RHEUMATISM AND MUSCULOSKELETAL DISORDERS

INTERVERTEBRAL DISC
DEGENERATION
PREVALENCE, RISK FACTORS AND
TREATMENTS

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 RHEUMATISM AND
MUSCULOSKELETAL DISORDERS

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 RHEUMATISM AND MUSCULOSKELETAL DISORDERS

INTERVERTEBRAL DISC
DEGENERATION
PREVALENCE, RISK FACTORS AND
TREATMENTS

ALLEN L. HO AND ATMAN M. DESAI

EDITORS

VINOD RAVIKUMAR, MANAGING EDITOR

JULIAN LIANG, GRAPHICS DESIGNER

New York
Copyright © 2017 by Nova Science Publishers, Inc.

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 CONTENTS

Preface vii
Chapter 1 The Pathophysiology of
Intervertebral Disc Disease 1
Akwasi Ofori Boah, Nancy Abu-Bonsrah,
C. Rory Goodwin and Daniel Sciubba
Chapter 2 Nerve Structures Inside
the Intervertebral Disc: A Possible
Link to Symptomatic Lumbar Disc Disease 17
Manuel D. Oprea, Anca Maria Cimpean,
Marius Raica and Dan V. Poenaru
Chapter 3 Spinal Biomechanics 37
James Pan, Arjun V. Pendharkar
and Jongsoo Park
Chapter 4 Cervical Stenosis 63
Thomas Kosztowski,
Adetokunbo Oyelese and Ziya Gokaslan
Chapter 5 Thoracic Disc Herniations 87
Nathan E. Simmons
Chapter 6 Surgical Management of
Cervical Disc Herniation 105
Vinod K. Ravikuzmar, Jennifer L. Quon,
Allen L. Ho and Ali K. Ozturk
vi Contents

Chapter 7 Lumbar Stenosis: Prevalence,

Risk Factors, and Treatment 127
Daniel Shepherd, Panagiotis Kerezoudis,
Michelle J. Clarke and Mohamad Bydon
Chapter 8 Lumbar Disc Herniations 157
Ajit Jada, Roger Härtl
and Ali Baaj
Chapter 9 Lumbar Degenerative Spondylolisthesis 211
Sam Cartmell, Eric S. Sussman
and John K. Ratliff
Chapter 10 Emerging Treatments for
Intervertebral Disc Disease 235
Gregory D. Arnone, Shivani Rangwala
and Ankit I. Mehta
Editor’s Contact Information 267
Index 269
 PREFACE

Degenerative disc disease is a significant component of spine disorders

and lower back pain that now afflicts nearly one third of the adult population.
This represents a significant morbidity and cost burden — nearly a tenth of all
health-care spending — that is only increasing in prevalence as the elderly
population continues to grow. While current treatment modalities, ranging
from conservative approaches to surgical interventions, are continually
evolving, new therapies for intervertebral disc disease are also in development.
Increased research on the cellular mechanisms underlying DDD have led to
novel cell-based treatments which aim to delay rates of degeneration.
Intervertebral Disc Degeneration: Prevalence, Risk Factors and Treatments is
a comprehensive text on all facets of the disease process that covers the
pathophysiology, biomechanics, as well as the location specific pathology and
treatment options for degenerative disc disease. Written by nationally
renowned experts in neurosurgery and orthopedic surgery of the spine, each
chapter is a thorough, cogent discussion of an essential topic related to
intervertebral disc degeneration that includes many original, easy to
understand figures and illustrations. Also included are overviews of the most
cutting-edge and emerging surgical and biologic management options of disc
disease at all levels of the spine.
Chapter 1 - The degeneration of the intervertebral disc results from several
multi-factorial pathophysiologic processes. Here, the authors discuss the
anatomy of the intervertebral disc along with a presentation of several
pathologic processes including vascular insufficiency (possibly due to
cigarette exposure and endothelial dysfunction), anatomic variations,
poor nutritional status, infections, autoimmune and/or inflammatory processes,
genetic predispositions and iatrogenic occurrences as well as exposure to drugs
viii Allen L. Ho and Atman M. Desai

or toxins that lead to degeneration of the disc. This brief overview establishes
a necessary starting point for the understanding of these processes as well as a
preview into potential therapeutic targets.
Chapter 2 - Lumbar degenerative disc disease is a very common condition
with a high socio-economic burden. The etiology is multifactorial and not
entirely understood, and some of the main factors implicated include: genetic
predisposition, smoking, increased body mass index, weight lifting or impeded
nutrient transportation through the endplates.
The presence of some pro-inflammatory cytokines and growth factors are
well documented: the interleukin (IL) family, TNFα and PGE2. Alongside
these, recently there has been an increased interest in nerve growth factor
(NGF) and brain derived growth factor (BDGF). Their expression in a fibrous
cartilaginous enviroment, where normally there are no nerve fibers or blood
vessels, is of interest.
Neuronal proliferation is normally blocked out in the outer layers of the
annulus fibrosus by the presence of Sema3A and aggrecan, with the latter also
disrupting the endothelial proliferation. Degenerative changes may create
propitious conditions for the invasion of the disc by endothelial and nerve
structures.
Although it was assumed that differentiated cells lose the ability to
undifferentiate, recent research supports the hypothesis that these cells can
suffer a dedifferentiation process. In this respect, neural cells were obtained
through transdifferentiation from keratocites and chondrocytes after
stimulating these cells with nerve growth factors. Therefore, during
the degenerative process, it is possible that the chondrocyte type cells reach a
state of dedifferentiation and, due to the stimulation with nerve growth factors,
can have characteristics similar to the nervous cells. Hence chondrocyte-like
cells have the potential to transdifferentiate making them a possible source of
nerve cells inside the intervertebral disc, and of pain.
This chapter deals with the identification of positive NFAP chondrones in
degenerated intervertebral discs, suggesting a transdifferentiation of
chondrocyte-like cells into nerve cells. It also reports the presence of NFAP-
positive chondrones and pain score in patients with mild LDD (Lumbar Disc
Disease).
The number and imunohistological characteristics of chondrocyte-like
cells and their aggegated form, the chondrones, are correlated with the
symptoms of patients with LDD. The identification of NFAP positive cells
indicates the presence of nervous structures and the possibility of chondrocyte-
 Preface ix

like cells transdifferentiating into nerve cells. This finding might explain the
different occurrences and characteristics of pain amongst patients with LDD.
Chapter 3 - The biomechanical properties of the spine offer insights into
the mechanisms and consequences behind intervertebral disc degeneration.
The intervertebral disc is a dynamic structure which serves a critical function
in allowing the many components of the bony vertebrae to interface with and
work with one another. The biomechanical properties of the intervertebral disc
afford it’s properties in helping the spine to withstand compressive, shear,
bending, and rotational forces. These biomechanical properties are derived
from the biochemical and cellular composition of the disc which afford it
unique properties such as its viscoelastic behavior. Degeneration of the disc —
either due to injury or aging — perturb the biochemical composition of the
disc, and subsequently the biomechanical properties. This chapter will explore
the composition and the mechanistic properties of the disc which give the disc
it’s unique characteristics, and how theses parameters change in degenerative
states.
Chapter 4 - Cervical stenosis involves the narrowing of the spinal canal in
the cervical spinal region. Cervical spondylosis is oftentimes used
synonomously with cervical stenosis, but spondylosis implies age-related
degeneration of the spine including congenital spinal stenosis, degeneration of
intervertebral discs resulting in focal stenosis, and hypertrophy of spinal
elements resulting in narrowing of the spinal canal. One of the most
debilitating conditions associated with cervical stenosis is cervical spondylotic
myelopathy. Multiple treatments including surgical and non-surgical options
are available. However, once symptoms of cervical spondylotic myelopathy
are severe, surgery becomes necessary to treat the cervical stenosis.
Chapter 5 - Thoracic disc herniations occur less frequently than cervical or
lumbar herniations, yet are common enough that surgeons should understand
management strategies. Preoperative assessment of the size, location, presence
of calcification, and spinal level are all important factors for deciding upon a
surgical approach. While some disc herniations will require anterior
approaches, these are typically associated with higher levels of morbidity and
lengthier hospital stays, suggesting posterior approaches, when feasible, offer
better outcomes. In most surgeries, the need for fusion is low but the final
decision needs to be tailored for the individual patient.
Chapter 6 - Cervical disc herniation (CDH) occurs with regular frequency
and is the most common indication for cervical spine surgery. While
conservative treatment is the first line of defense when managing CDH, severe
cases may be treated with anterior, posterior, or combined approaches. Choice
x Allen L. Ho and Atman M. Desai

of an approach is dependent on careful synthesis of symptoms, exam findings,

and imaging results by the surgeon. Studies offer conflicting views regarding
which approach results in superior outcomes. The eventual decision on
surgical approach, if determined to be necessary, must be individually tailored
for each patient.
Chapter 7 - Lumbar spinal stenosis (LSS) is a clinical syndrome
characterized by buttock and/or lower extremity pain with or without back
pain secondary to degenerative spinal canal narrowing and compression of the
neurovascular elements. LSS is the most common reason for spinal surgery in
patients over 65 years of age. It results in significant pain and disability,
compromising the quality of life and everyday activities of the affected
patients. Pain is aggravated by certain postures, including walking, standing or
lumbar extension and characteristically alleviated by recumbency, sitting and
forward flexion. Initial treatment options include conservative management
such as lifestyle modification, physiotherapy, epidural injections and
medications. Very few randomized controlled clinical trials have assessed the
role and the efficacy of non-surgical modalities for the management of patients
with LSS and therefore there is a lack of sufficient evidence to suggest a
specific method is superior. Surgical intervention is performed when there is
failure of conservative management or neurologic emergency. Current
techniques include open or minimally invasive approaches that aim at
restoring spinal canal diameter and relieving neurovascular compromise.
Chapter 8 - Lumbar disc herniations occur with relatively high frequency
such that surgeons should be aware of prevention, management, and treatment
strategies. Clinical presentation including assessment of location, morphology,
symptoms, and imaging are crucial sources of information in the determination
of the necessity for surgery. Conservative management may include one or a
combination of medication, physical therapy, and epidural steroid injections. If
needed and depending on the surgeon’s preference, minimally invasive
microdiscectomies or endoscopic procedures may be utilized to treat patients.
Ultimately, the ongoing debate between non-interventional and interventional
approaches to treatment requires surgeons to make final decisions tailored to
each patient.
Chapter 9 - Lumbar Degenerative Spondylolisthesis (LDS) is a common
condition affecting the lumbar spine characterized by chronic arthritis and
bony remodeling of the facet joints. Epidemiologic studies have revealed that
LDS is a relatively common condition among older patients, and may be
asymptomatic in many affected individuals. While conservative treatment
measures are often utilized initially, the mainstay of management for
 Preface xi

persistently symptomatic LDS is surgical decompression. Despite a number of

recent well-designed randomized clinical trials, there remains no consensus
regarding the optimal method of surgical treatment, including whether or not
lumbar spinal fusion provides added clinical benefit beyond decompression
alone. This chapter reviews the epidemiology and clinical presentation of
LDS, as well as the existing evidence for the range of surgical treatments that
have been utilized in patients suffering from this condition.
Chapter 10 - Degenerative disc disease (DDD) is a significant component
of spine disorders and low back pain, and the prevalence of disc disease
is increasing with an aging population. While current treatment modalities,
ranging from conservative approaches to surgical interventions, are
continually evolving, new therapies for intervertebral disc disease are also in
development. Increased research on the cellular mechanisms underlying DDD
have led to novel cell-based treatments which aim to delay rates of
degeneration [1, 3]. Most of these cellular therapies remain in the research
phase. Recent innovations in engineering have also pioneered several types of
surgical constructs that improve the durability of treatment, while minimizing
device-associated complications. Several examples include hybrid materials
for intervertebral cages, zero-profile implants, expandable cages, sagittal
correction implants, and disc arthroplasty. Finally, surgical techniques have
been refined and adapted to allow less invasive modalities such as endoscopic
and percutaneous techniques to reach adequate treatment effect with less risk
of adverse event and further degeneration of the incident and adjacent spinal
segments. This chapter highlights several emerging non-surgical and surgical
treatments for intervertebral disc disease.
In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 1

THE PATHOPHYSIOLOGY OF
INTERVERTEBRAL
DISC DISEASE

Akwasi Ofori Boah, MD, Nancy Abu-Bonsrah, BS,

C. Rory Goodwin, MD/PhD and Daniel Sciubba, MD
The Johns Hopkins University School of Medicine
Departments of Neurosurgery, The Johns Hopkins University School of
Medicine, Baltimore, MD, US

ABSTRACT
The degeneration of the intervertebral disc results from several multi-
factorial pathophysiologic processes. Here, we discuss the anatomy of the
intervertebral disc along with a presentation of several pathologic
processes including vascular insufficiency (possibly due to cigarette
exposure and endothelial dysfunction), anatomic variations, poor
nutritional status, infections, autoimmune and/or inflammatory processes,
genetic predispositions and iatrogenic occurrences as well as exposure to
drugs or toxins that lead to degeneration of the disc. This brief overview
establishes a necessary starting point for the understanding of these
processes as well as a preview into potential therapeutic targets.


Daniel M. Sciubba, M.D. Department of Neurosurgery, Johns Hopkins University School of
Medicine, 600 North Wolfe Street, Meyer 7-109, Baltimore, MD 21287, E-mail:
[email protected].
2 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

INTRODUCTION
In this chapter we will aim to elucidate the pathophysiology behind the
degenerative processes for an intervertebral disc as well as its biomechanical
and clinical impact. This is a multifaceted disease process that may take place
in several stages throughout our lives [18]. Highlighted will be: disc
development, anatomic considerations, plausible but non-exhaustive
mechanisms, and key developments in our recent understanding of this
phenomenon.
Although pain is the most common symptom, radiculopathy and other
symptoms may also ensue with intervertebral disc degeneration. Diagnosis is
made with a detailed history, clinical exam findings as well as imaging
(MRI/CT/X-ray). Discogenic back pain/neck pain may be under-diagnosed as
the quality of discograms and their subjective nature have led to its
controversial association. The Derby criteria are one method of interpreting
discography, where concordant responses produce pain greater than 6 out of
10 at a pressure of less than 50 psi above the opening pressure of the disc
(having a negative control disc) [28]. The modified Dallas discogram scale is
another photographic and descriptive form of identifying radial fissure patterns
in the disc, which correlate with provocative studies [29].
Intervertebral discs have a complex anatomical configuration, which is a
key determinant in the individual mobility of segmental joints (zygapophyseal)
as well as overall regional (cervical, thoracic, and lumbar) flexibility.
Intervertebral discs not only anchor segments of vertebral bodies to one
another but they distribute gravitational forces throughout the spine in order to
protect against rapid breakdown. Understanding the inherent complexity of
their design allow us to understand their protective qualities.

ANATOMY AND PATHOPHYSIOLOGIC MECHANISMS

Embryonic development:
 The Pathophysiology of Intervertebral Disc Disease 3

Figure 1. Germ Layers.

In humans, the development of three separate germ layers occurs during

gastrulation, which takes place in the third week of gestation. Gastrulation
produces ectoderm, mesoderm, and endoderm (Figure 1). Ectodermal
precursor epiblast cells invaginate at the primitive node/streak [6]. These
epiblast cells will then migrate to the mesodermal layer and eventually form
the notochord. Sonic hedgehog growth factor (Shh) along with transforming
growth factor - beta (TGF-β) have been established as the necessary stimuli for
the development of the eventual nucleus pulposus and annulus fibrosis [5, 10].
These two factors have the ability to orchestrate the migration and apoptosis of
cells in the maturing sclerotomes, which will lead to vertebral bodies along
with the discs and their subchondral regions along the endplates (Figure 2).
Shh factors, Paired box 1 and Paired box 9 (Pax1/9), dictate the vertebral
endochondral ossification process and TGF-β helps the endplates form the
subsequent fibers of the annulus fibrosis (Sharpey’s fibers) [5, 10]. Detailed
understanding of the embryology and initial signaling cascades involved in
disc formation may provide the basis for future etiologies as well as targeted
therapies as we will review later in this chapter.
4 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

Figure 2. Growth Factors and the Intervertebral Disc.

Anatomy

To deepen our understanding of the intervertebral disc, we will now

evaluate the intervertebral disc-endplate complex anatomically. At each
intervertebral segment (excluding abnormal ankylosis across the disc space
which may or may not be pathologic [33]) the anatomy is preserved and
repetitive as a result of the complex differentiation of sclerotomes under the
Shh/TGF-β pathways [32]. We must evaluate each structure separately. This
includes the nucleus pulposus, annulus fibrosis, and vertebral endplate.

The Annulus Fibrosus

Figure 3. Disc Components.

 The Pathophysiology of Intervertebral Disc Disease 5

Named for its shape and texture, the “fibrous ring” which surrounds the
nucleus pulposus and is deeply engrained into the subchondral endplate has an
inner and an outer layer. (Figure 3) It is composed of multiples of concentric
lamellae with roughly 9,000 cells per cubic millimeter [10]. The outer layer is
composed of fibroblasts and type I collagen, which accounts for the strength
we ascribe to it traditionally [26]. Its extracellular matrix is also highly
organized which accounts for a very high tensile strength. The inner layer of
the annulus contains type II collagen and proteoglycans with a poorly
structured extracellular matrix. This is also known as the “transition zone.”

The Nucleus Pulposus

Surrounded by the concentric lamellae of the annulus fibrosus, the nucleus

pulposus is made of predominantly proteoglycans and water but much less
type II collagen. (Figure 3) It contains roughly 3,000 cells per cubic millimeter
[10]. This provides the nucleus and thus the disc with its elastic mobile
properties, which are able to withstand tensile forces. Chondrocyte-type NP
cells help to regulate the amount of Hypoxia Inducible Factors (HIF) - 1 and 2
as this is a relatively avascular structure in order to maintain nutrient levels
and thus viability.

The Endplates

The vertebral endplates, which themselves are composed of cortical bone,

have a subchondral region subjacent to a very thin layer of additional hyaline
cartilage where the Sharpey’s fibers of the annulus fibrosus insert/anchor
themselves. A small microscopic plexus can be found in this region. There are
also many negatively charged proteoglycans and type II collagen fibers.
Combined with H20, this loose extracellular matrix allows for diffusion of
small positively charged ions from a microscopic vascular network [22]. The
vertebral endplates play a key role in the degenerative process with
characteristic MRI findings, which would eventually be described by Dr.
Michael Modic in 1988 (Figure 4) [21]. As our knowledge of the role of the
vertebral endplates in degenerative process increases, we are learning that
certain conditions which predispose them to decline also compromise the discs
themselves [35].
6 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

Figure 4. Modic Changes.

PATHOPHYSIOLOGIC MECHANISMS
The degeneration of an intervertebral disc is a complex process, which
typically takes place after skeletal maturity is reached. Many factors will
account for its deterioration over time. We will attempt to outline and tie
together some of a myriad of reasons that this process occurs as people age,
which produces some typical alterations. For example, histologic analysis by
Yasuma et al., explained that in cadaveric specimens (the majority of discs
from patients in their sixth decade) the orientation of the inner fiber bundles of
the annulus fibrosus was reversed, so that they bulged inward [39].

Vascular

As previously mentioned, the intervertebral disc is relatively avascular and

has a microscopic vascular supply system. Due to these factors, compromise
of the vessels supplying the disc-endplate complex is often seen. Without
adequate blood supply, the intervertebral disc will, in theory, degenerate at the
rate that its blood supply is unable to keep up with nutritional requirements.
Microcirculatory perfusion of the vertebral marrow can be measured with CT-
perfusion [23]. The microcirculation develops to maturity by 25 years, remains
stable at 35 years, and then begins to decline after 35 years. The age-related
decrease of microcirculatory perfusion in the lumbar vertebral marrow
 The Pathophysiology of Intervertebral Disc Disease 7

precedes the loss of bone mineralization density and the onset of intervertebral
disc disease, indicating their possible causal relationship.
Cigarette smoking has deleterious effects throughout the human body. It
can play a role in intervertebral disc degeneration via multiple mechanisms,
which include vascular insufficiency. In a rabbit model, Iwahashi et al.
demonstrated the effects of nicotine on the intervertebral disc [13]. Nicotine
treatment caused necrosis and hyalinization of the nucleus pulposus in all
rabbits. The micro-analysis of the annulus fibrosus demonstrated a disturbance
of the pattern of overlapping lamellae with and without clefts. There was also
stenosis of vascular buds with perivascular calcification. Nicotine treatment
created hypertrophy of vascular walls, necrotic endothelial cells, and stenotic
vascular lumens. Lastly, it also caused a decrease of vascular buds in the
vicinity of the vertebral end-plates. Akmal et al. also demonstrated using an in
vitro model with nicotine and nicotine-free media (bovine specimens at
concentrations simulating the typical serum nicotine concentrations of
smokers) the adverse morphologic changes observed on histology [1]. These
included reduced cell proliferation, disrupted cell architecture, and the
disintegration of cells and extracellular matrix. Immunohistochemistry further
revealed the presence of type I collagen in the extracellular matrix rather than
the normal type II collagen seen in controls.
Another postulated mechanism with vascular etiology involves endothelial
dysfunction. Due to the oxygen poor nature of the intervertebral discs'
components, Papalia et al. believed there must be a degree of endothelial
dysfunction worthy of further investigation [25]. There appears to be a failure
to appropriately activate the vasodilatory nitrous oxide cascade, which
eventually dilates vessels using cGMP in order to maintain the appropriate
nutrient levels. Repetitive compressive traumatization of the microvasculature
is postulated and may explain, in part, the chronic progressive nature of this
condition.

Anatomic/Biomechanical

Anatomic variations may produce altered distribution of biomechanical

forces. In his evaluation of degenerative intervertebral discs, Boden et al.
showed the mean orientation of the lumbar facet angles relative to the coronal
plane was more sagittal at all levels in the patients who had degenerative
spondylolisthesis [3]. (Figure 5) The mean facet angle was 41 degrees in the
asymptomatic volunteers versus 60 degrees in the patients who had
8 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

degenerative spondylolisthesis. Also noted were that the facet joints were
more sagittally oriented in the patients who had degenerative
spondylolisthesis.
Intervertebral discs must maintain their structural integrity. Brock et al.'s
comparison between 242 intradiscal pressure/volume recordings with
corresponding discograms (performed at the same occasion) showed a
statistically significant relationship between degeneration (radiographic) and
compliance [7]. Without appropriate collagenous deposition and
reinforcement, a degenerative process can be expected to ensue within the
intervertebral disc, which disperses multiple axial and radial forces [11, 19].
Iatridis et al. demonstrated that an increased elastic modulus with
degeneration is likely related to an increase in tissue density resulting from the
loss of water content within the disc [12]. The significant effects of
degeneration reported in this study also were suggestive of a shift in load
carriage from fluid pressurization and swelling pressure to deformation of the
solid matrix of the annulus fibrosus. Walter et al., in a large ex-vivo animal
model, demonstrated asymmetric discal compression has direct deleterious
effects on both tissue and cells, which could lead to a degenerative cascade,
including apoptosis, the production of inflammatory mediators, and a catabolic
shift [36].
Magnetic resonance elastography (MRE) is non-invasive form of imaging
which is capable of measuring of the shear modulus of soft tissues including
intervertebral discs [38]. This was not able to be performed until twenty years
ago. With future advancements in this modality, changes in the shear modulus
may provide a reliable way to predict the degenerative process of
intervertebral discs.

