson 7: Best practices and recommendations
Example 60: Historical development and evolution
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Assessment criteria and rubrics
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Definition: Fundamental concepts and principles
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 63: Diagram/Chart/Graph]
Practice Problem 63: Theoretical framework and methodology
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Case studies and real-world applications
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Best practices and recommendations
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Interdisciplinary approaches
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Research findings and conclusions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Practice Problem 68: Best practices and recommendations
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 69: Interdisciplinary approaches
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 70: Diagram/Chart/Graph]
Summary 8: Ethical considerations and implications
Practice Problem 70: Case studies and real-world applications
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Ethical considerations and implications
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Remember: Research findings and conclusions
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 73: Best practices and recommendations
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 74: Diagram/Chart/Graph]
Practice Problem 74: Theoretical framework and methodology
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 75: Diagram/Chart/Graph]
Remember: Case studies and real-world applications
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Current trends and future directions
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 77: Current trends and future directions
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Assessment criteria and rubrics
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 79: Experimental procedures and results
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Unit 9: Best practices and recommendations
Important: Historical development and evolution
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Key terms and definitions
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 82: Study tips and learning strategies
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Current trends and future directions
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 84: Diagram/Chart/Graph]
Important: Critical analysis and evaluation
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 85: Diagram/Chart/Graph]
Note: Problem-solving strategies and techniques
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 86: Experimental procedures and results
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Assessment criteria and rubrics
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 88: Diagram/Chart/Graph]
Definition: Interdisciplinary approaches
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 89: Study tips and learning strategies
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Exercise 10: Case studies and real-world applications
Definition: Literature review and discussion
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Key Concept: Critical analysis and evaluation
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 92: Fundamental concepts and principles
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Key Concept: Historical development and evolution
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Remember: Learning outcomes and objectives
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Problem-solving strategies and techniques
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Important: Best practices and recommendations
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Historical development and evolution
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Practical applications and examples
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Study tips and learning strategies
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Quiz 11: Practical applications and examples
Important: Critical analysis and evaluation
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Case studies and real-world applications
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 102: Problem-solving strategies and techniques
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Key Concept: Critical analysis and evaluation
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Historical development and evolution
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 105: Case studies and real-world applications
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 106: Diagram/Chart/Graph]
Practice Problem 106: Practical applications and examples
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 107: Diagram/Chart/Graph]
Key Concept: Study tips and learning strategies
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Best practices and recommendations
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 109: Experimental procedures and results
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Review 12: Key terms and definitions
Note: Ethical considerations and implications
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 111: Key terms and definitions
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 112: Diagram/Chart/Graph]
Note: Literature review and discussion
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 113: Research findings and conclusions
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 114: Critical analysis and evaluation
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 115: Interdisciplinary approaches
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Literature review and discussion
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Theoretical framework and methodology
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 118: Historical development and evolution
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Important: Key terms and definitions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Practice 13: Interdisciplinary approaches
Key Concept: Statistical analysis and interpretation
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Historical development and evolution
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 122: Diagram/Chart/Graph]
Remember: Historical development and evolution
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Example 123: Case studies and real-world applications
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Remember: Current trends and future directions
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 125: Diagram/Chart/Graph]
Key Concept: Problem-solving strategies and techniques
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Case studies and real-world applications
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 127: Study tips and learning strategies
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Fundamental concepts and principles
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Ethical considerations and implications
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Test 14: Literature review and discussion
Definition: Case studies and real-world applications
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Problem-solving strategies and techniques
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Best practices and recommendations
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Learning outcomes and objectives
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 134: Current trends and future directions
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Comparative analysis and synthesis
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 136: Critical analysis and evaluation
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 137: Critical analysis and evaluation
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Study tips and learning strategies
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Case studies and real-world applications
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Chapter 15: Theoretical framework and methodology
Important: Interdisciplinary approaches
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Example 141: Historical development and evolution
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Welcome to our website – the ideal destination for book lovers and
knowledge seekers. With a mission to inspire endlessly, we offer a
vast collection of books, ranging from classic literary works to
specialized publications, self-development books, and children's
literature. Each book is a new journey of discovery, expanding
knowledge and enriching the soul of the reade

Our website is not just a platform for buying books, but a bridge
connecting readers to the timeless values of culture and wisdom. With
an elegant, user-friendly interface and an intelligent search system,
we are committed to providing a quick and convenient shopping
experience. Additionally, our special promotions and home delivery
services ensure that you save time and fully enjoy the joy of reading.

Let us accompany you on the journey of exploring knowledge and

personal growth!

ebookfinal.com