Nutritional/Metabolic

Poor delivery of nutrients to the disc space can also account for disc
degeneration leading to inadequate production of collagen fibers and
proteoglycans. Many conditions, including Cystic Fibrosis and marasmus,
alter the body’s metabolism and thus the delivery of nutrients, such as Vitamin
C deficiency (scurvy), to the disc [30]. More in depth studies are required
regarding this topic but the inability to appropriately strengthen the annulus
fibrosis with further collagen deposition or add elasticity to the nucleus with
more proteoglycans and hydration is implicated in the degeneration of
intervertebral discs [15].
 The Pathophysiology of Intervertebral Disc Disease 9

Infectious

Infections of the disc space as seen in osteomyelitis/discitis lead to a

rapidly accelerated degeneration of the intervertebral disc in the setting of a
significant inflammatory response. (Figure 6) Once appropriately treated with
antimicrobials or surgery (or both), a robust fusion can ensue due to the
stimulation of the subchondral endplates by the relative surge in cytokines.
Patients who undergo simultaneous instrumentation and decompression were
shown by Bydon et al. to not only have a similar reoperation rate (compared to
non-instrumented patients) but also have a significantly decreased
pseudoarthrosis rate (only 2.4%) [4]. Increased neovascularity in degenerative
discs/endplates may represent a robust blood supply that alters the risk profile
for an infectious discitis [31]. Discitis is typically spread via hematogenous
routes although direct seeding (post-procedural versus local infections) may
also be implicated. The rapid reabsorption of the extracellular matrix by
pathogens in combination with a severe inflammatory cascade is responsible
for the time course of the disease’s progression. Discitis may represent the
most exaggerated form of degenerative disc disease, which will require further
investigation to elucidate.

Genetic

There are significant genetic implications with regards to intervertebral

disc degeneration that require further investigation. Programmed cell death
and expression of inflammatory cytokines can be altered [20]. It appears that
environmental factors influence the variation in disc signal, as monozygotic
and dizygotic twins will have separate manifestations of disc degeneration. [2,
27] Ozkanli et al. showed MMP-1 and MMP-3 expressions were significantly
higher in patients with recurrent lumbar disc herniations and also had higher
magnetic resonance degeneration score (Pfirmann score) [24]. Interestingly,
this may be independent of age as Canbay et al. showed that the relationship
between Pfirrmann grade, immunohistochemical expression of MMP-3, and
the histopathologic signs of intervertebral disc degeneration were not
correlated with age [8]. Weber et al. also reminded us that terminal
deoxynucleotidyl transferase-mediated dUTP nick-end labeling) which detects
breaks in double-stranded DNA that arise through apoptotic endonuclease
activity was noted to be higher in patients with degenerative discs versus those
without [37]. Also noted was that in comparison to fetal discs (less than 2%),
10 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

the number of dead cells was significantly increased in the discs of the
skeletally mature (50%).
Although many micro RNAs are expressed in degenerative human
intervertebral discs, their true impacts are still yet to be elucidated. Thus far,
we have been able to ascertain that their expression helps to regulate the
intradiscal inflammatory response, extracellular matrix regeneration, and
nucleus pulposus cellular apoptosis [14, 34]. Further advancements multi-
dimensional genomic analyses applied towards IVD disc disease, particularly
involving micro RNAs, are required. There remains potential for a vast array
of gene therapies once more is understood regarding the expression of proteins
and their potential deleterious effects on disc cells and extracellular matrix.

Iatrogenic

Common iatrogenic causes for disc degeneration are post procedural after
injections, discectomies, and fusion procedures. Kim et al. demonstrated that
facet joint orientation (relative to the coronal plane) and tropism at the
adjacent segment above fusion produces overstress of the adjacent segment in
the form of increased anterior shear force [16]. Discectomies and intradiscal
injections may also be implicated in an accelerated degenerative process
although the etiology surrounding these processes remain poorly understood.

Autoimmune/Inflammatory

Intervertebral disc degeneration is a chronic inflammatory process, which

may respond to anti-inflammatory modalities early in its course. Attempts
have been made to use systemic and intradiscal anti-inflammatory
medications/therapies without success as of yet. Klatwitter et al. measured
expression levels of Toll-like receptors (TLR)-1, 2, 4, and 6 and they were
found to be elevated with increasing degeneration severity [17]. Walter et al.
demonstrated that inflammatory cytokines in NP cells (in vitro model) were
shown to produce IL-1β, IL-6, and IL-8 in response to TNF-α at variable rates
and magnitudes, which suggests different functions at different times in the
disease process overall [37]. Capossela et al. also confirmed that degenerated
and post-traumatic discs do in fact contain IgG antibodies against typical
extracellular proteins of the nucleus pulposus using immunohistochemical
staining on postoperative specimens9.
 The Pathophysiology of Intervertebral Disc Disease 11

Drugs/Toxins

Many substances will affect the systemic microvasculature and thus its
ability to deliver nutrients to the disc/subchondral endplate complex. We are
yet to characterize the broadly labeled group of exogenous toxins, which may
accelerate intervertebral disc degeneration with the exception of nicotine. As
the study of the degenerative process continues, other substances will be
implicated as we evaluate their deleterious effects on the microphysiology of
the disc-endplate complex in each spinal segment.

CONCLUSION
The pathophysiology of intervertebral disc degeneration is a complex
multifactorial process that still requires further investigation for a clearer
understanding. There are genetic, anatomic, physiologic, and biomechanical
factors, which affect its onset, rate of progression, penetrance, and
responsiveness to treatment. Continuation of research efforts in field will
maximize our therapeutic yield in the future.

Figure 5. Sagittal (A) and Axial (B) T2 MRI showing degenerative changes in the
lumbar spine, worse at the level of L4-L5 with bulging disc and ligamentous
hypertrophy. Left-sided synovial cyst and prominence of the dorsal epidural fat
contribute to moderate to severe spinal canal narrowing.
12 Akwasi Ofori Boah, Nancy Abu-Bonsrah, C. Rory Goodwin et al.

Figure 6. Sagittal T1 (A), T2 (B) and T2 STIR (C) MRI showing discitis/osteomyelitis
at the T5-T6 level with associated intravertebral abscess involving the T5 and to a
lesser extent T6 vertebral bodies, anterior paraspinal soft tissue phlegmon and right
anterior paraspinal abscess.

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 2

NERVE STRUCTURES INSIDE THE

INTERVERTEBRAL DISC: A POSSIBLE LINK
TO SYMPTOMATIC LUMBAR DISC DISEASE

Manuel D. Oprea1, Anca Maria Cimpean2, , *

Marius Raica2 and Dan V. Poenaru1

1
Second Department of Orthopedics, “Victor Babes”
University of Medicine and Pharmacy, Timisoara, Romania
2
Department of Microscopic Morphology/Histology,
Angiogenesis Research Center, “Victor Babes”
University of Medicine and Pharmacy, Timisoara, Romania

ABSTRACT
Lumbar degenerative disc disease is a very common condition with a
high socio-economic burden. The etiology is multifactorial and not
entirely understood, and some of the main factors implicated include:
genetic predisposition, smoking, increased body mass index, weight
lifting or impeded nutrient transportation through the endplates.
The presence of some pro-inflammatory cytokines and growth
factors are well documented: the interleukin (IL) family, TNFα and
PGE2. Alongside these, recently there has been an increased interest in
nerve growth factor (NGF) and brain derived growth factor (BDGF).

*
Corresponding Author Email: [email protected]
18 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

Their expression in a fibrous cartilaginous enviroment, where normally

there are no nerve fibers or blood vessels, is of interest.
Neuronal proliferation is normally blocked out in the outer layers of
the annulus fibrosus by the presence of Sema3A and aggrecan, with the
latter also disrupting the endothelial proliferation. Degenerative changes
may create propitious conditions for the invasion of the disc by
endothelial and nerve structures.
Although it was assumed that differentiated cells lose the ability to
undifferentiate, recent research supports the hypothesis that these cells
can suffer a dedifferentiation process. In this respect, neural cells were
obtained through transdifferentiation from keratocites and chondrocytes
after stimulating these cells with nerve growth factors. Therefore, during
the degenerative process, it is possible that the chondrocyte type cells
reach a state of dedifferentiation and, due to the stimulation with nerve
growth factors, can have characteristics similar to the nervous cells.
Hence chondrocyte-like cells have the potential to transdifferentiate
making them a possible source of nerve cells inside the intervertebral
disc, and of pain.
This chapter deals with the identification of positive NFAP
chondrones in degenerated intervertebral discs, suggesting a
transdifferentiation of chondrocyte-like cells into nerve cells. It also
reports the presence of NFAP-positive chondrones and pain score in
patients with mild LDD (Lumbar Disc Disease).
The number and imunohistological characteristics of chondrocyte-
like cells and their aggegated form, the chondrones, are correlated with
the symptoms of patients with LDD. The identification of NFAP positive
cells indicates the presence of nervous structures and the possibility of
chondrocyte-like cells transdifferentiating into nerve cells. This finding
might explain the different occurrences and characteristics of pain
amongst patients with LDD.

Keywords: degenerative disc disease, neuronal and endothelial proliferation,

cluster type chondrones

INTRODUCTION
The etiology of lumbar degenerative disc disease (LDDD) is multifactorial
and poorly understood. The main etiologic factors identified are genetic
predisposition, smoking, increased body mass index, heavy weight lifting or
an alteration of nutrient transportation pathways through the endplates [1-4].
The exact mechanisms through which these factors induce the degenerative
process have not yet been elucidated, but research reveals that they
 Nerve Structures Inside the Intervertebral Disc 19

globally lead to a loss of the cell population in the intervertebral disc, to an

increased activity of pro-inflammatory cytokines, proteoglycans and collagen
degradation, to the disc dehydration and to the cellular phenotype alteration.
As the degenerative process continues, these changes lead to intervertebral
disc (IVD) height loss resulting in an alteration of normal biomechanics, in
structural instability, and may finally cause a disc herniation with root
compression or spinal stenosis [5].
A high percentage of patients with degenerated IVD remains
asymptomatic, and can be attributed to the normal aging process. As such, in
addition to structural changes of normal aging, in degenerative disc disease
(DDD) there is a secondary process following either a traumatic event, or a
disc herniation that causes acceleration and accentuation of the degenerative
processes. The IVD tissue recruits immune cells and triggers pro-inflammatory
processes that result in the emergence of different intensities of pain [3, 5].
Thus, intervertebral disc degeneration is thought to be mediated by an
abnormal production of pro-inflammatory cytokines secreted by the nucleus
pulposus and the annulus fibrosus, but also by macrophages, T cells or
neutrophils. In the IVD cells these cytokines can initiate autophagy, cell
senescence or apoptosis. The secreted pro-inflammatory mediators are TNF-α,
IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IFN-γ, and PGE 2. Apart
from all these cytokines, the most frequently studied ones are IL-1 and TNF-α,
which were proven to increase and regulate the activity of genes encoding the
degradative enzymes within the extracellular matrix.
In the early stages, the degenerative process involves the intervertebral
disc, but afterwards the inflammatory changes also extends to the surrounding
tissues. The gelatinous discal material may herniate via cracks and fissures
forming inside the nucleus pulposus and annulus fibrosus, and causing the
activation and infiltration of the immune cells. Therefore, in addition to blood
vessels that may proliferate, different cells like macrophages, neutrophils and
T cells can also migrate into the IVD. Following these changes, nociceptive
nerve fibers emerge from the dorsal root ganglia [6]. Later studies on
chondrocyte type cells from the degenerated nucleus pulposus found the
presence of the NGF (nerve growth factor), the neuronal proliferation factors
and the BDNF (brain-derived growth factor). These neurotrophins induce the
expression of pain associated cation channels within the dorsal root ganglion
[5, 7].
Neuronal proliferation inside the intervertebral disc is blocked on the
external surface of the annulus fibrosus by the presence of semaphorin, family
member of the Class 3 semaphorins (Sema3A). In the nucleus pulposus,
20 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

aggrecan is also a natural barrier against endothelial and neuronal proliferation

[7, 8]. Studies on animal models reported that a gap in the annulus fibrosus
triggers an inflammatory process mediated by cytokines, followed by
endothelial and neuronal proliferation and also leading to an increase in
sensitive nerve-endings within the intervertebral disc [9].
A direct link between the nerve fibers and blood vessels invading the
intervertebral disc was reported, meaning that the NGF secreted by endothelial
cells is necessary for neuronal survival and growth [6]. The nerve fibers that
encroach on the intervertebral disc are considered nociceptive, deriving from
the dorsal root ganglion, and they express acetylcholinesterase, substance P,
BDNF and neurofilament associated protein (NFAP) [10-12]. IL-1β activity is
also increased in the degenerated disc, stimulating NDF and BDNF expression
by the nucleus pulposus cells, while TNF-α stimulates the expression of
substance P. These players interact to form a link between pro-inflammatory
cytokines, neurotrophins and the occurrence of pain.
Chondrocyte-like cells from the nucleus pulposus are derived from the
notochord’s cells originating from the mesoderm. Formed during
embryogenesis, mesodermal cells are multipotent migrating cells, that can
differentiate into chondrocytes, melanocytes, endocrine cells, glial cells,
neurons and many other mesenchymal-derived cells. Until recently, it was
assumed that mesodermal cells, once differentiated into functional cells, lose
the ability to become undifferentiated. However recent research demonstrates
that dedifferentiation can still occur [13, 14]. This process where differentiated
and functional cells can turn into a different type of cells is called
transdifferentiation. Transdifferentiation is the result of a certain modification
in the expression of regulating genes, responsible for the identification of
future developing tissues. Reports of nerve cells being obtained via
transdifferentiation from keratocytes and chondrocytes after stimulation with
nerve growth factors such as Neurobasal-A, EGF (epidermal growth factor),
IGF-1 (insulin growth factor 1) and FGF-2 (fibroblast growth factor 2) are
present in the literature [15, 16]. Therefore, during the degenerative process,
chondrocyte-like cells may reach a state of dedifferentiation and may acquire
characteristics similar to those of neural cells following their stimulation with
nerve growth factors. This possible evolution may explain the occurrence of
pain in degenerative disc disease, and its different characteristics among
patients.
Previous research carried out by the authors of this chapter aimed at
investigating the morphology of chondrocyte-like cells within the degenerated
intervertebral disc [17]. It shown that chondrocyte-like cells aggregate into
 Nerve Structures Inside the Intervertebral Disc 21

bulk structures – cluster chondrones, that form from multiple cells during the
degenerative proccesses. The size of these chondrone clusters were correlated
with the degenerative changes and were quantified by clinical and
radiographic means. It was also noted that endothelial structures were
identified. However, endothelial structures alone could not explain the
presence and characteristics of pain in these patients; therefore, another
hypothesis had to be considered. One of the currently accepted hypothesis
regarding the onset of pain in DDD describes the presence of the nervous
structures within the degenerated cartilage tissue. This hypothesis was
corroborated by our data, since the possibility of neuronal growth occurs at
places where endothelial structures might grow. Currently, there are no data to
support the existence of other cellular structures within the intervertebral disc
that can cause acute pain. This chapter aims to characterize the potential for
chondrocytes to express the neurofilament associated protein during disc
degeneration, and to identify possible correlations between expression of these
factors and the clinical and imaging parameters of disc degeneration. In order
to identify the neurofilaments, immunohistochemical marker NFAP was
utilized given its high specificity for Class IV intermediate filaments from the
neuronal cells cytoskeleton [16, 18].

METHODS
The current research was undertaken in accordance with the local ethics
committee, and was approved by the Ethical Board of Timis County
Emergency and Clinical Hospital. Written informed consent for the
experimental use of surgical samples was obtained from each patient.
The study included 47 patients treated in the IInd Clinic of Orthopedic and
Traumatology at the Clinical and Emergency County Hospital Timisoara, from
October 2012 to January 2015. All patients were diagnosed with lumbar disc
herniation and surgically treated according to standard of care. All patients had
recieved conservatory for 6 weeks before consideration for surgery.
The including criteria were:

 Lumbar disc herniation with neurological deficit, where the symptoms

did not improve after a minimum 6 weeks of conservatory treatment;
 Signs of lumbar degenerative disc disease on MRI Scan;
 Age between 18 and 65;
22 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

 Written consent from patients for participating to the clinical trial and
for using the data anonymously only for scientific purposes;

The excluding criteria were:

 Other lumbar spine diseases: fractures, congenital or acquired

deformities, infectious or inflammatory disease (spondylodiscitis,
spondylitis), segmental instabilities (spondylolisthesis, spondylosis);
 Severe cardiovascular disease: heart failure or angina at rest,
myocardial infarction or heart surgery 3 months before the inclusion,
uncontrolled high blood pressure, severe peripheric circulatory
insufficiency with vascular claudication;
 Severe respiratory disease: uncontrolled asthma, advanced chronic
obstructive pulmonary disease
 Endocrine or metabolic disease: poorly controlled diabetes with
neuropathy and/or advanced angiopathy, decompensated endocrine
diseases;
 Hematological diseases: coagulation disorder with high risk of
bleeding;
 Tumors no matter what the evolution or the origin;
 Infectious or febrile diseases: tuberculosis, active hepatitis (HbV,
HCV), HIV/AIDS
 Severe psychiatric disease, uncooperative patients, drug and alcohol
abuse;
 Pregnancy or breastfeeding;

Patients were evaluated based on the criteria of the Japanese Society of

Orthopaedics and Traumatology for evaluating low back pain (JOABPS score)
and using the visual analogical scale (VAS) for assessing lumbar pain and
sciatalgia. The possible scores of JOABPS vary between a minimum of -6 to a
maximum of 29 points.
Following their clinical evaluation, the patients underwent MRI scans, and
were afterwards taken to the operating room for a minimally invasive
discectomy (endoscopic or microscopic) by the same team of surgeons.
Intervertebral discs fragments obtained after surgical decompression of the
nervous elements were assessed histologically and morphologically.
 Nerve Structures Inside the Intervertebral Disc 23

MRI Assessment

MRI scans of the lumbar spine were performed using a 1.5 T scanner
(Siemens Magnetom Essenza, Siemens AG, Germany) and a spine-dedicated
antenna. The imaging protocol included sagittal and axial T1-weighted and
T2-weighted sequences. The images were evaluated and the degenerative
changes were classified according to Pfirrmann and Modic scales.

Herniated Disc Tissue Fragments

Intervertebral disc specimens were obtained following surgery of the L4-

L5 level or L5-S1. Immediately after surgical intervention, the specimens were
processed in a sterile manner by being washed in saline solution and fixed in
10% buffered formalin solution.

Immunohistochemistry

The antigen demasking and the methylene bridges destruction were

achieved via applying the Novocastra Bond Epitope Retrieval Solution 1 pH6
for 20 minutes (Leica Biosystems, Newcastle uponTyne, UK), followed by
blocking of the endogenic peroxidase with 3% hydrogen peroxide for 5
minutes. Incubation with the primary antibody, NF (mouse monoclonal, clone
N52.1.7, Leica Biosystems, uponTyne Newcastle, UK) 30 minutes prior to
visualization by the Bond Polymer Refine Detection System (Leica
Biosystems, uponTyne Newcastle, UK). 3.3 diaminobenzidine, applied for 10
minutes, was used as chromogen and counterstaining was carried out using
hematoxylin, applied for 5 minutes. All steps of the immunohistochemical
technique were accomplished with the immunohistochemistry automat Leica
Biosystems Leica Bond III. At the end of the program, the sections were
placed in absolute ethanol for 5 minutes, and then dried and clarified in
benzene for 5 minutes. Mounting was performed using an Entellan type
permanent mounting medium, Leica CV Mount (Leica Biosystems, UponTyne
Newcastle, UK). The sections prepared were fixed and histologically
evaluated with a light microscope at magnifications of 100x, 200x, 400x and
1000x (Axio Imager 2, Carl Zeiss AG, Jena, Germany).
24 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

Morphometry

The systematic assessment of sections was performed with the light

microscope in order to obtain a well-defined surface. Six visual fields were
assessed for each section, using the lens with 400x magnification. Chondrones
(defined as a group of cells with distinct territorial chondrocytic matrix) were
identified and manually counted. The surface area of chondrones was
measured (expressed in μm2) using ZEN software (Zeiss Efficient Navigation,
Carl Zeiss AG, Jena, Germany).

Statistical Analysis

The data were subjected to standard statistical analysis using SPSS 21.0
software (IBM Corporation, Armonk, NY, USA), with both parametric and
non-parametric correlations being carried out. The noted coefficients were r,
Kendall tau-b (τ) and Spearman rho (ρ). P values of ≤0.05 were considered
statistically significant, and ≤0.001 very statistically significant.

RESULTS
A total of 47 patients with an average age of 40.54 years (ranging between
21 and 62 years), gender distribution: 21 women (44.68%) and 26 men
(55.32%) were evaluated.
With respect to duration of symptoms, 21 patients had a symptoms
duration of one year (44.68%) and 26 had a symptoms duration longer of over
one year (55.32%). The JOABPS average clinical score was 7.32 (ranging
between 1 and 14), with 48.7% of patients having a score less than 7.
The VAS mean for back pain was 7.35 (ranging between 2 and 10), and
the average VAS for sciatica was 8.03 (range of 5 to 10).
The degree of degenerative disc disease was graded according to the
Modic classification: 15 patients showed no change (31.91%), 7 patients had
type I changes (14.89%), 22 patients had type II changes (46.81%) and 3
patients had type III changes (6.39%).
In terms of the Pfirrmann disc degeneration classification, there were 4
cases of type 2 modifications (8.51%), 15 cases of type 3 (31.92%), 20 cases
of type 4 (42.55%) and 8 cases of type 5 (17.02%).
 Nerve Structures Inside the Intervertebral Disc 25

Following the evaluation of the herniated disc tissue fragments, regions

corresponding to the nucleus pulposus and containing ovoid chondrocyte-like
cells surrounded by pericellular matrix, as well as elongated and fusiform
fibroblast type cells originating from annulus fibrosus.
Some specimens also contained hyaline cartilage with chondrocyte cells
arranged in lacunas. In the quasi-normal nucleus pulposus the chondrones
were rare, scattered, and surrounded by rich extracellular matrix. The
specimens that displayed a higher degree of degeneration contained either a
greater number of chondrones, or multi-cellular cluster-type chondrones, with
cells in different stages of evolution.
The extracellular matrix presented a series of discontinuities, with a
disorganized appearance. The annulus fibrosus was identifiable due to the
characteristic fibroblast-like cells deposited between fibrous bands with
alternating orientation. At the interface between the annulus fibrosus and the
nucleus pulposus, this specific arrangement of collagen fibers decreased and
both fibroblast-like and chondrocyte-like scattered cells were identifiable.
The immunohistochemical analysis was focused on the regions of nucleus
pulposus tissue identified using the previously described characteristics. All
specimens contained the nucleus pulposus, but there were specimens without
hyaline cartilage or annulus fibrosus. The immunohistochemical assessment of
the fibrocartilaginous tissue sections revealed the NFAP-positivity of the
chondrones, especially in the specimens with severe degenerative changes
(Figure 1).
Bands and cords of NFAP-positive extracellular matrix bypassing the
chondrones and their pericellular matrix were observed at the interface
between the nucleus pulposus and the endplates or the annulus fibrosus
(Figure 1). Some sections, especially at the periphery of the analyzed
specimens, exhibited small nerve fibres (similar to nerve fibers) that could be
pinpointed.
In general, the small chondrones that contained one or two cells, were
NFAP-negative, while the larger chondrones were mainly NFAP-positive
(Figure 2). There were also cases when the small chondrones were positive
and rare cases of medium-large sized chondrones that were NFAP-negative.
A total of 235 fields of view corresponding to a total of 47 specimens
were assesed (using x40 magnification). 1,367 chondrocytes were identified
and measured. The statistical analysis of the performed measurements
performed revealed a mean surface area of 555.89 μm2 (values between 81.94
and 9923.85 μm2), with a median of 327.10 µm2 and a geometric median of
355.44 μm2 (ranging 337.1 to 374.8 μm2) (Figure 3).
26 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

The average ratio of chondrones/field of view (with the total surface area
of a field of view at 40x magnification is 200,000 μm2) was 5.82
chondrones/visual field (with values between 4 to 10 chondrones/field of
view). The analysis of the surface area histogram, clearly pointed out that
89.49% of the chondrones had areas smaller than 1100 μm2 (Figure 4),
indicating the presence of large cluster type chondrones as a special feature,
and suggesting its association with the degenerated tissue.

Figure 1. A. Area of fibrocartilaginous tissue with a high degree of degeneration,

containing clusters of chondrones positive for NFAP (magnification x10); B.
Imunohistological stain of a NFAP-positive cluster-type chondrone (magnification
x100) C. Microscopic detail demonstrating a nerve structure at the periphery of a
NFAP-positive cluster type chondrone (magnification x40) D. NFAP-positive
extracellular matrix zones surrounding chondrones, starting from the endplate and
penetrating nucleus pulposus (magnification x10).

Figure 2. Chondrones in detail during different evolutionary stages. A. Monocellular

chondrone B. Hypocellular chondrone that is NFAP-positive C. Chondrone composed
of two cells D, E, F. Chondrones containing multiple NFAP-positive cells.
 Nerve Structures Inside the Intervertebral Disc 27

Figure 3. Chondrone areas size distribution.

Figure 4. Chondrones size histogram.

Based on these observations, patients were divided into two groups,

according to the chondrones area size, 327.10 μm2 being considered the
threshold value. As a result, the patients in group A presented a low degree of
degeneration, with a median area lower than 327.10 μm2. This group consisted
of 22 patients representing 46.8% of total. The group B of patients, with a
measured median area larger than 327.10 μm2, consisted of 25 patients,
representing 53.2% of the total number of patients. In group A, patients had
28 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

NFAP-positive chondrones in 13 cases (59.09%) and NFAP-negative

chondrones in 9 cases (40.91%). In group B, there were 18 NFAP-positive
cases (72%) and 7 negative cases (28%).
In group A, the average JOABPS score was 8.18 and mean VAS score for
back pain was 6.89, while the mean VAS value for sciatica was 7.65.
Pfirrmann degenerative changes were mostly type III in a percentage of
41.2%, and 52.9% of the patients had no Modic changes.
In group B, the average JOABS score was 6.6 and VAS for back pain was
7.75 while mean VAS for sciatica was 8.35. Pfirrmann degenerative changes
were mostly type IV (in 56% of cases), and 72% of patients had type II Modic
changes.
In group A there was a direct correlation between age and median area
(r=0.507; p=0.038; tau=0.436; rho=0.506), age and symptom duration over a
year (r=0.592; p=0.012; tau=0.475; rho=0.555), and a negative correlation
between age and VAS for back pain (r=-0.603; p=0.010; tau=-0.418;
rho=0.526). A correlation between the median area and the symptom duration
was observed (r=0.571; p=0.017; tau=0.401; rho=0.477), as well as the median
area and Pfirrmann degeneration changes (r=0.591; p=0.012; tau=0.364;
rho=0.465). Duration of symptoms was correlated with the mean of NFAP-
positive chondrones (r=0.560; p=0.019; tau=0.515; rho=0.591), NFAP-
positive chondrones (r=0.545; p=0.024; tau=0.545; rho=0.545), Pfirrmann
type degenerative changes (r=0.606; p=0.010; tau=0.560; rho=0.601) and VAS
for low back pain (r=0.578; p=0.015; tau=0.614; rho=0.683). JOABPS clinical
score was correlated with the mean NFAP-positive chondrones (r=-0.509;
p=0.037; tau=-0.408; rho=-0.566) and NFAP-positive chondrones (r=-0.497;
p=0.042; tau=-0.431; rho=-0.495). The NFAP-positive mean of the
chondrones was correlated with the duration of symptoms, JOABPS score, the
number of NFAP-positive chondrones (r= 0.830; p=0.000; tau=0.739;
rho=0.848) and VAS for back pain (r=0.547; p=0.023; tau=0.453; rho=0.629).
The number of NFAP-positive chondrones was correlated with the duration of
symptoms, the JOABPS score, the mean of NFAP-positive chondrones and
VAS for low back pain (r=0.547; p=0.015; tau=0.486; rho=0.541). Pfirrmann
degenerative changes were correlated with the median of the surface area of
chondrones, Modic type changes, duration of symptoms and VAS for low
back pain (r=0.589; p=0.013; tau=0.466; rho=0.534).
In group B there was a correlation between age and the median surface
area of chondrones (r=0.463; p=0.040; tau=0.349; rho=0.456), patients age
and duration of symptoms (r=0.624; p=0.003; tau=0.580; rho=0.683), age and
the number of NFAP-positive chondrones (r=0.559; p=0.010; tau=0.487;
 Nerve Structures Inside the Intervertebral Disc 29

rho=0.572), age and Pfirrmann type changes (r=0.537; p=0.015; tau=0.434;

rho=0.540), and age and Modic type changes (r=0.601; p=0.005; tau=0.555;
rho=0.642). The mean of surface area of NFAP-positive chondrones was
correlated with VAS for low back pain (r=0.526; p=0.016; tau=0.566;
rho=0.650). The number of NFAP-positive chondrones were correlated with
the duration of symptoms and VAS for back pain (r=0.619; p=0.004;
tau=0.486; rho=0.541). VAS for low back pain correlated with age, the median
of the surface area of NFAP-positive chondrones, the number of NFAP-
positive chondrones, and VAS for sciatica.

CONCLUSION
The normal intervertebral disc has a very high threshold for mechanical
stimuli and does not contain sensitive nerve fibers, which makes it is relatively
inert to nociceptive stimuli.
In the early stages of degeneration there was an observed proliferation of
the blood vessels accompanied by nerve fibers, along the cracks and tears
beginning from the annulus fibrosus, towards the interior of the intervertebral
disc, which is normally an avascular, aneural and lymphatic-free organ [5, 19,
20]. This process might be the result of synergistic action of pro-inflammatory
cytokines and neurotrophins, and of decreased suppression, due to decreased
concentration of aggrecan and decreased expression of Sema3A semaphorin.
In a healthy intervertebral disc, aggrecan and other matrix molecules
serve as a natural barrier against endothelial and neuronal proliferation.
In the degenerative process, cytokines mediate the activity of the ADAMTS 4
and 5 proteolytic enzymes resulting in an increase of the keratan
sulphate/chondroitin sulphate ratio, decreasing the concentration of aggrecan
and thus creating the optimal conditions for endothelial and neuronal
proliferation. Another barrier against neuronal proliferation is the expression
on the outer surface of the annulus fibrosus of Sema3A, a member of
semaphorins class 3. It was observed that this expression is reduced in patients
with advanced stages of disc degeneration, suggesting that it has an inhibitory
role towards neural proliferation [21].
The normal innervation of the intervertebral disc is limited to the first 2-3
external layers of the annulus fibrosus. It consists of different types of nerve
fibers, including nociceptive peptidergic NGF-dependent fibers, non-
peptidergic GDNF-dependent fibers that are morphologically similar to Pacini
mechanoreceptors, and Ruffini endings and Golgi complexes [22, 23]. They
30 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

originate in the small neurons of the dorsal root ganglion, and express TrkA,
TrkB and Ret receptors with a high affinity for NGF, BDNF and GDNF [10].
Lee et al. have reported increased levels of NGF in the degenerated discs,
using the ELISA technique. Furthermore, Aoki et al. have reported high levels
in the herniated discs, which implies that these neurotrophins may be playing
an important role in the modulation of disc degeneration [24, 25]. Purmessur et
al. reached the same conclusion after using an immunohistochemical method
to identify increased levels of NGF. Although these authors detected the same
phenomena, the cells responsible for NGF expression were not identified. It is
speculated that the cells responsible for the secretion of these neurotrophins
might be chondrocyte-like cells, endothelial cells or inflammatory cells [6, 26,
27]. Results detailed in this chapter confirm the presence of the neurofilaments
inside chondrocyte-like cells that form cluster type large chondrones
frequently identified in the specimens with high grade degenerative changes.
Greene et al. managed to induce the transdifferentiation of chondrocytes into
neural cells, although they could not assess their functionality [13]. It is
possible that some of the chondrocyte-like cells inside the nucleus pulposus
are transdifferentiating into neural cells (capable of expressing TrkA, TrkB
and Ret receptors), thus explaining the appearance of pain during disc
degeneration. Furthermore, inside the degenerated disc there was reported
an increased expression of growth factors IGF, FGF, VEGF, NGF, BDNF
that could create an ideal environment for chondrocyte-like cells to
transdifferentiate into neural cells, as observed by Greene et al., but further
research is required to confirm this hypothesis.
Kokubo et al. asssessed of 500 degenerated intervertebral discs and
identified NGF-positive free nerve fibers, GAP-43 and substance P in the
external layers of herniated disc fragments. However, they did not report any
information about the immunopositivity of the chondrocyte-like cells [28]. The
research carried out in this chapter, identified both nerve fibers within the
extracellular matrix of herniated disc tissue as previously described by Kokubo
et al., and NFAP-positive chondrocyte-like cells.
Utilizing a three-dimensional microscopic study of porcine chondrocytes
harvested from the femoral condyle, Choi et al. [29] measured the volume of
chondrones and found average values of 2,218 ± 832μm3 (in the average
cartilage region where chondrones have a predominantly spherical shape),
which corresponds to an approximate area of 206 ± 106 μm2. The assessed
chondrones in this research had an average area of 555.89 μm2 (values
between 81.94 and 9923.81 μm2). 71.14% of them had values less than 540
μm2. However, these differences underscore the morphometric differences
 Nerve Structures Inside the Intervertebral Disc 31

between normal chondrones and those found in the degenerated

fibrocartilaginous tissue.
Another observation resulting from this research is that in the group with
more advanced degeneration changes (defined by a mean surface area of
chondrones higher than 327.10 μm2), the intervertebral discs also presented
radiographic changes of degenerative disease quantified with Pfirrmann and
Modic classifications. At the same time, these patients also recorded clinical
pain assessment scores higher than the patients with more mild degenerative
changes. NFAP-positive chondrones were frequently found among the larger
chondrones.
The correlations between age and the median values of the chondrones
surface area, duration of symptoms under one year, and VAS for low back
pain suggests the involvement of the senile degenerative changes. Notably, the
patients included for this research had herniated discs resulting not from
normal disc aging. In group A patients, this may simply reflect the natural
history of disc changes over time. This hypothesis is supported by the
correlation between age and the NFAP-positive or -negative nature of the
chondrones, in that the number of chondrones increases with age. Moreover,
the evolving nature of this condition is also supported by the correlation
between the median of the chondrones surface area and the symptoms onset,
with lower values of chondrone areas being found in patients whose symptoms
have occurred for less than one year. The duration of symptoms was correlated
with the VAS for low back pain in group A, a correlation not seen in patients
with more advanced degenerative changes. Considering that the chondrones
dimensions correlate with the symptoms duration, we can hypothesize that
once the degenerative process has started, there is an initial phase where the
intensity of the symptoms increases in parallel with the size chondrones size,
after which the intensity of the symptoms reaches a plateau, then stagnates or
regresses, while the chondrones continue to grow in size. Degenerative
changes quantified using Modic and Pfirrmann systems were corroborated,
and correlated with histological changes; however, they were not an objective
of this research [30-34]. However, there was a correlation between the
Pfirrmann type changes and both the median of the chondrones surface area
and the symptoms duration. These observations emphasize the important role
played by the morphometry of chondrones in the pathophysiology of disc
degeneration and its clinical expression.
This chapter confirmed the presence inside the degenerated intervertebral
disc of nerve structures which are not normally present. Moreover, the results
have clinical significance, indicating that the presence of NFAP positive
32 Manuel D. Oprea, Anca Maria Cimpean, Marius Raica et al.

chondrones is correlated with pain scores and with duration of symptoms

greater than one year. However, further research is needed to investigate the
functionality of these chondrocytes with neural expression and their possible
involvement in the generation of pain.

 Degenerated intervertebral discs contain chondrones positive

for NFAP, suggesting the possible transdifferentiation of the
chondrocyte-like cells into neural cells.
 Within the extracellular matrix of the degenerated fibrocartilaginous
tissue, nerve fibers or free nerve endings were identified.
 Patients presenting with larger chondrones had more severe
symptoms.
 NFAP-positive chondrones correlate with the clinical and imaging
scores in patients with herniated discs with symptoms duration greater
than one year.
 NFAP-positive chondrones are correlated with clinical VAS score for
low back pain, suggesting that the former are involved in the
development and the modulation of pain in patients with degenerative
disc changes.

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 3

SPINAL BIOMECHANICS

James Pan, BS, Arjun V. Pendharkar, MD

and Jongsoo Park*, MD
Department of Neurological Surgery, Stanford University School of
Medicine, Stanford, California, US

ABSTRACT
The biomechanical properties of the spine offer insights into the
mechanisms and consequences behind intervertebral disc degeneration.
The intervertebral disc is a dynamic structure which serves a critical
function in allowing the many components of the bony vertebrae to
interface with and work with one another. The biomechanical properties
of the intervertebral disc afford it’s properties in helping the spine to
withstand compressive, shear, bending, and rotational forces. These
biomechanical properties are derived from the biochemical and cellular
composition of the disc which afford it unique properties such as its
viscoelastic behavior. Degeneration of the disc — either due to injury or
aging — perturb the biochemical composition of the disc, and
subsequently the biomechanical properties. This chapter will explore the
composition and the mechanistic properties of the disc which give the
disc it’s unique characteristics, and how theses parameters change in
degenerative states.

*
Corresponding author: Jongsoo Park ([email protected]), Department of Neurosurgery,
Stanford University School of Medicine, 300 Pasteur Drive, R281, Stanford, CA 94303-
5327.
38 James Pan, Arjun V. Pendharkar and Jongsoo Park

INTRODUCTION
The vertebral column is the hallmark feature of vertebrates and serves to
house the spinal canal, which encloses the spinal cord. Rigid vertebral bodies
work in concert with the intervertebral disc to allow for large, complex, three
dimensional motions of the spine. Intervertebral discs also perform the
function of absorbing large loads sustained by normal motion of the body and
stabilizes the spine to prevent it from injury. Though the primary function of
the intervertebral disc is mechanical, these properties are derived from the
unique cellular and biochemical composition of the disc. A crucial balance of
cell types, extracellular matrix components, and water give rise to the
biomechanical properties of the disc and explain regional differences in
mechanics and mechanisms of injury. Injury and degeneration of the disc
occurs due to a perturbation in the biochemistry of disc components which
translates into distinct biomechanical failures which make the disc more
susceptible to tears, fissures, herniations, and pain. Therefore, an appreciation
of the biomechanical properties of the spine is crucial to understanding the
pathophysiology of degenerative disc disease and the consequences of
treatment and rehabilitation.

GENERAL ANATOMY OF THE SPINE

Bony Vertebrae

The spine is composed of 33 vertebrae, which are divided into five distinct
regions — cervical, thoracic, lumbar, sacral, and coccygeal. Adjacent
vertebrae in the cervical, thoracic, and lumbar regions are connected by the
intervertebral disc anteriorly and by the facet joint ligaments and other
connective tissues laterally and posteriorly. One noticeable difference is that
the sacral and coccygeal regions contain three to five fused vertebrae. All the
vertebrae have a similar general structure with sight variations in size and
anatomy. The increasing size of vertebrae from top to bottom is reflective of
the increasing weight and axial load sustained by each successive vertebra.
Each vertebra is comprised of an anterior body, and a posterior arch
composed of two pedicles and two laminae. The laminae are joined posteriorly
in the midline to form the spinous process. On the lateral aspects of the
vertebra, the posterior arch also supports a transverse process and superior and
 Spinal Biomechanics 39

inferior articular processes. The transverse and spinous processes provide

levels for muscles which attach to them. The articular processes are part of
synovial joints that are posterior contact points for adjacent vertebral
segments.
The cervical spine consists of seven vertebrae in a lordotic shape and is
generally the most flexible portion and most susceptible to injury. The
craniocervical junction is comprised of the occiput and the first two bony
vertebrae: C1 (atlas) and C2 (axis). Atlas has only a bony ring with no
vertebral body, encircles the dens of axis at the point where it protrudes
rostrally from C2, and articulates with the occiput of the skull via a pair of
bilateral synovial condylar joints. The complex bony and ligamentous
articulations of the craniocervical junction gives its unique biomechanical
properties which accounts for 25% of the flexion and extension, and 50% of
rotation of the neck. Subaxial cervical vertebrae (C3-C7) are distinct
anatomically from the atlas and axis and are generally the smallest in size
compared to other regions of the spine. The end plates of the subaxial cervical
vertebrae are concave superiorly and convex inferiorly, and they articulate to
form the uncovertebral joints (of Luschka). The pedicles associated with this
region are short and are derived from the midpoint of the vertebral bodies.
The thoracic spine consists of 12 vertebrae and is kyphotic. In general, the
thoracic spine is quite rigid due to its association with the chest wall. As it is
the transition zone between the cervical and lumbar sections of the cord, the
first thoracic vertebrae share cervical features, and the last four maintain some
lumbar features. Notable landmarks include the superior vertebral notch in T1,
and the lateral direction and inferior articular processes of T12. The inferior
and superior faces of the vertebral body are generally flatter and the transverse
processes are located more posteriorly and appear to be more elongated than in
the cervical spine. The thoracic vertebrae laminae overlap and are broader
compared to that of the cervical region. The transverse processes also increase
in size as the thoracic spine descends (Berry et al. 1987). Finally, ribs
articulate with the lateral processes in the thoracic spine.
The lumbar spine consists of five vertebrae and is lordotic. The largest
vertebral bodies of the spine, each lumbar vertebra increase in diameter when
approaching the sacrum and are larger in transverse width relative to
anteroposterior diameter. The lateral processes are the longest and are located
at the junction between the lamina and the vertebral body. That articular pillars
are located more posteriorly compared to the cervical vertebrae and are
integrated within the laminae in the thoracic and lumbar regions. Pedicles in
the lumbar region are derived from the rostral aspect of the vertebral body.
40 James Pan, Arjun V. Pendharkar and Jongsoo Park

Intervertebral Disc

The intervertebral disc (IVD) is a structure found between adjacent

vertebrae and acts as a ligament to hold the vertebrae together. This separates
the bony vertebral bodies and allows for complex three-dimensional motion of
the spine. Accounting for roughly 20-33% of the height of the entire vertebral
column, it is the largest avascular and aneural structure in the body and
connects adjacent vertebral bodies via a cartilaginous endplate form which
nutrients are received by diffusion. There are twenty three discs in the
vertebral column starting between C2 and C3 and extending distally to L5-S1.
The diameter and shapes of the disc vary according to the region of the spine
— they are generally ellipsoid in the cervical and lumbar regions, and more
triangular shaped in the thoracic region. Each disc is comprised of four
concentrically arranged layers: the outer annulus fibrosus, the
fibrocartilaginous inner annulus fibrosus, the transition zone, and the nucleus
pulposus (Figure 1) (Buckwalter 1995). The superior and inferior aspects of
the IVD are associated with the cartilage end plates (Figure X). These
components are intricately linked to one another such that the pathology of one
can affect the ability of the others to carry out their normal functions.
Furthermore, the discs remain in an intricate balance of having to be rigid
enough to support the vertebral bodies, but soft enough to allow spinal
motions of axial compression, flexion–extension, lateral bending, and axial
rotation (Figure 2).

Figure 1. Anatomy of the Intervertebral Disc.

The outer annulus consists of approximately 90 collagen sheets bonded

together in concentric laminated bands, within which the fibers are arranged in
a helicoid manner (Doers and Kang 1999). The sheets are found 30° to the disc
plane and 120° to each other in alternate bands. This orientation allows the
annulus to resist the high pressure of the nucleus and also to withstand
 Spinal Biomechanics 41

rotational forces. The inner annulus fibrosus is softer, less dense, and has a
larger fibrocartilagenous component, composed mostly of type II collagen
fibers. The fibers of the outer annulus attach directly to the vertebral body as
Sharpey fibers while the fibers of the inner annulus attach to the cartilaginous
endplate. Additionally, due to the dense collagen network, the outer annulus is
less permeable than the inner annulus (Figure 1) (Houben et al. 1997; Poole
1997).

Figure 2. Spinal Loading Configurations.

The nucleus pulposus (NP) comprises the central core of the intervertebral
disc. It’s embryological origin is distinct from that of the other components of
the intervertebral disc- it is derived from the notochord (or endodermal origin)
which contrasts with the mesodermal origin of the other components of the
disc (Roberts et al. 2006). Biochemically, the NP is made from a soft
gelatinous material comprised of proteoglycans surrounded by the annulus
fibrosus. The high proteoglycan content allows for the NP to maintain an
increased hydration state, which allows for its viscoelastic properties leading
to its load-bearing properties in the spine (Iatridis, Setton, Weidenbaum, and
Mow 1997b). The NP is also rich in type II collagens, which comprises 80%
of the collagen content in the NP. Elastin fibers are also present, and are
42 James Pan, Arjun V. Pendharkar and Jongsoo Park

arranged in both a radial distribution from the center to the periphery and a
vertical orientation anchoring the NP to the end plates (Yu et al. 2002). This
orientation is thought to be important for the maintenance of the structure of
the NP within the annulus fibrosus by restoring the NP to its original form
following load bearing, in addition to facilitating load transmission to the
surrounding annulus fibrosus.
The cartilaginous end plates are composed of a thin layer of hyaline
cartilage which interfaces between the bony vertebral body and the IVD. Their
composition is similar to that of the disc itself, being comprised of
proteoglycans, type II collagen, and water (Raj 2008). The thickness of the
endplate ranges from 0.5 to 1.5 mm and is thinnest at the points there they
interface with the NP (Grignon et al. 2000). The plate is attached to the
vertebral body by a thin layer of calcium and is discontinuous in regions where
perforations exists throughout the endplates. These perforations exist to allow
the passage of vascular channels which traverse from the adjacent vertebral
body into the disc which are usually obliterated by the second decade of life
(Conventry, Ghormley, and Kernohan 1945). The stiff but porous nature of the
endplate serves as a site of diffusion of nutrients and fluid into and out of the
disc and to prevent herniation of the disc material into the adjacent vertebral
body. Weakness of the endplates can lead to herniation of disc into bone
resulting in Schmorl nodes and can be attributed to a perturbation in endplate
composition such as a significantly decreased proteoglycan concentration
(Roberts, Menage, and Urban 1989).

FUNCTIONAL BIOMECHANICS
Physiology of the Intervertebral Disc

The IVD is primarily a load-bearing structure that absorbs axial loads and
redistributes them across the entire disc. The characteristics and capacity of
load distribution is partly determined by the molecular and biochemical
composition of the disc. The extracellular matrix of the outer annulus is
comprised of approximately 80% of type I collagen and 3% of type V
collagen. On the interior of the outer annulus, a concentration gradient exists
whereas type II collagen proteoglycan increases towards the center of the disc,
whereas type I collagen decreases. The concentration of type II collagen can
reach 80% inside the nucleus, while type I collagen is typically absent
(Buckwalter 1995).
 Spinal Biomechanics 43

These differences in composition in different areas of the disc are thought

to be responsible for the dynamic structural properties that allows it to bear
and distribute loads across the entire structure. Furthermore, the mix of type I
and II collagen in the annulus fibrosus gives it tensile strength. Other
molecules such as type V and XI collagen are also found which interlink
collagen fibrils, leading to the overall strong fibrillar collagen meshwork
(Setton and Chen 2006). Specifically, when the disc is subjected to axial loads,
the NP and inner annulus absorbs the weight to generate hydrostatic pressure
which is then distributed evenly to the adjacent outer annulus. The tensile
strength of the outer annulus is derived from the lamellar structure of the type I
collagen network.
In addition to collagen, proteoglycans are also a significant molecular
component of the IVD as they can be found to constitute up to 50% of the cells
in the NP. Many types of proteoglycans exist in the extracellular matrix
including aggrecan, versican, decorin, biglycan, fibromodulin, lumican, and
perlecan. These molecules are characterized by a central core protein with side
chains composed of keratin sulfate and chondroiton sulfate. At their N-
terminus, proteoglycans such as aggrecans attach to hyaluronic acid, and their
C-terminus attaches to components of the extracellular matrix such as collagen
(Antoniou et al. 1996; Feng et al. 2006). Because the proteoglycans attach to
hyaluronic acid through linkage proteins, they can also form aggregates
(Buckwalter, Einhorn, and Simon 2000). Proteoglycans also have a net
negative surface charge and is therefore hydrophilic — thus affording the NP’s
propensity to retain hydration. Proteoglycans are implicated in age-related disc
degeneration as breakdown of aggrecans are replaced by non-aggregated
proteoglycans, which have a decreased ability to retain water.
The disc matrix is maintained by cells, which comprise only 1% of the
disc volume. Histologically, the disc is comprised of at least three distinct cell
populations: the chondrocyte-like cells in the NP, fibrocartilaginous cells in
the inner annulus, and fibroblast-like cells in the outer annulus (Bibby et al.
2001). The shape and cytoskeletal organization of these cells seems to
influence the type of matrix components synthesized (Figure 3) (Horner et al.
2002). These cells respond to a variety of stimuli, and studies how suggested
that mechanical stress, nutrient supply, cytokines, and the osmotic and ionic
environment have the most profound effects on cellular activity (Bruehlmann
et al. 2002).
44 James Pan, Arjun V. Pendharkar and Jongsoo Park

Figure 3. Disc Components.

Table 1. Biomechanical characteristics of the NP

Parameter Description Normal NP Degenerate NP

Shear modulus Slope of the shear stress versus 0.2 kPa 0.6-0.8 kPa
angle of displacement
Dynamic shear Ratio of stress to strain under 5-60 kPa Increased
modulus vibratory conditions
Compression Ratio of compressive stress applied 0.5 MPa N/A
modulus to the resulting compression
Viscoelastic Tendency of a material to exhibit 3×10^-16 N/A
behavior both viscous and elastic m4/Ns
characteristics when subjected to
deformation
 Spinal Biomechanics 45

The mechanism in which the chondrocytes of the NP respond to

mechanical stress is not fully understood. However, it is known that the cells
are surrounded by a pericellular matrix (PCM), which is characterized by the
presence of type VI and III collagen, not found elsewhere in normal cartilage
(Hessle and Engvall 1984; Rombers et al. 1991; Söder et al. 2002). In-vitro
experiments on isolated cells have suggested that the PCM is a protective layer
for chrondrocytes during axial loading through an adaptive water loss from
PCM proteoglycans (Poole, Flint, and Beaumont 1988). Additionally, the
PCM may also have mechanical transduction properties (Poole 1997).

Nucleus Pulposus

The three components of the IVD — the annulus, NP, and endplates —
work together to give the disc its unique load absorption abilities. In healthy
discs, each component works in concert to provide a balance between stability
and mobility of the disc. This is enabled by the viscoelastic properties of the
disc, which is secondary to the high concentrations of proteoglycans in the NP.
These proteoglycans allow the NP to retain water, thus allowing it to weight-
bear compressive loads by conforming its shape to redistribute axial loads to
the adjacent AF by transmitting hydrostatic forces. Bulk fluid flow from the
disc also contributes to its viscoelastic properties in addition to nutrient
transport. The hydrostatic forces transmitted to the annulus is contained by the
tensile strength of the collagen meshwork. This allows the annulus to share the
compressive load without being directly exposed to external forces.
The NP’s highly hydrated mix of proteoglycans and collagens afford it its
swelling pressure, compression modulus, permeability, and shear modulus
properties. The hydrophilic nature of the NP can be demonstrated by
submerging it in water and observing it to swell to at least twice its original
volume. This swelling pressure can be measured in vivo and in cadaveric
spines under mechanical loading. The swelling pressure of a healthy nucleus is
0.1-0.2 MPa in a recumbent position, and 1-3 MPa under axial load (e.g.,
standing or lifting) (Wilke et al. 1999). These values are also consistent in
cadaveric motion segments under external loads (Castagnera and Lavignolle
1989; McNally and Adams 1992). Osmometry methods have also been used to
measure swelling pressure, which produces values consistent with in vivo
measurements (Urban and McMullin 1988). Finally, the swelling pressure has
also been shown to be influenced with the glycosaminoglycans content of the
NP (Johannessen and Elliott 2005).
46 James Pan, Arjun V. Pendharkar and Jongsoo Park

Recent studies have also provided insights into specific tissue properties
of the NP and their changes with degeneration. These findings are summarized
in Table 1.

Annulus Fibrosus

The annulus fibrosus, like the NP, also undergoes axial loading as a result
of bending and torsional loading. In addition to axial loading due to body
weight, the annulus receives forces radially from swelling of the NP. The
swelling pressure, which represents the pressure generated when the annulus is
held at the in-situ displacement, is derived from the biochemical properties of
glycosaminoglycans when they balance their negative charges. Because
glycosaminoglycans are found in the NP and the annulus, the swelling
pressure is a similarly important biomechanical property. Studies have shown
that the compressive modulus and permeability of the annulus to be 0.6 MPa
and 2 × 10-16 m4/Ns (Iatridis et al. 1998; Yao et al. 2002).
Compression behavior in the annulus is nonlinear and not homogenous.
Non-linearity is ascribed to the increase in compressive modulus and the
decrease in permeability as a function of increasing compressive forces
(Iatridis et al. 1998). Studies have shown that non-linearity is more
pronounced for compressive stiffness than for permeability (Best et al. 1994).
Non-homogeneity is due to regional and radial variations in both
biomechanical properties and biochemical composition (Iatridis et al. 1998;
Best et al. 1994). Compression properties are also not very anisotropic as very
little anisotropy is observed for samples oriented in the axial and radial
direction, which suggests that the alignment of the collagen fibers in the
annulus does not strongly affect its behavior during compression (Iatridis et al.
1998). Therefore, loading configuration is primarily influenced by fluid
pressurization. Permeability in the annulus is dependent on direction, with the
highest permeability in the radial direction (Gu et al. 1999). Swelling is also
observed to be more prominent in the radial direction rather than the axial
direction (Urban and Maroudas 1980).
Tensile forces applied to the disc is primarily resisted by the annulus.
When the NP undergoes axial compression, this force is transmitted to the
annulus by tensile forces. Tensile loads are also generated directly on the
annulus itself. The nature of the stress-strain curve observed for the annulus
under tensile stress is nonlinear and is similar to the material properties of
other soft collagenous tissues such as articular cartilage, tendon, and ligament.
 Spinal Biomechanics 47

Under axial deformation, the annulus exhibits a nonlinear portion of the stress-
strain curve known as the “toe region” which represents a lower force
observed for small tensile strains. This nonlinear region is then followed by a
linear region, and then failure of the tissue at the highest strains. For example,
the modulus in the toe region was found to be 2 MPa and in the linear region
to be 20 MPa, which demonstrates a nonlinear relationship between modulus
and increasing strain (Acaroglu et al. 1995; Ebara et al. 1996; Elliott and
Setton 2001).
Anisotropy is another important property of the annulus since it allows it
to support large and complex loads. This is evident by the near 1000-fold
increase in tensile modulus when loads are applied along the fibril as supposed
to across the fibrils. A single layer of the annulus, when loaded parallel to the
collagen fibres, has a modulus of 136 MPa at the anterior outer site (Skaggs et
al. 1994). Furthermore, the circumferential modulus is 20 MPa, the axial
modulus is 0.8 MPa, and the radial modulus is 0.2 MPa (Elliott and Setton
2001; Fujita, Duncan, and Lotz 1997) which illustrates that the anisotropic
properties of the annulus is due in part to the structural contributions of
aligned collagen fibers.
The annulus is also known to have spatial variation in structure and
composition due to its non-homogenous nature. Water, collagen, and
proteoglycan content has been found to vary significantly from the outer to
inner sites and from the anterior to posterior sites (Eyre and Muir 1976).
Despite biochemical non-homogenity, little variation is observed in both radial
and axial tensile properties, possibly due to the small contributions of the
collagen fibers in these orientations (Yin and Elliott 2005). However, in the
circumferential direction, the anterior annulus is stiffer than the posterior
annulus, and the outer annulus is stiffer than the inner (Acaroglu et al. 1995;
Ebara et al. 1996; Elliott and Setton 2001). The relative lack of structural
integrity in the posterolateral region can be due to incomplete lamellar layers,
increased fiber interlacing angles, and loose interconnections of fibers
(Marchand and Ahmed 1990). Regional variations in composition and
biomechanical properties of the posterolateral annulus can point to regions of
weaker structural integrity, and can be predisposed to tears, fissures, and
herniations (Figure 4).
Shear loading of the annulus has been shown to be nonlinear, viscoelastic,
and aniostropic. The shear modulus of the annulus at equilibrium was
measured to be 0.1 MPa; however, modeling studies have predicted the shear
modulus to be as large as 20 MPa (Yin and Elliott 2005; Spilker, Jakobs, and
Schultz 1986; Elliott and Sarver 2004). Although there have been studies
48 James Pan, Arjun V. Pendharkar and Jongsoo Park

showing that the shear modulus increases slightly with degeneration (Iatridis,
Kumar, et al. 1999; Iatridis, Mente, et al. 1999), more studies regarding this
biomechanical parameter is needed.

Figure 4. Relative Stiffness and Structural Integrity of the IVD.

Endplate

The cartilaginous endplates, which are thin layers of hyaline cartilage

between the IVD and the bony vertebra, play an important role in supporting
and distributing the load from the disc to the vertebra (Broberg 1983). For
example, as the hydrostatic pressure in the NP increases, this load is
transmitted to the endplate, which tends to bulge into the vertebra. For very
large axial loads, the endplate is usually the structure that fails first
(Brinckmann et al. 1983). Damage to the endplate can result in reduced
swelling pressure in the NP and increased stresses in the annulus fibrosus.
Another important feature of the endplate is the facilitation of diffusion of
nutrients into the IVD (Maroudas et al. 1975; Roberts, Menage, and Urban
1989).
 Spinal Biomechanics 49

Quantitative biomechanics regarding the endplate is lacking compared to

the NP and annulus fibrosus. For example, studies on the compressive
properties of the cartilaginous endplates have been limited to the baboon
lumbar spine (Setton et al. 1993). This particular study found that the endplate
has a hydraulic permeability associated with rapid transport and pressurization
of the interstitial fluid in response to loading and an increased emphasis on
flow-independent viscoelastic effects.

DEGENERATIVE DISC DISEASE

Characteristics of Injury

Generally, IVD failure occurs when it is exposed to loads and stresses that
exceed the strength of the tissue. Stresses to the IVD can be tensile,
compressive, or shear. Pure axial compression, even at high loads, does not
usually cause herniation of the nucleus pulposus. However, the end plate of the
vertebra is usually the first structure to fail (LIU et al. 1983).
At rest, the axial loads on the lumbar spine in vivo is 500 newtons (N)
when standing, and 700 N when sitting. These loads can increase to 3000-6000
N with moderate weights. Disc prolapse can be observed when axial
overloading is combined with bending. Although disc prolapse does not
usually occur with pure compression, cyclic overloading can cause tears in the
annulus which can lead to disc herniation (Liu et al. 1985). The IVD can also
show creep, relaxation, and hysteresis (Twomey and Taylor 1982; Kazarian
1975; Koeller, Meier, and Hartmann 1984). Hysteresis was shown to
positively correlate with load, and negatively correlate with age. Non-
degenerated discs also creep less slowly than degenerated discs which may
indicate decreased viscoelasticity in degenerating discs. It has not been
demonstrated however, that mechanical forces alone in vitro is sufficient
enough to cause disc herniation.
The functional spinal unit (FSU) has also been examined and modeled by
finite element analysis (Shiraz-Adl 1989). These studies have shown that
during compression, the load is transferred from one vertebra to another
through the end plates via the NP and the annulus fibrosus. Specifically, axial
forces causes pressure to develop within the disc, pushing structures away and
out from the center of the disc. Progressively increasing the load caused
rupture of the annular fibers posterolaterally in the innermost layer. Another
model showed that under axial compression, disc failure originated at the end
50 James Pan, Arjun V. Pendharkar and Jongsoo Park

plates and not in the annulus (Natarajan, Ke, and Andersson 1994). This
suggested that annular injuries were unlikely to be produced purely by
compressive loads, and that the presence of discrete peripheral tears may lead
to the development of concentric tears and possible acceleration of the
degenerative process.
More recently, the FSU in the context of IVD degeneration was
investigated in the presence of a compressive follower load. The results of this
study indicated that IVD degeneration led to a statistically significant changes
in segmental stiffness, range of motion (ROM), and hysteresis area in axial
rotation and lateral bending and statistically significant changes in ROM and
normalized hysteresis in flexion-extension (Zirbel et al. 2013).

Nucleus Pulposus

The molecular process of IVD degeneration is thought to start in the

nucleus pulposus which involves a decreasing concentration of proteoglycans
and a gradual change of collagen into fibrotic tissue (Haefeli et al. 2006).
These changes in effect dehydrate the NP, with water levels decreasing from
approximately 20-30% (Bibby et al. 2001). Desmoplasia of the disc results in a
stiffer NP and the shock-absorption properties of the normally hydrated
nucleus becomes severely limited. Specifically, the NP loses its hydrostatic
pressure feature as a fibrotic nucleus will not behave in the same way as a
fluid or hydrogel (Haefeli et al. 2006; Buckwalter 1995) (Figure X). The
fibrotic process is associated from a gradual loss of proteoglycan and a
transition of collagens from Type II to Type I (Roughley 2004; Buckwalter
1995). This leads to a fibrous and solid tissue mass (Iatridis, Setton,
Weidenbaum, and Mow 1997a; Stokes and Iatridis 2004) which amalgamates
into one solid phase with the anulus fibrosus in up to 75% of cases shown in
one cadaveric study (Haefeli et al. 2006). The loss of proteoglycans decreases
the swelling pressure in the NP, which is the main load-bearing mechanism in
the normal NP (Urban and McMullin 1988).
Fibrotic causes in the NP causes the shear stiffness to increase, the
pressure to decrease, the compression stiffness to increase, and the
permeability to decrease (Iatridis et al. 1996; Urban and McMullin 1988).
Swelling pressure can decrease to 0.03 MPa or less which represents 15-30%
of normal pressures (Nachemson and Morris 1964; Wilke et al. 1999; Sato,
Kikuchi, and Yonezawa 1999). Despite the fact that fibrosis increases with
degeneration and that the behavior of the NP becomes more solid-like,
 Spinal Biomechanics 51

osmometry and mechanical compression tests still suggest that even in the
context of degeneration, the swelling component still remains the dominant
property in the overall function of the NP (Urban and McMullin 1985) (Figure
5).

Annulus Fibrosus

Degeneration of the annulus fibrosus is characterized by disorganization

of collagen fibers, and perturbations in the elastic response (Schollum,
Robertson, and Broom 2010; Wagner and Lotz 2004). Defective annulus tissue
also exhibits a two-fold increase in the toe-region modulus in tensile testing
and fiber realignment towards the loading region, the prior of which was
positively correlated with age (H. A. L. Guerin and Elliott 2006; O’Connell,
Guerin, and Elliott 2009). Dynamic viscoelastic testing has also revealed that
the dynamic modulus of the annulus increases with degeneration at tensile
strains greater than 6% (Sen et al. 2008). Other studies have also shown that
degeneration has a strong effect on other elastic properties such as Poisson’s
ratio, failure stress, and strain energy density of the annulus (Acaroglu et al.
1995; Galante 1967). Permeability of the annulus has also shown to be
affected by generation, age, and water content in the disc and these properties
have been incorporated in a finite element simulation (Gu et al. 1999;
Natarajan, Williams, and Andersson 2006).
Similar to NP degeneration, the swelling pressure of the annulus also
decreases dramatically from 0.13 MPa to 0.05 MPa (Iatridis et al. 1998; Best
et al. 1994). The permeability of the annulus is also affected by degeneration
as the radial permeability decreases and the axial and circumferential
permeabilities increase (Gu et al. 1999). This combination of decreased
swelling pressure and altered permeabilities results in transfer of a
compressive load onto the solid matrix, which is likely to accelerate
degeneration due to mechanical wear-and-tear and an altered cellular response.
The compromised swelling pressure is compensated in part by an increase in
the stiffness of the solid matrix from 0.5 MPa to 1.1 MPa (Iatridis et al. 1998;
Best et al. 1994), which can be due to an increase in density after dehydration,
increased collagen cross linking, and cellular remodeling in response to the
perturbations in loading mechanics.
Although the lamellar structure of the annulus makes it somewhat resistant
to mechanical failure, fatigue loading, or extremely high loads can
compromise the structural integrity of the annulus (Green, Adams, and Dolan
52 James Pan, Arjun V. Pendharkar and Jongsoo Park

1993; Iatridis and ap Gwynn 2004). The tensile properties of the annulus also
change with aging and degeneration, however, it is not as significant when
compared to gross anatomical perturbations. In the degenerate annulus, failure
stress, strain energy density, and Poisson’s ratio are significantly lower
(Acaroglu et al. 1995). The toe region in the stress-strain curve is also
perturbed with degeneration (H. A. L. Guerin and Elliott 2006). Overall, these
changes causes the annulus to fail at lower stresses and can contribute to IVD
injury.

Endplate

The endplates show three major failure patterns: central, peripheral, and
the complete endplate (Perey 1957). Central failure in non-degenerate discs is
associated with excessive loading caused by forces transmitted by the NP
under compressive loads. Peripheral failure is observed in degenerate discs
when the NP loses its hydrostatic pressure and most of the compressive load is
transmitted through the annulus fibrosus. This causes peripheral loading of the
endplate and can result in fracture. In general, the central portion and superior
aspect of the endplate is weaker than the peripheral regions and the inferior
endplate (Grant, Oxland, and Dvorak 2001). More degeneration is seen with
decreased failure properties in the bony endplate, but stiffness is not affected
(Grant et al. 2002).

Degeneration Cascade

The degeneration of the aging spine has been categorized into three stages
by Yong-Hin and Kirkaldy-Willis (Yong-Hing and Kirkaldy-Willis 1983). The
first stage is known as the dysfunction stage which is associated with synovial
reaction in the dorsal joints and small tears in the IVD. These changes are a
result of natural age-related load bearing and wear-and-tear degeneration of
the disc. This eventually progress to the destabilization stage, which is
characterized by a loss of disc high and load-bearing capacity of the disc,
resulting in an increased load to the zygapophyseal joints. This increase in
transmitted load can lead to joint capsule laxity and the subluxation of the
joints. Anterior translation of the rostral vertebral body with the caudal
vertebral body can occur as a result of this instability. These movements of the
vertebral body can result in narrowing of the neural foramina and the
 Spinal Biomechanics 53

weakened joints result in an ever increasing load applied to already damaged

discs, thus accelerating the process.
The restabilization stage occurs as a result of joint instability and bony
movement. Osteophyte formation is observed between vertebral segments
which combined with further degeneration and calcification can lead to fusion
of the intervertebral level and loss of joint function. Although the motion
segment becomes stabilized, the IVD essentially loses its functional
characteristics, and represents the endpoint of the degenerative process.

Relationship to Back Pain

The lumbar intervertebral discs are supplied by a variety of nerves,

notably receiving contributions from the sinuvertebral nerves, the ventral
primary rami, and the recurrent branches of the rami communicantes (Bogduk,
Tynan, and Wilson 1981). In the normal disc, only the superficial layers of the
annulus fibrosus have sensory nerve endings, which achieve a depth of 3 mm
and only involve the outer three lamellae (Roberts et al. 1995; Palmgren et al.
1999). However, in degenerative discs, nerve fibers have been observed to
extend deeper — extension up to the inner third of the disc has been seen in
50% of painful degenerative discs (McCarthy et al. 1991). The ectopic nerve
growth has been observed growing in a perivascular pattern, suggesting that
they were induced by granulation tissue growing into the degenerative disc.
Moreover, it is also thought that nerve fibers cannot withstand the high
pressure environment of the normal disc, however, with the loss of pressure in
degenerative discs, nerve fibers and capillaries are allowed to proliferate
(Adams 2004).

Figure 5. Loss of Swelling Pressure Alters the Biomechanical Properties of IVD.

54 James Pan, Arjun V. Pendharkar and Jongsoo Park

Histological analysis of the degenerate disc showed substance-P and

vasoactive intestinal polypeptide associated with granulation tissue which
extended deep into the disc (Peng et al. 2005). Nerve histology was consistent
with fibers associated with nociceptive function, and in one study,
mechanoreceptors were found in 50% of patients with degenerative discs and
back pain (Roberts et al. 1995). This suggests that in the presence of
degeneration, the neural microenvironment is perturbed towards proliferation
of sensory receptors such as Golgi tendon organs and Ruffini endings.
Furthermore, exposed nuclear material is known to irritate the spinal nerve
roots and possibly the sinuvertebral nerve, and inflammatory processes
associated with degeneration can further cause granulation tissue
accumulation, neovascularization, and nerve invasion (Kuslich, Ulstrom, and
Michael 1991; Olmarker et al. 1995).

CONCLUSION
The intervertebral disc is a dynamic structure which plays an essential role
in mitigating compressive loads sustained during upright posture and weight
bearing activities. It is a complex structure with each unique component
contributing to the overall function of the disc. Degenerative disc disease,
either from normal aging, or from exposure to excessive loads cause changes
both on the microscopic and anatomical level. These changes perturb the
biomechanical properties of the IVD and because each part of the disc is
intricately linked, failure of one component can lead to a degenerative cascade
which cause gross functional and anatomical changes to the spine.

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Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 4

CERVICAL STENOSIS

Thomas Kosztowski1, MD, Adetokunbo Oyelese2, MD,

PhD and Ziya Gokaslan2,, MD
1
Department of Neurosurgery, Johns Hopkins University School of
Medicine, Baltimore, Maryland, US
2
Department of Neurosurgery, Warren Alpert Medical School of Brown
University, Providence, Rhode Island, US

ABSTRACT
Cervical stenosis involves the narrowing of the spinal canal in the
cervical spinal region. Cervical spondylosis is oftentimes used
synonomously with cervical stenosis, but spondylosis implies age-related
degeneration of the spine including congenital spinal stenosis,
degeneration of intervertebral discs resulting in focal stenosis, and
hypertrophy of spinal elements resulting in narrowing of the spinal canal.
One of the most debilitating conditions associated with cervical stenosis
is cervical spondylotic myelopathy. Multiple treatments including
surgical and non-surgical options are available. However, once symptoms
of cervical spondylotic myelopathy are severe, surgery becomes
necessary to treat the cervical stenosis.


Corresponding author: Ziya Gokaslan ([email protected]), Department of
Neurosurgery, Warren Alpert Medical School, Brown University, Providence, Rhode
Island.
64 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

Keywords: cervical spondylotic myelopathy, cervical stenosis, cervical

spondylosis, anterior cervical disketomy and fusion, posterior cervical
decompression and fusion

INTRODUCTION
Cervical stenosis results from a narrowing of the spinal canal. This can
occur secondary to a multitude of conditions, but most commonly, it is related
to degenerative diseases of the spine. Cervical spondylosis is used
interchageably with the term cervical stenosis, but it is important to understand
that spondylosis implies widespread age-related degeneration of the spine.
This chapter will focus on cervical stenosis related to degenerative processes.
Cervical spondylosis can ultimately lead to cervical spondylotic myelopathy
(CSM) and it is the most common cause of myelopathy and spinal cord
dysfunction in patients older than 55 years [10].

CAUSES
Multiple different degenerative conditions lead to cervical spondylosis and
subsequent stenosis. Some patients are born with congenital stenosis of the
cervical spine predisposing them to cervical spondylotic myelopathy. But for
most, cervical stenosis results from the accumulation of degenerative changes.
Degeneration of the intervertebral discs can lead to protrusion or herniation of
disc material resulting in focal stenosis. Hypertrophy of the articular facets,
ligaments, lamina, or even dura can also result in stenosis (Figure 1). With
regards to the ligaments, hypertrophy of the ligamentum flavum can lead to
worsened stenosis in neck extension due to the buckling of the ligament. This
has been demonstrated on cadaveric and MRI studies [37]. Anterior to the
spinal cord, ossification of the posterior longitudinal ligament (OPLL) may
also contribute to stenosis often times involving multiple levels. Herniated disc
material may often times be seen in combination with osteophytic spurs.
Subluxation secondary to facet joint and disc degeneration may also result in
cervical stenosis. Severely spondylotic levels can eventually lead to
autofusion, which can result in hypermobility at adjacent spinal segments and
subsequent narrowing of the spinal canal. If the vertebral bodies lose height,
this can result in telescoping of the spine and shingling of the laminae.
 Cervical Stenosis 65

Loss of cervical lordosis is also a significant contributor to cervical

stenosis and cervical spondylotic myelopathy. Thus, as the cervical spine
straightens out or even becomes kyphotic, the spinal cord is forced against the
vertebral bodies inducing anterior cord pathology and increasing the
longitudinal cord tension on the spinal cord, which is tethered by the dentate
ligaments and cervical nerve roots. Over time, as the curve of the spinal
canal deviates further away from its natural lordotic curvature, the anterior
and posterior margins of the cord compress, and the lateral margins expand
(Figure 2) [2].

PATHOPHYSIOLOGY
Musculoskeletal structures that bear weight, such as the cervical spine, can
develop spondylitic (osteoarthritic) changes. These spondylytic changes result
in hypertrophy of osteophytes, articular facets, and ligaments, which narrow
the spinal canal. Cervical stenosis can be accompanied by axial neck pain and
radiculopathy. However, myelopathy is the most important and potentially
most dangerous complication of cervical stenosis that the physician must be
aware of.
Cervical myelopathy that results from cervical stenosis in the cervical
spine is known as cervical spondylotic myelopathy (CSM). Myelomalacia
demonstrating cord signal changes on MRI is the radiographic counterpart of
myelopathy. The primary pathophysiological mechanism resulting in
myelopathy is static mechanical compression of the spinal cord resulting in
increased spinal cord tension and reduced vascular supply [40]. There is also a
dynamic component involved from repeated microtrauma from segmental
instability. Patients with cervical spinal stenosis are also at higher risk of
developing myelopathy or deterioration of already existing myelopathy in the
event of hyperextension of the neck [57].

CLINICAL PRESENTATION
The majority of people greater than 50 years of age will have radiologic
evidence of degenerative disease of the spine, however, only a small number
actually experience pain and/or neurologic symptoms. The signs and
symptoms related to cervical stenosis may be characterized as nerve root
66 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

compression, spinal cord compression, and idiopathic pain of the head, neck
and shoulders.

Figure 1. Cervical Stenosis.

Figure 2. Spinal Cord Changes.

Nerve root compression may be related to cervical stenosis, and the

offending element (e.g., herniated intervertebral disc) causes stenosis of both
the spinal canal as well as the neural foramen. This may result in weakness of
the muscles of the arms (C5-T1 innervation) in the affected myotomes. It may
also result in paresthesia or hyperesthesia in the affected dermatomes. In fact,
sensory involvement is more common than motor or reflex changes.
Patients with cervical myelopathy often present with paresthesias,
dyskinesias, or weakness of the upper or lower extremities. Other symptoms of
cervical myelopathy include upper motor neuron involvement, including
hyperreflexia, gait problems, balance difficulty, bladder dysfunction, and loss
of dexterity. The Nurick classification scheme is an important score for
evaluating the severity of cervical spondylotic myelopathy ranging from zero
to five: grade 0, for only nerve root symptoms or normal; grade 1, for evidence
 Cervical Stenosis 67

of spinal cord compression but no gait problems; grade 2, for gait difficulty
but able to fulfill activities of daily living (ADL’s) and employment; grade
3, for gait difficulties affecting employment but the patient not requiring
any assistance with ambulation; grade 4, if the patient requires assisted
ambulation; and grade 5, if wheelchair bound (Table 1) [41]. The Ranawat
clinical grading system is a similar score for assessing cervical myelopathy,
but it is used in rheumatoid arthritis patients [43]. The Japanese Orthopedic
Association proposed a scale for cervical myelopathy that has been utilized
heavily in clinical studies because it is able to assess the four functions that are
most commonly affected in cervical myelopathy: motor strength in the upper
extremities (including dexterity), motor strength in the lower extremities
(including ambulatory status), sensation, and bladder function [21]. The JOA
scale is based on a seventeen point scale, with seventeen indicating normal.
However, a limitation of the scale in its application to Western cultures was
that it assesses manual dexterity with use of chopsticks. Thus, modified
versions have been proposed so that the scale is more applicable to Western
cultures. A very important scale that is heavily used today is the modified
Japanese Orthopedic Association scale (mJOA) [3]. There are a few versions
of the mJOA. One version was proposed by Benzel et al. (Table 2), whereas
another was proposed by Chiles et al. [8]. In the version proposed by Benzel et
al., the ability to button a shirt is used to substitute for chopstick handling,
whereas the version proposed by Chiles assesses the ability to handle a knife
and fork.
There is variation in regards to the progression of CSM [9, 30]. In almost
75% cases, patients experience exacerbations interrupted by periods of stable
neurologic function, which can last years in some cases. Another 20% of
patients experience a steady disease progression. Only 5% of patients suffer
from a rapid progression of CSM.

Table 1. Nurick Disability Classification for Cervical Spondylotic

Myelopathy [41]

Grade Description
0 Root signs and symptoms, but no spinal cord involvement
1 Normal gait, signs of spinal cord involvement
2 Mild gait involvement, able to work employed still
3 Gait abnormality that prevents employment
4 Able to ambulate only with assistance
5 Wheelchair-bound or bedridden
68 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

Table 2. Modified Japanese Orthopedic Association Scale (Benzel version)

for Cervical Spondylotic Myelopathy Functional Assessment [3]

Score Definition
Motor dysfunction score of the upper extremities
0 Inability to more the hands
1 Inability to eat with a spoon, but able to move hands
2 Inability to button shirt, but able to eat with spoon
3 Able to button shirt with great difficulty
4 Able to button shirt with slight difficulty
5 No dysfunction
Motor dysfunction of the lower extremities
0 Complete loss of motor and sensory function
1 Sensory preservation without the ability to move the legs
2 Able to move the legs but unable to walk
3 Able to walk on flat floor with a walking aid (e.g., crutch or cane)
4 Able to walk up and/or down stairs with hand rail
5 Moderate to significant lack of stability, but able to walk up and/or down
stairs without hand rail
6 Mild lack of stability but walks with smooth reciprocation unaided
7 No dysfunction
Sensory dysfunction score of the upper extremities
0 Complete loss of hand sensation
1 Severe sensory loss or pain
2 Mild sensory loss
3 No sensory loss
Sphincter dysfunction score
0 Inability to micturate voluntarily
1 Marked difficulty with micturition
2 Mild to moderate difficulty with micturition
3 Normal micturition

RADIOGRAPHIC EVALUATION
Although cervical x-rays were performed in the past, they serve little
utility in the diagnosis and evaluation of cervical stenosis today. The primary
imaging modalities in the evaluation of cervical stenosis are magnetic
resonance imaging (MRI) and computed tomography (CT) imaging.
MRI is the most helpful diagnostic modality in the evaluation of stenosis.
It is able to capture many of the pathologies that contribute to canal stenosis,
especially soft tissue pathology. It also can rule out other pathologies such as
 Cervical Stenosis 69

tumor or Chiari malformation. When assessing for degenerative changes, the

MRI should be evaluated for herniated discs encroaching on the spinal canal or
the neural foramina. MRI can identify hypertrophic ligamentum flavum or
PLL causing compression on the spinal cord. In the case of OPLL, a
hypertrophic PLL may be seen, but CT is helpful in visualizing the
calcification in the ligament and making the diagnosis. MRI is able to provide
essential information about the spinal cord including signs of edema, spinal
cord atrophy, demyelination, and syringomyelia. It can be used to evaluate the
degree of spinal cord compression by assessing the cord ratio, CSF
effacement, and the degree and extent of myelomalacia. Hyperintense signals
on MRI may be indicative of spinal cord edema and neuronal death. These
signal changes are known as myelomalacia. Myelomalacia findings on MRI
have been found to be associated with a higher degree of clinical disability and
are a poor prognostic factor that the patient will experience neurologic
recovery following surgery [34, 36]. Spinal cord signal changes should be
scrutinized as this will influence whether a patient will need surgery and how
soon. Furthermore, MRI allows the evaluation of extent of compression (how
many levels are involved) and whether the pathology is primarily anterior,
posterior, or both in relation to the spinal cord. Studies have shown that
normal mid-sagittal spinal canal diameter measures about 17 mm in depth
whereas the normal average spinal cord diameter is 8-13 mm in the
anteroposterior plane [12, 39]. Soft tissue structures, including the anterior and
posterior longitudinal ligaments and the ligamentum flavum, can add an
additional 2-3 mm to the spinal canal contents [5]. Relative stenosis is
narrowing of the canal to 13 mm, whereas absolute stenosis is classifies as
narrowing of the spinal canal to 10 mm [13]. If there is a contraindication to
obtaining an MRI, then a CT myelogram can be performed.
CT myelography may be very useful in situations that a patient cannot
undergo an MRI. This study can find if there are focal areas of stenosis and if
there are levels of myelographic block. CT may also be useful in the
evaluation of cervical stenosis in regards to the bone elements. It is able to
provide spinal canal dimensions and suggest spinal canal or neural canal
stenosis based on the measurements of the boney structures but it is not helpful
in evaluating the extent that neural structures are affected by the stenosis. CT
can also be very helpful in differentiating osteophytes from herniated discs,
both of which may look alike on MRI. Like MRI, CT can also evaluate the
coronal and sagittal alignment of the cervical spine, although standing plain
films are most appropriate for evaluating global spinal balance.
70 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

TREATMENT OPTIONS
The physician must carefully consider both the clinical presentation as
well as the radiographic imaging to determine whether a patient can be
managed conservatively or requires surgery. Radiographic findings may not
always correlate with the clinical picture, and, thus, a patient may have very
concerning radiographic findings without severe clinical symptoms or signs.
Furthermore, spondylotic changes may be present in up to 60% of
asymptomatic individuals depending on age [4, 54].

Non-Surgical Options

Non-operative treatment options are reserved for patients primarily

complaining of neck or radicular pain without any neurologic deficits or
radiographic signs of myelopathy. There have been many studies that have
studied the role of surgery or conservative management in the setting of
asymptomatic cervical spondylotic myelopathy despite radiographic evidence
of severe stenosis [23, 48]. Kadanka et al. performed a prospective,
randomized and blinded clinical study of patients with non-progressing or very
slowly progressing mild and moderate forms of CSM (mJOA score C 12
points). Patients were randomized into two treatment arms: 1) conservative
and 2) surgical. At 10-year follow, the authors suggested that conservative and
surgical treatment in mild and moderate forms of CSM had not shown, on
average, a significant difference in outcomes such as modified Japanese
Orthopedic Scale (mJOA) and in subjective evaluation of the patients
themselves [23].
Prolonged immobilization with rigid cervical bracing is occasionally
utilized to reduce neck movement with the hope of reducing trauma to the
cervical spine. Patients may also be recommended to reduce their activity and
eliminate “high risk” activities. Lastly, patient may also try anti-inflammatory
medications to see if there is any benefit to the neck pain. In formulating a
management strategy, patient factors such as level of activity, age, and risk of
injury should be considered in formulating a management plan.
 Cervical Stenosis 71

Surgical Options

Surgical intervention is the appropriate treatment for advanced cases of

CSM with severe symptoms. Patients who develop moderate to severe
symptoms of CSM are unlikely to experience regression of their myelopathy.
Surgical intervention is considered to alter the natural progression of the
disease and prevent further neurologic deterioration. Progression of symptoms,
presence of myelopathy for more than 6 months, transverse area of the spinal
cord less than 40 mm2, and compression ratio approaching 0.4 are all poor
prognostic factors that conservative treatment will be successful [29]. These
factors are indicators for surgical management [29]. The goals of surgery are
to decompress the spinal cord, stabilize the spinal column, and re-establish
normal sagittal alignment. Preoperative findings that have been found to be
associated with successful surgical outcome include younger age at
presentation, presence of Lhermitte sign, presence of unilateral symptoms,
duration of symptoms less than a year, and pathological involvement limited to
fewer levels [35]. Surgical decompression helps to alleviate preoperative pain
and paresthesia associated with CSM [15]. Anterior and posterior surgical
approaches may be used depending on the pathology and its association to the
spinal cord [14]. Other factors that influence whether an anterior and/or
posterior approach is appropriate include the number of levels involved, the
patient’s overall medical status, and the overall alignment and mobility of the
spine.

Anterior Surgical Options

Anterior pathologies such as herniated discs, spondylotic bars, and

uncovertebral osteophytes can contribute to spinal stenosis in the cervical
spine. The anterior approach can be used to directly ventrally decompress the
spinal cord and nerve roots. In regards to anterior approaches, anterior cervical
discectomy and fusion (ACDF) is commonly the procedure of choice
especially when the source of stenosis is discogenic and restricted to one or
two levels (Figure 3) [27, 56]. Some argue that ACDF should be restricted to
the treatment of cervical spondylosis of no more than 3 levels. With more
extensive compression, posterior procedures should be used [56]. Furthermore,
sagittal alignment abnormalities resulting in loss of normal cervical lordosis or
kypothic deformity are indications for an anterior approach [50, 52]. Anterior
cervical corpectomy and fusion (ACCF) may be considered in cases of more
72 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

extensive compression to the spinal cord along with focal kyphosis in that
segment of the cervical spine (Figure 4). Thus, the anterior approach allows
direct decompression of ventral compressive pathology, fusion of instable
segments, and possible restoration of the cervical lordosis.
The literature suggests that ACDF is associated with good outcomes for
patients with CSM. As high as 90% improvement in overall neurologic
outcome and functional status have been observed [55, 59]. In regards to long-
term outcomes, Irvine and Strachan retrospectively evaluated patients who had
undergone ACDF for CSM with an average of ten years follow-up and found
that at last follow-up, 78% of the patients had improved ambulation. Only 9%
of patients experienced progression of symptoms [22]. In regards to fusion,
autologous bone graft remains the gold standard for fusion in ACDF. An 85%
fusion rate was observed when autogenous bone graft was used, whereas a
50% fusion rate when allograft was used [59]. However, autologous bone graft
harvest has been associated with a significant morbidity rate of 20% including
hip fracture, hematoma, seroma, infection, and meralgia paresthetica [51]. This
has resulted in the preferred use of allogeneic bone graft.

Figure 3. Anterior Cervical Discectomy and Fusion (ACDF).

 Cervical Stenosis 73

Figure 4. Anterior Cervical Corpectomy and Fusion (ACCF).

Figure 5. Anterior Cervical Disc Arthroplasty (ACDA).

Another option with increasing popularity is anterior cervical disc

arthroplasty (ACDA) (Figure 5). ACDA has been demonstrated to improve
clinical outcomes and segmental motion with long-term follow-up [6]. ACDA
efficacy has been demonstrated in clinical outcomes, stability, and
preservation of index level motion [16, 38]. It has been suggested that anterior
fusion may increase the stresses at adjacent levels and thus accelerate adjacent
segment disease, whereas total disc replacement (TDR) better preserves
motion at the index level [11, 47]. However, thus far, studies comparing
ACDF to ACDA have not found any significant difference in adjacent
74 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

segment disease after surgery [6, 33]. Problems like heterotopic ossification,
implant migration, device wear and failure, and segmental kyphosis are
potential complications [31, 42].

Figure 6. Open Door Laminoplasty (ODL) and French Door Laminoplasty (FDL).

Figure 7. Facet Resection Over Twenty Five Percent.

Posterior Cervical Approaches

The posterior approach has proven to be a safe and effective option in the
surgical treatment of CSM (Figures 10, 11, 12). It is indicated for congenital
OPLL, ossification of the ligamentum flavum, congenital cervical stenosis,
multilevel spondylosis, and posterior compression by a hypertrophied and in-
folding ligamentum flavum. The posterior approach provides for direct and
indirect compression of the neural elements. If the elements contributing to
CSM are ventral to the spinal cord, a posterior decompression indirectly
decompresses the spinal cord. In other situations where myelopathy is a
 Cervical Stenosis 75

consequence of congenital stenosis or posterior compression from redundant

ligamentum flavum, the posterior approach allows the surgeon to directly
decompress the spinal cord. In order to decompress posteriorly, it is important
that the preoperative cervical spinal alignment be neutral or lordotic to allow
for posterior translation of the spinal cord after decompression [1]. Some argue
that a cervical lordosis of at least ten degrees should be present if posterior
decompression is to be considered [17].
Laminectomy is the most common means of decompressing the spinal
cord from a posterior approach. It is indicated in cases of multi-level
compression in elderly patients or patients with multiple comorbidities.
Patients must also have some cervical lordosis as instrumentation can only
correct alignment to a certain degree. Laminectomies are performed with
decompression to the extent of the junction between the lamina and the lateral
mass. Decompression should include all levels that exhibit stenosis on
imaging. It has been reported that there is no benefit to limiting the number of
levels decompressed when it comes to development of post-laminectomy
kyphosis or instability [24]. There are increased rates of recurrent symptoms
resulting from disease progression at adjacent segments not involved in
the initial decompression [25]. Instrumentation may be necessary after
laminectomy. Factors that influence the need for posterior cervical
instrumentation include focal and/or iatrogenic instability and flexible
kyphosis. Instrumentation is used to stabilize the spine until a mature bony
fusion mass forms. Posterior instrumentation helps maintain cervical lordosis
and decreases the chances of post-laminectomy kyphosis [19, 28].
Studies have demonstrated that laminectomy is an effective procedure in
the treatment of elderly myelopathic patients found to have multilevel cervical
spondylosis and lordotic cervical alignment. In one study by Snow and
Weiner, of 90 patients who were treated with laminectomy, 77% had
neurologic improvement, 13% remained unchanged, and 10% had neurologic
deterioration [49]. In another study of 32 patients treated with multi-level
cervical laminectomies and instrumented fusion, Huang et al. found a post-
operative improvement in Nurick score of at least one grade in 71% of patients
[20]. In the study, the other 29% experienced no improvement in Nurick score,
and no patients experienced deterioration in the Nurick score.
Laminoplasty is another option of attaining decompression posteriorly,
while maintaining cervical alignment and stability through preservation of the
posterior spinal elements. Laminoplasty may avoid the potential complications
related to instrumented fusion including implant malposition and/or failure and
adjacent segment accelerated degeneration. Laminoplasty is indicated in
76 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

congenital stenosis, OPLL, multi-level disc herniations, and spondylosis.

However, the spine should be in a neutral or lordotic cervical alignment.
Numerous laminoplasty techniques have been described, including French-
door [53] and open-door laminoplasty techniques (Figure 6) [18]. All these
techniques involve decompression of spinal canal stenosis through the
expansion of the posterior arch with preservation of the posterior elements and
of segmental motion. With preservation of the posterior tension band,
laminoplasty is rarely associated with iatrogenic instability. Studies have
demonstrated a 54% improvement in the JOA scores of patients who
underwent laminoplasty. However, with this technique, one must be mindful
of closure of the laminoplasty [46], continued thickening of the ligamentum
flavum [46] and of an ossified OPLL [26] that may lead to neurologic deficits
from root or cord irritation/injury [45].
If the patient has nerve root symptoms, selective foraminotomies may be
performed. In cases of selective nerve root compression from lateral herniated
disc without any spinal cord compression, foraminotomies may be considered.
However, selective posterior foraminotomies had been reported to have
reoperation rates of 18.3% and 24.3% at 2 and 10 years, respectively [7].
Studies suggest that when ACDF and posterior cervical foraminotomy are
compared, the reoperation rates are statistically equivalent [32]. It must also be
noted that if too aggressive of a facet resection is performed that
foraminotomy may result in post-operative instability eventually and require
fusion [58]. Thus, it is imperative to try to limit facet resection to no more than
25% of the joint to preserve stability (Figure 7) [44].

Figure 8. C5-6 Foraminal Narrowing, A-P view.

 Cervical Stenosis 77

Figure 9. C5-6 Foraminal Narrowing, R-L view.

CONCLUSION
Cervical stenosis may eventually lead to spondylotic cervical myelopathy.
Once patients develop severe enough symptoms and signs, operative
management is necessary. Several options exist with the anterior and posterior
surgical approaches. The chosen procedure should be tailored to the individual
patient’s pathology targeting the areas of spinal cord and nerve root
compression. The goal of surgery should be to halt further neurologic
deterioration while preserving the sagittal balance of the spinal column.
Further research is necessary to better understand and treat cervical
spondylotic myelopathy as a result of cervical stenosis.

Figure 10. Posterior cervical-thoracic segmental fixation.

78 Thomas Kosztowski, Adetokunbo Oyelese and Ziya Gokaslan

Figure 11. Posterior cervical-thoracic segmental fixation.

A 44 year-old man originally presented with acute onset left-sided upper

extremity numbness and weakness. The patient’s clinical picture appeared
consistent with cervical myelopathy and a left-sided C6 radiculopathy.
Imaging studies reportedly demonstrated large disk herniation with significant
compression of the spinal cord. The patient had an anterior cervical
discectomy and implantation of an artificial disk device at the C5/6 level at
another hospital. Following the surgical procedure, the patient felt better for a
week, but afterwards, the patient’s symptoms recurred.
He presented to our clinic with worsening symptoms, not only on the left,
but also on the right side. He also had some paresthesias in both upper
extremities as well. The patient exam demonstrated left-sided upper extremity
weakness with 4/5 strength in the biceps and dorsiflexion of the wrist
consistent with left-sided C6 radiculopathy. The patient also had exaggerated
reflexes except for the left knee jerk, which was absent. The clinical picture
was consistent with myelopathy.
The patient’s MRI of the cervical spine demonstrated myelomalacia on the
left side of the spinal cord, as well as significant left-sided C5-C6 foraminal
narrowing (Figures 8, 9). Imaging studies demonstrated evidence of
osteophyte formation immediately behind the artificial disk at the C5-C6 level,
with ventral compression of the spinal cord as well as dorsal compression of
the spinal cord at the C6-C7 levels posteriorly.
We recommended a surgical procedure, involving a two-stage anterior-
posterior 360 degrees operation. The patient underwent a two-stage surgery.
The first stage was performed through an anterior approach. The motion-
preserving spacer at C5/6 was removed. Partial corpectomies of C5 caudally
and of C6 rostrally were done to aid in the removal of the motion-preserving
 Cervical Stenosis 79

spacer. The spinal cord and the bilateral nerve roots of C6 were decompressed
bilaterally. Anterior reconstruction was performed using a cage with
demineralized bone matrix, and a variable angle plate was placed. The second
stage was performed through a posterior approach. Laminectomies were
completed at C5, 6, and 7. A left-sided laminoforaminotomy was performed to
decompress the tight C6 nerve root. Posterior cervical-thoracic segmental
fixation was placed from C4-T1 using cervical lateral mass screws and
thoracic pedicle screws (Figures 10, 11). Autologous bone harvested during
the laminectomy was utilized for posterior cervical-thoracic fusion.
The patient did well after surgery. Post-operative MRI demonstrated
excellent decompression of the spinal cord (Figure 12). The patient’s motor
exam improved to full strength, and he had resolved pain. At 10-months post-
op, the patient had achieved solid bony fusion.

Figure 12. Post-Operative MRI.

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 5

THORACIC DISC HERNIATIONS

Nathan E. Simmons, MD1,

Division of Neurosurgery, Dartmouth Hitchcock
Medical Center,Lebanon, NH
1
Department of Neurological Surgery, Stanford University School of
Medicine, Stanford, California

ABSTRACT
Thoracic disc herniations occur less frequently than cervical or
lumbar herniations, yet are common enough that surgeons should
understand management strategies. Preoperative assessment of the size,
location, presence of calcification, and spinal level are all important
factors for deciding upon a surgical approach. While some disc
herniations will require anterior approaches, these are typically associated
with higher levels of morbidity and lengthier hospital stays, suggesting
posterior approaches, when feasible, offer better outcomes. In most
surgeries, the need for fusion is low but the final decision needs to be
tailored for the individual patient.

Keywords: thoracic herniated disc, thoracotomy, lateral extracavitary,

transpedicular, costotransversectomy


Correspondence to: Nathan E. Simmons ([email protected]) Department of
Neurosurgery, Dartmouth-Hitchcock Medical Center. One Medical Center Dr, Lebanon,
NH 03753.
88 Nathan E. Simmons

INTRODUCTION
Thoracic disc herniations comprise but a small portion of the total
spectrum of degnerative spine conditions managed by surgeons. However, due
to their location and variable presentation, they require as much, if not more,
evaluation and strategic planning for successful operative intervention.
As opposed to the cervical and lumbar regions which experience a greater
range of motion and force, the thoracic spine is relatively immobile due to its
minimal anatomic curve and the presence of supporting skeletal elements such
as theribcage and sternum. Consequently, the development of degenerative
conditions such as herniated discs are much less frequent in the thoracic spine.
Estimates suggest symptomatic thoracic herniated discs occur in one out of
every 1,000,000 people [14, 18]. This translates to 0.15-4% of all surgical
procedures for degnerative spinal conditions [22]. Therefore, while
uncommon, spinal surgeons will undoubtedly encounter patients with
symptomatic thoracic discs and need to understand the salient features of their
management.
The thoracic region shares elements of both the cervical and lumbar area
when considering surgical approaches. While the anatomy of the spinal
column is similar to the lumbar region, the presence of the spinal cord
complicates and limits posterior approaches. In the cervical region, this
hindrance is managed by commonly addressing the degnerative disc via an
anterior approach. However, unlike the cervical region, anterior approaches in
the thoracic spine are much more involved and potentially morbid.
Consequently, complication rates for thoracic disc surgery are higher than
those for cervical or lumbar regions (Figure 1) [17].
A variety of anterior, posterior, and posterolateral vectors have been
developed for the surgeon, each offering unique benefits and disadvantages.
Likewise, the development of more minimally invasive has also been
efficacious in the management of these conditions. This chapter will attempt to
review these indications and surgical approaches.

Symptom Presentation

As in the cervical spine, patients can present with either or both of the
following: radicular symptoms with more laterally located herniated discs
compressing the exiting nerve roots and/or myelopathic findings associated
with spinal cord compression in central disc hernations. Given that most
 Thoracic Disc Herniations 89

thoracic herniated discs occur centrally or centrolaterally, it is not unsurprising

that most patients will harbor some form of motor weakness (55 - 61%) and/or
sensory deficit (61 - 64%) [15]. While bowel/bladder impairment is possible,
these symptoms are seen in only a minority of patients [15].

Figure 1. Anatomy of the Thoracic Spine.

It is noteworthy to consider axial pain and the presence of a herniated

thoracic disc. Asymptomatic thoracic herniated discs can be discerned on
imaging in 10-37% of random MRIs [12]. However, Stillerman has shown that
a significant percentage of patients improve with respect to axial pain
following treatment of thoracic herniated discs [15]. The correlation bewteen
axial back pain and degenerative/herniated discs is problematic for patient and
surgeon alike and will require individualized analysis.

Preoperative Management

One of the most important aspects of preoperative evaluation for these

patients is the determination of the exact level of the pathology. For example,
when a radiology report indicates the T9-T10 level, the surgeon will need to
know how this level was labeled and whether that method can be simulated in
the operating room. Generally, a lower level thoracic process can be counted
from the sacrum. This will require assessment of whether or not transitional
90 Nathan E. Simmons

vertebrae exist in the lumbar spine. Likewise, if the body habitus is favorable,
upper thoracic lesions can sometimes be counted caudally from the cranium
and cervical spine. However, midthoracic lesions (and potentially any thoracic
level depending on habitus) may require intraoperative anterior/posterior x-
rays for localizationg and, thus, the surgeon needs to verify the presence or
absence of cervical ribs and/or the vertebral count from whatever reference
point which appears reproduceable.
In addition to the radiologic assessment of the level, the type of imaging
also needs to be reviewed. Most surgeons will assess surgical patients based
on MR images. However, given the surgical approach options, disc hernations
laying with the anterolateral canal can be accessed through posterior,
posterolateral, and anterior approaches. Often a key determinant is whether or
not the disc herniation is calcified as calification increases the difficulty in
removing disc herniations through posterior trajectories (Figure 2).
Occasionally, the surgeon should consider obtaining preoperative CT to better
assess for calcification. Softer discs can often be teased safely through
posterior approaches while calcified discs often require more aggressive
curettage and potentially drilling. If the disc is causing spinal cord
compression, this may often be the deciding factor in addressing the lesion
anteriorly.

Figure 2. Calcified Thoracic Disc.

Neuromonitoring must also be considered in the preoperative planning. If

the herniated disc lays within the foramen, monitoring may not be necessary as
spinal cord manipulation will be minimal. However, if the disc is more
centrally located and spinal cord manipulation may be necessary, it would be
 Thoracic Disc Herniations 91

prudent to consider neuromonitoring. As such, preoperative testing of motor

evoked potentials and somatosensory evoked potentials will give the operative
team a baseline from which to compare any changes. While obviously not a
guarantee of spinal cord injury avoidance, monitoring can serve as a useful
tool to avoid unnecessary manipulation of the cord.

Surgery

In the operating room, a number of tenets will aid in the successful

management of thoracic herniated discs. As mentioned earlier, localization is
of prime importance in these cases. Various techniques have been reported for
direct localization of levels including dye, PMMA vertebroplasty, Gugliemi
coils, percutaneous wires [21]. However, these require the patient to undergo
an additional procedure and probably are only needed in uncommon situations
where traditional images might be difficult. Typically, thoughtful use of
conventional xrays without markers will suffice.
Borrowing a rule from carpentry, the surgeon would be wise to “measure
twice and cut once.” As such, the patient will need to be positioned for ideal
imaging. Lateral approaches lend themselves to anterior/posterior (A/P)
radiographs, thus the surgeon should be ready and comfortable with counting
ribs and have similar preoperative studies by which to compare. In the prone
position, one may be able to count from cervical or lumbar references if the
disc herniation is close to these junctions and the patient’s body habitus
allows. However, sometimes the surgeon will need to obtain A/P or P/A
imaging. This would necessitate placing the patient on an operating
table/frame suited for through-table imaging (Figure 3).
Neuromonitoring will need to be performed in many such cases.
Anesthesia will need to rely primarily on total intravenous anesthesia (TIVA),
propofol/narcotics and limit paralytics to only the period around induction. In
addition, medications causing for decreases in cardiac output should be used
cautiously for fear of compromising spinal cord perfusion during the
operation. Neuro-anaesthesiologists will be familiar with these requests but
surgeons should review goals of the anasthesia prior to induction.
Prior to incision, the patient is often bolused with intravenous steroid in
order to prevent spinal cord injury. Blood pressure should be closely managed
as the perfusion of the spinal cord can be limited from the herniation and
subsequent surgical manipulation. Zuckerman, et al., reported on three patients
in which a decline in mean arterial pressure was folllowed by worsened
92 Nathan E. Simmons

electrophysicalogical monitoring [23]. Recommendations vary, but mean

arterial pressure should be mantained above at least 70-80 mmHg, though it
also has been suggested above 90mmHg. Zuckerman, et al., uses a strategy of
maintaining the mean arterial pressure at least 10% above baseline pre-
induction levels [23].
Operative approaches (detailed descriptions of the approaches can be
found at the respective references)

Figure 3. Lateral Positioning.

Posterior midline:

Figure 4. Transpedicular [16].

 Thoracic Disc Herniations 93

Figure 5. Transforaminal/Transfacet pedicle sparing [16].

These approaches are likely the most commonly used methods for thoracic
disc surgery. Detailed descriptions of the techniques can be found elsewhere.
Briefly, these procedures typically employ a midline incision on a prone
patient. The ipsilateral musculature is elevated off the spinous processes,
laminae, and facets. The transpedicular approach (Figure 4) starts with a
lateral laminotomy, usually performed with a combination of a high speed drill
and 1 and 2mm Kerrison rongeurs. As the lateral dura is identified, the medial
facet joint is similarly removed and the exiting nerve root and pedicles are
exposed. The high speed drill is used to drill into the medullary bone of the
inferior pedicle, thinning the cortex medially and superiorly. This allows the
surgeon to then fracture this portion of the pedicle laterally (away from the
cord), thus developing a greater working space to the disc lying just above the
pedicle. Disc herniations within the lateral canal can then be mobilized with
down biting currettes and removed safely with rongeurs.
The transfacet/transforaminal technique (Figure 5) represents a slight
refinement of the transpedicular route in which the pedicle is spared. As the
facet joint overlies the foramen and disc, pedicle removal is not mandatory.
This technique requires drilling through the facet, avoiding the pedicle, and
working in the disc space adjancent to the exiting nerve root. Usually the nerve
root exits throught the superior portion of the foramen, enabling a working
corridor just inferior for disc retrieval.
Posterior lateral:
94 Nathan E. Simmons

Figure 6. Costotransversectomy approach [8].

These approaches commonly employ a lateral incision (hockey stick,

curivilinear, or straight) in order to allow for a shallower viewing angle toward
the disc space (Figures 6 and 7). Each requires resection of the lamina, facet,
transverse process, and rib/costovertebral joint. The major difference between
these two proceudres is the amount of rib resected, with the lateral
extracavitary approach resecting a larger amount of rib. Given the larger
incisions and more extensive tissue dissection, these procedures typically
create more postoperative pain and also bring forth the potential for
inadvertent thoracic cavity entry as the pleura will require dissection from the
rib before rib removal. Lubelski, et al., compared the two procedures in a
restrospective review and noted a trend toward greater blood loss and length of
stay in the lateral extracavitary group. However, complications proved similar
in both groups, though the authors noted that both these procedures were
inherently risky [8].

Figure 7. Lateral extracavitary approach [8].

 Thoracic Disc Herniations 95

Kshettry et al. recently published a cadaveric study quantifying the

exposures obtained of the ventral spinal canal in various posterior approaches.
[7] Their findings also drew attention to the fact that a given approach may
have better exposure in certain regions of the spine than others, For instance,
the lower thoracic spine typically has straighter pedicles which place the facet
joints in a more medial location. Thus a transfacet approach in the lower spine
may result in less ventral visualization than in the upper thoracic spine. The
transpedicular approach provided superior visualization to the facetectomy
only in the T1-2 and T11-12 regions. Similarly, the lateral extracavity
approach gave a significant benefit over the costotransversectomy only in the
T7-T10 location. While these measurements were only from cadaveric
specimens, it emphasizes the variability of anatomy in the thoracic spine and
the need for the surgeon to discerningly review the images in order to plan the
best surgical approach.

Anterior/Anterior-lateral:

Figure 8. Transsternal or Modified Sternotomy approach [5].

96 Nathan E. Simmons

Figure 9. Transthoracic approach [20].

Figure 10. Retropleural approach [10].

Anterior approaches are typically reserved for large, central, and/or

calcified herniations that require additional mobilization than can be offered
 Thoracic Disc Herniations 97

through posterior access. The transsternal approach (Figure 8) is used

exclusively in the upper thoracic region for rare herniations in the T1-T5
region. In the mid to lower thoracic region, anterior approaches are usually
approached on the left side so as to avoid the vena cava, thoracic duct, and
liver.
While the anterior approach offers the benefit of accessing the disc space
directly and mobilizing the herniation away from the neural structures, the
surgery is nevertheless a significant undertaking for patient and surgeon, alike.
Yoshihara and Yoneoka reviewd data from the National Inpatient Sample and
concluded a significant increase in morbidity associated with anterior
approaches for thoracic disc herniations [22]. In their review, they
demonstrated a significant increase in complications (particularly pulmonary),
hospital length of stay, and hospital costs for anterior apporaches. Similarly,
Arts and Bartels reviewed 100 consecutive patients undergoing either a mini-
transthoracic discectomy or transpedicular discectomy and concluded the
former was associated with a longer surgical time, lengthier hospital stay,
increased blood loss, and higher complication rate [3]. While both studies are
limited by selection bias, they suggest that while necessary in some situations,
herniated discs not mandating an anterior approach are probably best
addressed from posterior corridors.
Minimally Invasive:

Figure 11. Video assisted thoracoscopic procedure [1].

98 Nathan E. Simmons

Figure 12. Tubular retractor [4, 11, 13].

As with many surgical procedures, an increasing emphasis on “minimal

invasive” procedures is growing within the treatment of thoracic disc
herniations. The first of these procedures involved modifying the techniques of
thoracic surgeons in using video-assited thoracoscopic surgery (VATS)
(Figure 11). As with thoracoscopic or general endoscopic surgeries, the patient
will require multiple small incisions for camera and working port access sites.
As the thoracic cavity is entered, these patients will require postoperative chest
tubes in most cases.
Though a number of surgeons have shown excellent results with
thoracoscopic surgery, most surgeons are unfamiliar with these instruments
and techniques [2]. The learning curve for such a procedure is very steep and
likely can only be maintained by surgeons in facilities with relatively high
volumes of such pathology. Not surprisingly, thoracoscopic techniques are
practiced by a relatively small number of surgeons.
 Thoracic Disc Herniations 99

Surgeons have since adopted tubular retractors from the lumbar spine to
the thoracic spine. (Figure 12) The tubular retractor systems offer the benefit
of minimal incision length, familiarity with approach and instrumentation, and
avoidance of thoracic cavity complications. A number of successful techniques
have been reported using tubular retractors including the use of primary
microscopic views, endoscopic views through the retractor, transfacet
approaches, and even lateral extracavitary tubular approaches [4, 11, 13].
Uribe and colleagues have modified the McCormick’s retropleural approach
with the introduction of a “mini-open” approach utiliziing a smaller incision
and retractor blades from lumbar approaches [19]. These approaches will need
to be further evaluated for their efficacy in treating thoracic herniated discs
and for incorporation into mainstream surgical techniques.

To Fuse or Not to Fuse?

The thoracic spine is unique in that it has a greater inherent stability owing
to the presence of the ribs/sternum and a minimal curvature. As a result, the
majority of thoracic discectomies, both posterior and anterior, do not require
fusion. While some surgeons advocate for the routine use of fusion so as to
eliminate the risk of postoperative instability, the fusion can bring with it the
risk of hardware failure/pseudoarthorsis, misplaced hardware, and longer
operative times for the patient. Therefore, the surgeon can most likely defer on
a fusion following thoracic discectomies unless there exists significant
abnormal alignment (scoliosis, exaggerrated kyphosis), osteoporosis, or an
overly aggressive bone removal during the surgery. Krauss, et al., reviewed 18
patients having undergone transthoracic discectomies and demonstrated that
none developed a kyphosis nor scoliosis at the operative site with a follow-up
of 22 months [6]. While not randomized, the suggestions through case series
and clinical observations are that most discectomies, anterior or posterior, can
be safely performed without fusions.

Complications

Durotomy
Cerebrospinal fluid (CSF) leaks during posterior/posterolateral surgeries
are managed similarly to lumbar and cervical procedures. When possible, the
dural violation is directly sutured and tissue, synthetic pathches, and/or glue
100 Nathan E. Simmons

can be used to augment a closure. In cases where the dural injury is not well
visualized, an indirect repair may need to suffice with an onlay patch of
tissue/synthetic material, carefully administered glue along the gutters, and a
meticulous fascial closure. Lumbar drainage can also be considered for the
early postoperative period.
Dural leaks during anterior procedures pose a much greater challenge. The
risk of a leak during an anterior procedure may be greater due to the selection
bias for larger and more calcified disc hernations. Direct dural closures are the
ideal solution but are more often technically challenging due to the depth of
anatomy and the method of surgery (thoracoscopic, tubular retractor). Again,
indirect closure is often employed yet in these cases and a thoracic fistula can
complicate the postoperative course. In cases of CSF leak, a postoperative
chest tube can be placed to water seal to prevent fistula formation and the use
of a lumbar drain can additionally promote adequate closure.

Intercostal Neuralgia

A thoracic radiculopathy is not uncommonly encountered after anterior

approaches. Most of these will resolve, however, in some cases, the patient
will complain on ongoing pain that can be debilatating. Strategies to avoid
intercostal nerualgia have included care in the dissection of the neuro-vascular
bundle off the rib, watching for of excessive retraction against the underside of
the rib, and avoiding resection of the rib head at the entry site for mini-open
procedures [17]. In the event of intercostal neuralgia, pain specialists can often
perform percutaneous blocks and/or radiofrequency ablations to lessen the
pain.

CONCLUSION
Given their infrequent presentation, thoracic disc herniations offer a range
of challenges and surgical approaches for the surgeon to consider. Most spine
surgeons need not be experts in all these methods but need to know of the
options and maintain a variety of mastered techniques by which to address
these lesions.
 Thoracic Disc Herniations 101

CHECKLIST FOR THORACIC DISC SURGERY

Preoperative

o Confirming level and verifying intraoperative counting strategy

o Assessment of calcification
o Estimating access via posterior/anterior approaches
o Baseline MEP/SSEP
o OR table selection (AP vs lateral imaging)
o Consideration of preoperative marking for incision
o Need for fusion
Perioperative

o Arterial line for maintenance of MAP > 80mmHG

o Steroid administration
o Imaging modality
o Neuromonitoring

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[2] Anand, Neal, and John J. Regan. 2002. Video-assisted thoracoscopic
surgery for thoracic disc disease. Spine. 27: 871-879.
[3] Arts, Mark P. and Ronald H.M.A. Bartels. 2013. Anterior or posterior
approach
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Sean S. Armin, Vartan Tashjian, and Baron Zarate. 2011. Minimally
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[13] Smith, Justin S., Kurt M. Eichholz, Stephen Shafizadeh, Alfred T.
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[15] Stillerman, Charles B, Thomas C. Chen, William T. Couldwell, Wei

Zheng, and Martin H. Weiss. 1998. Experience in the surgical
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[17] Strom, Russell G., Vin Marthur, Heather Givans, Douglas S.
Kondziolka, and Noel I. Perin. 2015. Technical modifications and
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[19] Uribe, Juan S., William D. Smith, Luiz Pimenta, Roger Härtl, Elias
Dakwar, Urvij M. Modhia, Glen A. Pollock, Vamsi Nagineni, Ryan
Smith, Ginger Christian, Leonardo Oliveira, Luis Marchi, and Vedat
Devieren. 2012. Minimally invasive lateral approach for symptomatic
thoracic disc herniation: initial multicenter clinical experience. Journal
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[20] Vollmer, Dennis G. and Nathan E. Simmons. 2000. Transthoracic
approaches to thoracic disc herniations. Neurosurgical Focus. 9: 1-6.
[21] Yoshihara, Hiroyuki. 2014. Surgical treatment for thoracic disc
herniation. Spine. 39: E406-E412.
[22] Yoshihara, Hiroyuki, and Daisuke Yoneoka. 2014. Comparison of in-
hospital morbidity and mortality rates between anterior and nonanterior
approach procedures for thoracic disc hernation. Spine. 39: E728-E733.
[23] Zuckerman Scott L., Jonathan A. Forbes, Akshitkumar M. Mistry,
Harish Krishnamoorthi, Sheena Weaver, Letha Mathews, Joseph S.
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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 6

SURGICAL MANAGEMENT OF
CERVICAL DISC HERNIATION

Vinod K. Ravikuzmar1,2, BS, Jennifer L. Quon2, MD,

Allen L. Ho2, MD and Ali K. Ozturk3*, MD
1
Department of Neurosurgery, New York Medical College,
Valhalla, New York, US
2
Department of Neurological Surgery, Stanford University School of
Medicine. Stanford, California, US
3
Department of Neurosurgery, University of Pennsylvania Perelman
School of Medicine. Philadelphia, Pennsylvania, US

ABSTRACT
Cervical disc herniation (CDH) occurs with regular frequency and is
the most common indication for cervical spine surgery. While
conservative treatment is the first line of defense when managing CDH,
severe cases may be treated with anterior, posterior, or combined
approaches. Choice of an approach is dependent on careful synthesis of
symptoms, exam findings, and imaging results by the surgeon. Studies
offer conflicting views regarding which approach results in superior
outcomes. The eventual decision on surgical approach, if determined to
be necessary, must be individually tailored for each patient.

*
Corresponding Author address. Email: [email protected]. Washington Square West
Building, 235 South 8th Street, Philadelphia, PA.
106 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

Keywords: cervical herniated disc, ACDF, arthroplasty, decompression,

foraminotomy, disc replacement

INTRODUCTION
Cervical disc herniation (CDH) is a source of neck and arm pain whose
incidence peaks in the sixth decade of life [30]. The etiology of CDH is
multifactorial, and known risk factors include lifting heavy objects, cigarette
smoke, select occupations, and the male gender. Certain studies report that
CDHs occur in 19 out of every 100,000 people, making it a relatively
prevalent source of spinal cord and nerve root compression [39]. Most patients
experience either neck or arm pain, accompanied by motor weakness in the
upper extremity as well as sensory symptoms (e.g., tingling) presenting in a
dermatomal distribution [4].
The pathophysiology of cervical disc disease is related to continual
mechanical stress and the wide range of motion of the cervical spine that leads
to overstretching of the annulus fibrosis leading the annular tears and
intradiscal tissue displacement. The horizontal fissures are the primary sites of
these changes, which lead to disc protrusions in the direction of the neural
foramen. Large disc protrusions occur predominantly in younger patients
given that elderly individuals tend to have desiccated disc tissue that were less
likely to protrude.
Conservative therapy of CDH should be attempted for six to twelve weeks
before surgery is considered [4]. However, if the patient presents with a loss of
significant motor function or signs of myelopathy, surgery may need to be
performed more urgently.
Despite its prevalence and potential for progression of severe symptoms
over time, the clinical course of CDH is largely not understood [30]. Since it is
difficult to characterize, CDH treatments and prognosis of these interventions
are difficult to predict. Successful identification of risk factors and addressing
problems before severe symptoms manifest is thus the preferred solution. This
chapter will attempt to review all aspects of CDH care, beginning with
diagnosis and conservative treatment options, and terminating with an analysis
of various possible surgical approaches to treat the condition.
 Surgical Management of Cervical Disc Herniation 107

DIAGNOSIS

Symptoms

CDH results from protrusion of the intervertebral disc centrally into

the spinal canal causing cervical myelopathy or laterally into the foramen
causing radiculopathy. The three main clinical symptoms associated with CDH
are pain, radiculopathy, and myelopathy. Pain associated with cervical
syndrome is typically sudden onset, positional, and worse at night. Axial
pain can originate from the sinuvertebral nerve innervating the disc, PLL,
and meninges, or from the dorsal primary ramus innervating the facets
[1, 2]. Radicular pain and symptoms result from nerve root irritation from
foraminal disc herniation and can include upper extremity pain, diffuse
weakness/numbness of the hands, sometimes in a dermatomal distribution,
problems with gait and balance, fine motor impairment, as well as noticeable
clumsiness. When CDH causes narrowing of the spinal canal or cervical
stenosis, myelopathy symptoms typically develop insidiously manifesting as
weakness and spasticity of all extremities, gait imbalance, loss of dexterity, or
autonomic dysfunction of the bowel and bladder [9].

Exam

The signs can vary widely in CDH patients: motor weakness, hyper or
hypo-reflexia, Hoffmann’s or Babinski reflex, inversion of the brachioradialis
reflexes, crossed radial reflexes, or clonus. The onset of problems is often
sudden for radiculopathy but can be more insidious with myelopathyand
caused by direct impingement of nerve roots and the associated inflammation
[43].

Imaging

CDH can be seen on plain radiographs, myelography, computerized

tomography (CT) or magnetic resonance imaging (MRI). Myelograms can
directly demonstrate compression of the nerve or its root. Radiographs may
indirectly demonstrate pathology via osteophytes, a decrease in disc height
between vertebra, or protrusions/extrusions of calcified disc. MRI is useful for
its high soft tissue resolution and multi-planar images and is currently the most
108 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

frequently used modality in the diagnosis of CDH [44]. It can be utilized to

identify herniated disk fragments as well as compressed nerve roots. It can
also determine the amount of degeneration and the level of fibrosis of the disc
[5].
While MRI is superior for soft tissue anatomy, CT imaging is the
preferred modality for demonstrating the bony anatomy, calcification/
ossification, gas within the herniated disc space, or dural indentation. Thus,
CT and MRI have complimentary roles and the clinician should have a low
threshold to order both if necessary.
Kuijper et al. estimate that 89.7% of patients with radiculopathy present
with parasthesias, whereas 24%, 15.3%, and 64.2% of patients present with
sensory loss, weakness, and hypoactive tendon reflexes, respectively. Even
when a patient does not present with one of the classic symptoms physical
exam findings alone cannot rule out CDH [19].

CONSERVATIVE TREATMENT
Conservative treatment is recommended for patients in the absence of
neurologic deficit and/or intolerable pain and discomfort. Non-medical
therapies such as heat packs, soft collars for comfort, and positional and
activity changes to limit mechanical stress on the neck can be powerful
adjuncts. Patients should avoid heavy lifting, spinal vibration-inducing
activities such as running and prolonged neck extension. Medications such as
NSAIDs, ibuprofen, COX-2 inhibitors, or oral steroids may reduce
inflammation in the area of disc herniation, and are widely considered a first
line treatment for pain management of CDH. Physical therapy can
complement medical therapy and help reduce pain and increase mobility.
Epidural steroid injections (ESI) can also be considered if the prior first line
treatments are ineffective, and the patients’ symptoms relatively mild.
For patients with more severe CDH with significant neurologic deficit or
myelopathy, surgical treatment is recommended. Surgical options can be
categorized into the anterior, posterior, and combined approaches.

ANTERIOR APPROACHES
Anterior approaches for treating CDH include anterior cervical
discectomy and fusion (ACDF) and cervical disc replacement (CDR). The
standard anterior approach involves dissection, discectomy, and grafting. This
 Surgical Management of Cervical Disc Herniation 109

approach is utilized primarily when there is stenosis at three or fewer cervical

levels or when the patient presents with a kyphotic deformity. It is overall
considered to be a safe procedure with successful symptomatic relief.

Anterior Cervical Discectomy and Fusion (ACDF)

Smith and Robinson were the first to apply the anterior approach to the
cervical spine, using an iliac crest bone graft to replace the removed disc. In
essence, the ACDF involves removing the offending intervertebral disc via
discectomy and inserting a spacer to allow for spinal fusion. Driven by the
poor prognosis of posterior approaches in treating posterior osteophyte nerve
root compression, they were pleased to find that the ACDF was associated
with less mortality, less disruption of the spinal canal, and better fusion at the
pathological intervertebral region. Since then, modifications of Smith and
Robinson’s basic principles have enhanced the efficacy of the ACDF. For
example, the Cloward technique is very similar to Smith-Robinson’s, but
modifies the decompression to focus on direct anterior decompression of
central or lateralized pathology and he was the first to advocate for allograft
fusion [14, 36] (Figure 1).
Anterior cervical plates provide sufficient anterior stability and mobility
without the need for posterior stabilization, optimize conditions for
arthrodesis, and are highly efficacious in the setting of multi-level fusions [7].
Plates have been associated with the development of dysphagia, esophageal
injury, as well as adjacent level ossification, including osteophyte formation
and ligament ossification. These adverse effects may be largely minimized
with proper plate placement, as well as continued advancements in plate
technology [7]. The lower profile of newer anterior plating systems minimizes
esophageal trauma and post-operative swallow difficulties. Internal fixation
with plates and screws may also be a source of hardware failure if arthrodesis
is not achieved. Hardware breakage can occur as a result of differences in
tensile strength and elasticity between the bone and hardware. Depending on
the extent of hardware failure, it may be necessary to re-operate and remove
the broken construct, particularly if the patient has recurrent neck pain and a
non-union is present. Smaller locking screws prevent the plate from causing
spinal cord damage by obviating the need for bicortical fixation and have
decreased screw backouts and subsequent esophageal damage. Dynamic plates
allow for the appropriate distribution of stress onto bone as well as a reduction
in screw loosening and breakage. This leads to earlier bony fusion by
110 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

providing stress shielding onto the bone graft [3]. Finally, resorbable plates
have demonstrated improved hardware longevity and stress distribution
compared to metal plates, and are a promising therapy for the future.

Figure 1. Anterior Cervical Discectomy and Fusion (ACDF) via Cloward technique.
A) Axial view of ACDF anatomic exposure. B) Operative view of ACDF Cloward
technique exposure and disectomy.

An ideal graft should exhibit osteogenesis, osteoconduction, and

osteoinduction. Currently only a few types of grafts demonstrate all three of
these characteristics [37]. Grafts should be at least 7mm in height and 2 mm
greater than the original disc height to allow of restoration of prior normal disc
height. Autografts have been traditionally considered the gold standard graft
due to high fusion rates. However, they are associated with donor site
morbidity, additional OR time and issues with variable patient bone quality.
Donor site complications have lead to a morbidity rate of 20% of higher [33].
and can include, myalgias, paresthesias, hematomas, hip fractures, and
infections [28, 33]. Allografts avoids issues of donor site morbidity, is more
readily available, and lead to decreased blood loss and operative times.
Demineralized Bone Matrix (DBM) is another type of allograft that requires a
synthetic cage or mineralized allograft to support the disc space. Xenografts
such as bovine bone exhibits biocompatibility problems, creating
complications that can sometimes lead to repeated operations. Besides a lower
rate of fusion compared to autografts, other significant risks of allograft
 Surgical Management of Cervical Disc Herniation 111

include immunologic reaction, necrosis of graft, fracture, or delayed

union/non-union [24]. Pseudarthrosis or an irreparable bone fracture, can
occur in approximately 2-20% of procedures, thus requiring revision typically
from a posterior approach [11, 32]. However, when utilized in conjunction
with cervical plate fixation, fusion rates are comparable to autograft [31].
Finally, ceramics can also be utilized as graft material and are advantageous in
that they avoid donor site morbidity, have sufficient biocompatibility, and
have no inherent risks of infection or disease transmission. Hydroxyapatite and
tricalcium phosphate are the most widely used and demonstrated favorable
fusion rates and outcomes [8, 46].
Cages also can preserve and augment disc height and improve cervical
lordosis without the risk of donor site morbidity and complications [32]. They
are typically made with stainless tell, titanium, tantalum, or synthetics, and are
especially useful in multi-level fusions that involve corpectomies. They can,
however, cause a delay in fusion, which may subsequently lead to nonunion
and kyphosis due to cage migration, subsidence, and loss of lordosis [16].
Cages also have some potential magnetic artifact, which may decrease
imaging visualization [12]. In addition, ceramic materials including tricalcium
phosphate or calcium hydroxyapatite can be used that are cost effective,
biocompatible, and present almost no infection risk. Though initially
problematic because of fracture risk and slippage, modern ceramics have
minimized these risks. Bone morphogenic protein (BMP) is no longer
approved in the anterior cervical spine due to concerns with ectopic bone
formation, dysphagia, and severe edema. However, utilization of autologous
cancellous bone packed into cages can obviate the risk of donor site
complications and have demonstrated comparable fusion rates to autografts
[16, 38]. Advances in technique have chiefly involved the development of
novel grafts and spacers to improve fusion.
There are also synthetic materials that can be used in place of autografts
and allografts. For example, interbody spacers, such as those made from
porous tantalum, polyether-ether-ketone (PEEK), and the zero-Profile (Zero-P)
anchored spacer, are becoming increasingly popular. These cages are typically
box shaped within which cancellous autobone, DBM or ceramics can be
packed. In a recent study, Vanichkachorn et al. demonstrate that the use of
PEEK interbody spacers in single-level ACDF produces a high rate of fusion
without the associated complications of allografts [37]. Further, Cho et al.
demonstrate the potential of Zero-P for lowering the failure rate of ACDFs [6].
More recently, microdiscectomy and endoscopic techniques have been
pioneered as minimally invasive strategies to improve patient outcomes [42].
112 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

Full endoscopic cervical discectomy (FECD) can involve either an anterior or

posterior approach tailored to the offending pathology. FECD is thought to
have less soft tissue damage, faster rehabilitation, as well as fewer and easier
surgical revisions when compared with more invasive decompressive
techniques. Therefore, FECD is not only a good stand-alone treatment,
but may also be beneficial as a supplement to conventional procedures
[42]. Other noninvasive techniques include the cervical microendoscopic
foraminotomy/discectomy (CMEF/D) and the cervical microendoscopic
decompression of stenosis (CMEDS) [15]. When the canal diameter is
decreased at the level of the midvertebral body or the compression extends
beyond the disc space, corpectomy should be implemented following
discectomy in order to remove the offending vertebral body. Cages are often
helpful in these scenarios in order to help maintain and restore cervical
kyphosis lost with corpectomies.

Surgical Approach and Considerations

Positioning for the anterior cervical approach should take into account the
angle of the disc space to be fused. The head and neck should be supported
and hyperextended if possible (if there is no concern about posterior
instability) by raising the height of the shoulders with supports. Depending on
the level, mobilizing the shoulders as far inferior as possible may help
optimize visualization of the lower cervical levels. There is considerable
debate regarding optimal side of approach for the anterior approach [21-23,
25, 26]. The anatomically variant course of the recurrent laryngeal nerve is on
the right, thus a left side should be protective against nerve injury. However,
many surgeons are right handed and prefer approaching from the right. The
thoracic duct is also located on the left side, thus, a right-sided approach can
avoid a chylothorax complication [14]. Still others suggest allowing pathology
to dictate side of approach, that is, approaching from the side opposite the
compressive pathology for ease of access.
With respect to avoiding nerve and esophageal injury and devastating
vocal cord paralysis, many of these injuries occur as a result of retraction and
recognition of the structures held in retraction for exposure is critical.
Releasing intubation cuff pressure periodically and use of blunt versus sharp
dissection during exposure is prudent to avoid complications. After
localization of desired level with XR fluoroscopy, an incision made along a
convenient skin crease is preferred for a better cosmetic result. A horizontal
 Surgical Management of Cervical Disc Herniation 113

incision along the skin crease is adequate for exposure of multiple cervical
levels, if necessary. After dividing the skin and subcutaneous fat layer, the
platysma is encountered and divided horizontally. Deep cervical fascia
enveloping the sternocleidomastoid muscle (SCM) laterally and the omohyoid
muscle deep to the SCM. This deep cervical fascia must be released in order to
mobilize the trachea and esophagus medially. Often times, the omohyoid
muscle may need to be divided with impunity for adequate exposure. The
carotid pulse is palpated with a finger laterally and blunt dissection of the deep
cervical fascia is completed medial to the carotid and lateral to the trachea and
esophagus until the anterior vertebral bodies are felt. The alar fascia attaching
the trachea and esophagus is divided and the longus colli muscles are
visualized.
The mid-point between the longus colli approximate the mid-line and the
longus colli are dissected off the vertebral bodies via cautery. The target disc
space is then identified and confirmed with fluoroscopy and soft tissue
dissected off the anterior portion of the target vertebral bodies for fusion. Self-
retaining cervical retractors are utilized to maintain retraction soft tissue
structures and are typically anchored under the longus colli muscles. These
retractors optimize the operative window for the discectomy and ensure
adequate protection of soft tissue structures from injury. The annulus of the
disc is incised and the discectomy completed in standard fashion with a curette
or high-speed drill if necessary for hard disk with exposure, incision, and
resection of the PLL if possible to ensure optimal posterior decompression.
Direct visualization of the dura after removal of the PLL ensures complete
removal of soft disc herniation. Resection of disc material within the uncal-
vertebral joints with Kerrison rongeurs is also essential to relieve radicular
compression and a small blunt probe should the utilized to inspect the neural
foramen to ensure adequate nerve root decompression.
At this point, several different options exist for interbody grafting or
placement of a cage (especially following a corpectomy) as discussed above.
The plating options are also various, but generally both interbody graft or cage
and anterior plates are implanted to maintain or restore disc height, avoid
foraminal stenosis, cervical kyphosis, maintain anterior cervical stability, and
promote bony fusion across levels.
114 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

Disc Replacement – Arthroplasty

Cervical disc arthroplasty (CDA) is a form of total disc replacement that

arose as a motion-preserving alternative treatment to ACDF [20, 22]. With
standard anterior fusion there is decreased motion of the fused segments,
which increases the stress on the adjacent levels, with leads to adjacent
segment disease overtime. Disc replacement via CDA allows for preservation
of motion at the disease level to decrease stress at adjacent levels and
avoidance of adjacent segment disease. First described by Fernstrom with a
steel ball design, [13]. the designs have evolved significantly to include ball-
and-trough, semi-constrained metal endplate-on-polyethylene insert, or cross-
linked polyethylene annulus design. These differing designs allow for
rotational and translational movements while at the same time mimicking
the 'cushion' of a IVD with prosthetic annulus and nucleus. Indications for
CDA include single or two-level disc herniations and spondylosis with
radiculopathy and/or myelopathy. Contraindications include pre-operative
instability, facet join arthritis, osteoporosis, previous local infection or
ankylosis. Hu et al. demonstrate in their long-term meta-analysis that CDA
resulted in superior outcomes compared to ACDF with regards to neurological
outcomes, improvement in pain symptoms, number of follow-up procedures,
and the rate of adverse events [20]. Conflicting studies, however, make it
difficult to determine differences in cost-effectiveness and quality of life
between these two treatments [21, 27]. Improvements or maintenance of
sagittal balance with CDA was similar to ACDF [29]. Disc replacement can be
complicated by migration of the prosthesis, ossification, kyphosis, and failure
of the device. In fact, severe heterotopic ossification in a subset of cases may
restrict range of motion (ROM) and cause pain [20, 47]. Prostheses are
currently being tested and implemented alongside arthroplasty in order to
improve clinical and radiological outcomes [22, 25].

POSTERIOR APPROACHES
Posterior approaches to CDH treatment involve decompression,
disc removal, and cervical fusion. The earliest cervical spine operations
were performed posteriorly, prior to the development of anterior techniques.
Posterior approaches may lead to more post-operative pain due to dissection
of the paraspinal muscles and therefore longer hospital stays. Complications
 Surgical Management of Cervical Disc Herniation 115

from posterior approaches are often related to positioning and can

include ocular injury, postlaminectomy kyphosis or instability, air embolism,
pseudomeningoceles, vertebral artery injury, or brachial plexopathies. Cervical
laminectomy can also lead to a C5 or C6 nerve radiculopathy due to traction of
the extradural components of the roots following shift and expansion of the
cord after decompression. Nonetheless, posterior approaches are particularly
relevant for treating patients with extensive cervical lordosis, pathology
located dorsal or lateral. Many suggest that lordosis should be a prerequisite
for a posterior approach in order to facilitate spinal cord movement away from
anterior structures. Posterior approaches are relatively straightforward and
avoid many of the critical structures encountered in an anterior approach.
Patients are positioned prone and three-pin Mayfield fixation is used to
position the head in a tucked fashion. A neutral or lordotic position should be
assumed and over flexion avoided if a fusion is being performed. Fluoroscopy
can help identify the relevant level. Palpation of the spinous processes
can identify midline and dissection follows the ligamentum nuchae.
This allows minimal blood loss and minimizes dissection of the paraspinal
muscles. A bovie and Cob can be used for muscle dissection. Aggressive
devascularization or thermal damage can prevent fusion and wound healing. It
is also important to stay within the borders of the lateral masses because
beyond these borders are the venous plexi surrounding the vertebral arteries.
For closure the fascia should be reapproximated with absorbable sutures.

Decompression

Decompression-based approaches remain part of the standard for treating

cervical disk disease. They can be divided into three subtypes: laminoplasty,
laminectomy, and foraminotomy.

Laminoplasty and Laminectomy

The goals of surgery are to decompress the spinal cord at the level of
pathology. Preservation of cervical lordosis lends itself to a cervical
laminoplasty or laminectomy. These approaches allow the surgeon to
decompress at multiple levels with preservation of motion. Fusion can be
performed if there are concerns about stability. Some studies have suggested
that posterior fusions, with lateral mass screw fixation, may be prudent in all
116 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

cervical laminectomies in order to prevent such complications and post

laminectomy kyphosis.
In a laminoplasty, the vertebral lamina is cut unilaterally, creating a hinge
that widens the spinal canal and relieves pressure on the spinal cord. If
necessary, the spinous process can be extracted, and wedges can be used to
maintain the patency of the opening. Bilateral gutters are created using a high-
speed burr and kerrison rongeurs, followed by a green stick osteotomy, bone
graft insertion, and finally plate insertion for stabilization. Endoscopic
techniques can also allow for a minimally invasive technique. Patients who
have undergone a laminoplasty experience fewer complications and have
preserved cervical mobility compared to those who have undergone a
laminectomy [45]. Laminoplasty is contraindicated in patients with an ossified
ligamentum flavum, epidural scars, or pre-operative kyphosis [23].
Laminectomy, on the other hand, involves complete excision of the
posterior spinal ligament and spinous processing order to relieve pressure on
the spinal cord. As described above, the paraspinal muscles are dissected off of
the spinous process. The lateral dissection should expose the entirety lateral
masses unless instrumentation is also planned. Careful dissection of the
subperiosteal plane should be performed prior to using the drill in order to
ensure that there is no soft tissue damage. A Leksell rongeur and high-speed
bur can be used to thin the laminae and subsequently remove it en-bloc. A
small cutting bur allows the outer cortical and cancellous bone to be removed,
leaving only a thin layer of cortical bone. Notably, at the cervical levels the
dura is not protected by the ligamentum flavum at the superior extent of the
lamina. The laminae at these levels are also shingled and often the inferior
lamina of the level above must also be removed in the laminectomy.
Importantly, surgeons should be wary of placing instruments underneath bone
at the stenotic level. Intersegmental motion should be avoided in areas of cord
compression. Finally, the facets must be spared in the laminectomy so that the
spine is not destabilized, and the patient doesn’t subsequently develop a
kyphotic deformity (Figure 2).
 Surgical Management of Cervical Disc Herniation 117

Figure 2. Posterior cervical laminectomy.

Posterior Cervical Foraminotomy

Posterior cervical foraminotomy (PCF) was first described in 1944 by

Spurling and Scoville and is a motion-preserving alternative to ACDF [34].
This technique is reserved for cases of nerve root compression, rather than
myelopathy, favoring lateral disc herniations. Clinical symptoms must
correlate with radiographic findings. It is appropriate to use this approach after
conservative management has failed. Advantages to this approach are that it
does not destabilize the disk space and therefore require a fusion, and it
avoids many of the critical structures involved in anterior approaches.
Contraindications to PCF include cervical instability, posterior longitudinal
ligament ossification, cervical spine kyphosis, and axial neck pain [34].
In a posterior cervical formaninotomy, the patient is positioned either
prone or sitting, though the later is more difficult. The prone position requires
the torso to be supported with a Wilson frame, and the head is typically
stabilized with three-pin Mayfield fixation. The head should be slightly tucked
in a “military” position, and the surgeon should be cautious not to hyperextend
the neck. Intraoperative x-ray or fluoroscopy can identify the pathologic level
optimize the placement of the incision. Generally, a 1-2 inch incision allows
adequate dissection of muscle and fascia off the spinous processes as well as
minimizes the amount of muscle retraction. The medial 50% of the facet
should be exposed. A high-speed drill is used to decorticate the lamina of the
vertebral levels on the pathologic side. A kerrison or drill can be used to
118 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

remove bone, starting just medial to the junction of the lamina and the facet, in
order to expose the lateral most portion of the lamina. Removal of the superior
portion of the inferior lamina will expose the inferior pedicle. The ligamentum
flavum can be dissected with off with a nerve hook or small dissector. The
nerve root is then visualized exiting the thecal sac and the foramen is palpated
with a nerve hook. The bone overlying the nerve root is thinned with a drill.
The shell of bone can be removed with sharp curette then kerrison. These
instruments are then used to carefully decompress the nerve root by removing
the offending tissue, which often presents as bony overgrowth, ligament, or
disk overlying the dorsal surface of the nerve root. Small osteophytes
anteriorly can be carefully curetted. The bony decompression can be extended
accordingly. Typically only 30-50% of the foramen needs to be unroofed to
ensure adequate decompression. The nerve root should be palpated out
laterally and the color observed for signs of longstanding compression. Careful
hemostasis should be obtained, but care should be taken not to leave too much
hemostatic material at the site. The facia is reapproximated and the incision
closed (Figure 3).
Since its inception, PCF has developed into a minimally invasive
surgery, which has resulted in reduced blood loss, shorter hospital durations,
and decreased post-operative narcotic requirements. Minimally invasive
techniques, first implemented in 2000 have since dramatically reduced the
postoperative morbidity of posterior approaches.

Figure 3. Posterior cervical foraminotomy. A) Paramedian incision and unilateral

exposure of the lamina. B) Identification of lamina and target facet joint. C)
Facetectomy is performed. D) Removal of overlying ligamentum flavum to visualize
nerve root and ensure adequate decompression. E) Axial view of ideal foraminal
decompression of target nerve root.
 Surgical Management of Cervical Disc Herniation 119

Disc Replacement

Posterior disc replacement strategies arose as an alternative to the ACDF,

given the concerns for adjacent segment disease and post-operative dysphagia
[18, 26]. Disc replacement was originally devised in the late 1980s and
featured a metal ball-and-socket device, secured in place with screws. Over
time, a titanium alloy with a porous coating was used to facilitate bone
ingrowth. Current variants include polyethylene coats and calcium phosphate
layers.
Advantages of a posterior cervical discectomy include less destabilization
of the disc space and therefore no need for a fusion, less risk of damaging
surrounding structures, and the ability to simultaneously address foraminal
stenosis. Nevertheless, the need to dissect spinal muscle in this approach leads
to greater post-operative pain and longer recovery times.

Anterior vs. Posterior Approaches

A purely anterior or posterior approach for CDH can lead to varying

complications either in the immediate post-operative period or in the long-
term. Herkowitz et al. compared anterior and posterior approaches and
characterized disc herniations as one of two types. Type 1 represented single
level anterolateral herniations and includes patients who presented with
radiculopathies. In contrast, type 2 represented central soft disc herniations and
included patients who presented with myelopathy as well as potential upper
extremity paresthesias. Patients who were treated with anterior approaches had
better long-term outcomes than those treated with either laminectomy or
foraminotomy [17]. In contrast, Dohrmann et al. suggest that posterior
approaches had a 94% success rate at long-term follow-up compared with 80%
for anterior approaches [10].

COMBINED APPROACHES
A combination of anterior and posterior approaches has demonstrated
efficacy in treating certain pathologies. Yang et al. describe retrospective study
of patients undergoing either an ACDF or combined anterior-posterior
approaches for the treatment of CDH with concurrent ossification of the
posterior longitudinal ligament. They include 5 who underwent combined
120 Vinod K. Ravikuzmar, Jennifer L. Quon, Allen L. Ho et al.

ACDF and either single- or multi-stage posterior laminectomies and fusions.

Outcomes for the combined approach did not differ significantly from the
standard ACDF [41].
Microsurgical discectomy with laminoplasty (MDTL) is another
combined technique that was pioneered to address some of the disadvantages
of a purely anterior approach. Introduced by Fujimoto et al. in 2002, the
technique utilizes simultaneous discectomy and laminoplasty to preserve
motion in the operated spinal segments. A surgical microscope is used to
reduce the risk damaging surrounding neurological structures [35].
Another combined approach involves discectomy and nucleoplasty.
Discectomy is first performed to remove the herniated disc. The disc is
subsequently coagulated using the nucleoplasty technique [40]. Potential
complications are similar to nucleoplasty alone, and include hematoma, disc
infection, nerve damage, and equipment breakage inside the wound.

CONCLUSION
Due to their variable presentation, CDH treatment selection is highly
individualized, requiring many factors and challenges to be considered.
Though it is not necessary for all spine surgeons to be experts in these detailed
surgical methods, it is imperative to understand the fundamental differences
and advantages of each procedure.

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 7

LUMBAR STENOSIS:
PREVALENCE, RISK FACTORS, AND
TREATMENT

Daniel Shepherd1,2, MD, Panagiotis Kerezoudis1,2, MD,

Michelle J. Clarke1, MD and Mohamad Bydon1,2,, MD
1
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, US
2
Mayo Clinic Neuro-Informatics Laboratory, Rochester, MN, US

ABSTRACT
Lumbar spinal stenosis (LSS) is a clinical syndrome characterized by
buttock and/or lower extremity pain with or without back pain secondary
to degenerative spinal canal narrowing and compression of the
neurovascular elements. LSS is the most common reason for spinal
surgery in patients over 65 years of age. It results in significant pain and
disability, compromising the quality of life and everyday activities of the
affected patients. Pain is aggravated by certain postures, including
walking, standing or lumbar extension and characteristically alleviated by
recumbency, sitting and forward flexion. Initial treatment options include
conservative management such as lifestyle modification, physiotherapy,
epidural injections and medications. Very few randomized controlled
clinical trials have assessed the role and the efficacy of non-surgical


Correspondence to: Mohamad Bydon ([email protected]), Department of
Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, US.
128 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

modalities for the management of patients with LSS and therefore there is
a lack of sufficient evidence to suggest a specific method is superior.
Surgical intervention is performed when there is failure of conservative
management or neurologic emergency. Current techniques include open
or minimally invasive approaches that aim at restoring spinal canal
diameter and relieving neurovascular compromise.

Keywords: lumbar stenosis, spinal canal narrowing, aging, intervertebral disc

1. INTRODUCTION
Lumbar spinal stenosis (LSS) or lumbar stenosis is a degenerative
condition secondary to the normal aging process that affects the intervertebral
discs, the ligamentum flavum and the facet joints causing narrowing of the
spaces that surround the spinal neurovascular structures.
LSS was described back in the 1880s [1] but it was Verbiest in 1954 who
first tried to define central lumbar spinal stenosis. He reported a “particular
form of narrowing of the lumbar vertebral canal” that was not associated with
any other anomaly of the spine. He also noted that with walking and standing
these patients presented with signs of disturbance of the cauda equina: bilateral
radicular pains, disturbances of sensation and impairment of motor power in
the legs, However, when the patient was in recumbent position the symptoms
immediately disappeared. The neurological examination during testing
revealed nothing abnormal [2].
North American Spine Society defines lumbar stenosis as “a clinical
syndrome of buttock or lower extremity pain, which may occur with or
without back pain, associated with diminished space available for the neural
and vascular elements in the lumbar spine” [3].

2. PREVALENCE – EPIDEMIOLOGY
LSS is the most common indication for surgical intervention in the spine
in people older than 65 years of age [4], translating to more than 37,000
laminectomies in Medicare alone and an aggregated hospital cost of nearly
$1.65 billion [5]. It has been found that LSS affects more than 200,000 people
in the US [5].
 Lumbar Stenosis 129

According to the Framingham population study, the incidence of anatomic

spinal stenosis in people older than 60 based on cross-sectional imaging
studies, ranges between 19 to 47%. [6] Moreover, data from the National
Spine Network and the National Ambulatory Medical Care Survey, have
shown that LSS is diagnosed in 13-14% of patients with chronic low back pain
who seek a specialist’s opinion and 3-4% who see a general physician [7, 8].

3. SIGNS AND SYMPTOMS

Patients with acquired lumbar stenosis typically present in the sixth and
seventh decade of life, whereas patients with congenital lumbar stenosis
typically present in the third to fifth decade. Low back pain is one of the most
common symptoms and main reasons patients seek medical care [9–11]. Other
common sites of pain include the buttocks, the thighs and the legs. Patients
usually describe the pain as burning or cramping in nature, with symptom
varying from gradual, dull aching pain in the sacroiliac area and posterior
thighs to sharp, shooting radicular pain along the lower extremity. When
central canal stenosis is present, pain is often bilateral, but not always
symmetrical. In contrast, with pure lateral recess and foraminal stenosis, the
symptoms typically resemble unilateral radiculopathy.
Patients report symptom relief with positions that decrease lumbar
lordosis and increases central canal diameter such as sitting, squatting and
recumbency as these tend to reduce the inward buckling of the ligamentum
flavum and distract the facet joints thus enlarging the neural foramina and
relieving pressure on neurovascular structures.
The most cardinal manifestation of spinal stenosis is neurogenic
claudication. It is moderately sensitive (~60%), but highly specific for LSS.
[12] It consists of progressive onset of pain, weakness, numbness and tingling
in unilateral or bilateral buttocks, hips, thighs or legs, that is provoked by
standing and lumbar extension, aggravated by prolonged walking and
characteristically relieved by a change in posture. [13] Patients may
occasionally exhibit the “shopping cart sign,” where the patient is walking in a
flexed or a stooped position in order to relieve the symptoms. Intermittent
claudication secondary to peripheral vascular disease poses an important
diagnostic challenge, as it also presents with leg pain during walking
(Table 1). The key difference lies on whether the symptoms exacerbate with
posture versus exertion. Patients with neurogenic claudication improve with
sitting down and leaning over, whereas those with intermittent (vascular)
130 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

claudication report pain alleviation with rest. Nadeau et al. found that the
positive “shopping cart sign,” which is a constellation of symptoms, including
pain located above the knee, triggered by walking and relieved with sitting, is
highly suggestive of neurogenic claudication. (Positive Likelihood Ratio of
13) [14]. Conversely, pain located below the knees that is alleviated with
standing alone provides strong evidence of intermittent claudication (Positive
Likelihood Ratio of 20) [14].
Interestingly, the neurologic exam can be normal in up to 18% of cases,
including normal lower extremity muscle strength, normal reflexes and
negative straight leg raising test. Pain is typically reproduced by lumbar
extension and diminished knee reflexes and reduced or absent ankle reflexes
are also common finding.

Table 1. Neurogenic vs vascular claudication

Clinical Feature Neurogenic Claudication Intermittent Claudication

Pain distribution dermatomal (nerve Sclerotomal (muscle groups
distribution) with common vascular supply)
Quality of pain Shooting, electric shock- Cramping
like
Pain onset can be immediate, Gradual, consistent
inconsistent
Aggravating standing, waking, coughing fixed amount of exercise
factors variable amount of exercise
Alleviating posture-dependent sitting, posture-independent standing
factors bending over still
Sensory loss dermatomal distribution stocking distribution
Distance to Variable day-to-day Constant day-to-day
claudication
Legs affected usually both usually one
Foot pallor on none mild to marked
elevation
Peripheral pulses normal decreased or absent
Feet skin normal decreased
temperature
 Lumbar Stenosis 131

Neurological findings include motor, sensory, reflex and autonomic signs

that correspond to the level(s) of involvement [15]. The most common affected
root is the L5, followed by the L4, the L3 and the S1 [15, 16]. Bladder
dysfunction can also be seen and is most frequently encountered in the
geriatric population. Deen et al. performed two- to four- level laminectomies
in patients averaging 71 years of age for severe LSS and a variable degree of
bladder compromise. Although only 45% of patients exhibited improved
urinary function (post-void residual urinary volume, cystoscopy and
urodynamic studies) and 60% reported subjective recovery of bladder
function, the authors concluded that laminectomy can have a beneficial effect
on bladder function in patients with severe LSS [17].
In summary, LSS is a significant cause of chronic pain and disability. Its
symptoms can have significant impact on patient mobility and physical
activity. Most patients with LSS have limited walking capacity and the use of
walking aids is often necessitated. Compromised functional autonomy forces
most patients to follow a sedentary lifestyle behavior with serious
repercussions for overall health and physical performance.

4. CAUSES AND ASSOCIATED CONDITIONS

LSS can be classified into congenital and acquired (or both).

 Congenital LSS is a condition in which abnormalities during postnatal

development cause narrowing of the spinal canal [18]. According to
the Framingham study, the prevalence of congenital LSS in the
population ranges between 2.6 and 4.7% [6]. It has also been
associated with congenital spondylolisthesis and achondroplasia [19].
 Acquired LSS is the result of degenerative changes to the spine
secondary to aging. These changes include loss of intervertebral disc
height, disc bulging, facet joint hypertrophy and osteophyte formation
and hypertrophy of the ligamentum flavum. (Figure 1 and 2) Other
less common causes include trauma, excessive scar tissue after back
surgery, ankylosing spondylitis and infection [18].

It is important to mention that LSS is a process with dynamic component:

the association of symptoms with patient’s posture, such as standing, walking
and recumbency correlate with the dynamic changes in the spine. These
changes occur in a normal spines as well but in a degenerative spine with
132 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

baseline narrowing, lumbar spine extension and axial loading reduce lumbar
spinal canal diameter critically compressing neurovascular structures [20, 21].

4.1. Degenerative Spondylolisthesis

Spondylolisthesis is a degenerative spine pathology that is caused by one

vertebral body slipping forward or backward relative to the level below.
Patients are typically women (female-to-male ratio 2:1) aged 50 to 60 years
whose symptoms evolved over decades and exacerbated over months and
years. Neurological deficits late in the course and are correlated with the onset
of neurogenic claudication or radiculopathy associated with proximal
weakness or footdrop. The most commonly involved level is the L4-5,
followed by L3-4, L2-3 and L5-S1 (Figure 1a).

Figure 1a. Sagittal lumbar spine MRI without IV contrast of a 74 year old female with
a 1 year history of L5 radiculopathy. Imaging shows a marked central spinal stenosis at
L4-5. There is concurrent grade I spondylolisthesis at L4-5.
 Lumbar Stenosis 133

Figure 1b. Axial lumbar spine MRI scan without IV contrast showing severe spinal
canal stenosis at the L4-L5 level with advanced degenerative facet changes and
bilateral L4-L5 neural foraminal stenosis.

Figure 1c. Axial lumbar spine CT scan without IV contrast showing severe spinal canal
stenosis at the L4-L5 level with advanced degenerative facet changes and moderate
bilateral L4-L5 neural foraminal narrowing.
134 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

Figure 2a. Sagittal lumbar spine MRI without IV contrast of an 84 year old female with
a 1 year history of neurogenic claudication. Imaging shows multilevel congenital and
degenerative changes within the lumbar spine that is contributing to severe central
spinal stenosis at L4-L5 with compression of the cauda equina. There is also moderate
spinal stenosis L2-L3 and L3-L4.

Figure 2b. Axial lumbar spine MRI without IV contrast showing bilateral facet joint,
periarticular and interspinous inflammation at the L4-L5 level. There is also moderate
foraminal narrowing.

Guidelines for the management of patients with LSS and associated

degenerative spondylolisthesis are lacking, but general recommendations
include patient education, analgesic medication as well as flexion
strengthening and stabilizing exercises [22]. The SPORT trial is the
 Lumbar Stenosis 135

highest quality study to date that has evaluated the outcomes of surgical
versus nonsurgical treatment for patients with LSS and degenerative
spondylolisthesis. The study found no difference between the two groups in
the intention-to-treat analysis, although the as-treated analysis after the
crossover showed significant improvement in pain and function in favor of the
surgical group during a 2-year follow-up period [23, 24].

4.2. Disc Herniation

A herniated disc is a condition in which the annulus fibrosis of the

vertebral disc is ruptured, enabling the inner nucleus pulposus to herniate
outwards. The extruded disc materials may compress the surrounding nerves
and create pain or other neurological symptoms. Up to 45% of patients
undergoing surgery for LSS with or without spondylolisthesis will have some
form of disc herniation. [15] In a study of 100 patients that underwent
multilevel laminectomy (mean = 3.6 levels) with one-level (78 patients) and
two-level (22 patients) instrumented fusion, 57 herniated discs were identified
in 50 patients: 21 central, 7 foraminal, 24 far lateral and 5 recurrent disc
herniations.

4.3. Ossification of Ligamentum Flavum (OLF)

Ossification of the ligamentum flavum is a phenomenon in which there is

calcification of the ligamentum flavum which may result in central or lateral
recess stenosis. It can be a significant contributor to LSS. It presents as an
initial ingrowth of fibrocartilage and formation of ossific-calcific components
in the ligamentum flavum attributed to type II collagen proliferation. It is more
common in East Asians and sometimes coexists with ossification of the
posterior longitudinal ligament (OPLL) [25]. Hypertrophy or OLF usually
begins laterally and extend medially [26]. It is an important risk factor for
incidental durotomy: in a study of 110 predominantly geriatric patients, all of
the 10 cases that developed intraoperative dural tears exhibited severe OLF,
which extended to or through the dura in 3. For the remaining 100 patients
without dural tears, 57 exhibited moderate/hypertrophied yellow ligament and
22 showed marked OLF.
136 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

4.4. Ossification of the Posterior Longitudinal Ligament (OPLL)

OPLL is a condition that results in hypertrophy and calcification of the

posterior longitudinal ligament, which just lies anterior to the spinal dura.
Although the majority of OPLL is found in the cervical spinal canal (80%), the
frequency in the proximal lumbar spinal canal is around 10%, with the
remaining 10% being found in the proximal thoracic spine [27]. OPLL and
OLF can both contribute to lumbar stenosis [27]. In a study of 1100 patients
that underwent decompressive surgery for spinal stenosis, 23 patients (2.3%)
had OPLL and/or OYL (only OPLL-11, only OLF-12, OPLL and OLF-3) [27].

4.5. Limbus Vertebral Fractures

A limbus vertebral fracture, also called a posterior apophyseal ring

fracture, is an uncommon fracture pattern that may result in LSS. The
pathogenesis of this fracture still remains controversial. Mechanisms of injury
that have been reported to be important for this type of injury are acute trauma
and strenuous sports activity [28, 29]. They are classified into four types and
are best visualized by CT [30]. Type I lesions consist of avulsions of the
posterior cortical vertebral rim, Type II fractures are composed of central
cortical and cancellous bone fractures, Type III lesions are more lateralized
chip fractures and Type IV fractures span the entire length and breadth of the
posterior vertebral margin between the end plates [30]. The fragments are
typically large and warrant an extensive exposure and resection to afford
adequate decompression. Unilateral facetectomy is usually necessitated in the
setting of foraminal and far lateral lesions. Furthermore, piecemeal removal is
the safest method for resection, by first creating a depression or a defect at the
level of the disk space and then morcellating the fracture segment using a
curette, tamp and mallet technique [15]. Intraoperative somatosensory evoked
potentials (SEPs) and electromyography (EMG) can prove to be useful in
order to minimize excess manipulation and retraction of neural elements and
consequent neurological injury.

4.6. Synovial Cysts

Synovial cysts are small, benign, fluid filled sacs that can form around
facet joints as a result of degenerative joint changes. Similar to disc
 Lumbar Stenosis 137

herniations, they may compress the surrounding neural elements and

contribute to the pathology of LSS [31]. Epstein et al. compared patients with
a diagnosis of synovial cysts and LSS without (45 patients) versus with
coexisting spondylolisthesis (35 patients) based on the SF-36 questionnaire
[32]. Laminectomy was performed in both groups at an average of 3.8 vs
3.5 levels, respectively. Post-operatively, five patients from the first group
developed instability and 11 patients with Grade 1 preoperative
spondylolisthesis progressed to Grade 2. Two years following surgical
intervention, good/excellent results in SF-36 Function scale (+44 and +38
points) were documented in only 58% and 63% of patients, respectively. As
synovial cysts reflect intrinsic disruption and pathology of the facet joint and
therefore instability, spinal fusion should be considered in order to achieve
optimal operative results.

4.7. Scoliosis

Degenerative lumbar scoliosis (DLS) is mainly a disease of the elderly

population with an estimated prevalence ranging from 6% to 68% [34–36]. It
can be the sequelae of childhood scoliosis or be developed de novo with age,
as a result of degenerative disc and joint disease. Spine malalignment can lead
to gait instability as well as difficulty standing upright and walking with severe
repercussions on patient’s quality of life [33].
There are no current evidence-based guidelines for the treatment of adult
patients with DLS and therefore decision making and surgical candidacy
largely depends on the provider’s expertise and the patient’s preferences. The
benefits of correcting the spinal deformity and addressing the symptoms
should outweigh the associated risks, such as nerve injury, infection,
pseudarthrosis and further spinal instability [37]. The complication rates can
be as high as 60% for long fusion procedures [38]. An alternative to spinal
fusion, decompression with nonfusion dynamic stabilization is a safe and
effective procedure for patients with LSS and mild to moderate DLS (<30°)
with satisfactory outcomes, including correction of the scoliotic angle, visual
analog scale and Oswestry Disability Index [39]. There is an ongoing trial
comparing surgical vs non-operative management for adult patients with DLS
(clinicaltrials.gov; NCT00854828) and hopefully it will provide further insight
into the management of this complex disorder.
138 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

5. DIFFERENTIAL DIAGNOSIS
Differential diagnosis includes, but it is not limited to

1. Intermittent (vascular) claudication

2. Disc herniation
3. Degenerative disc disease: trochanteric bursitis
4. Facet joint arthropathy
5. Juxtafacet cyst
6. Arachnoiditis
7. Intraspinal tumor
8. Diabetic nephropathy
9. Spinal dural arteriovenous malformation

6. NATURAL HISTORY OF LSS

Given the fact that most patients with LSS seek medical care, particularly
those with incapacitating symptoms that limit everyday life activities, the
natural history of this condition is still largely unknown. The North American
Spine Society (NASS) has recently released guidelines concluding that the
natural course is favorable in approximately one third to a half of patients with
clinically mild to moderately symptomatic LSS. [3] Moreover, several older
studies have shown that the condition can improve in up to one third of
patients and most patients remain unchanged for up to eight years of follow-up
[40, 41]. A more recent study by Minamide et al. [42] followed up 34 patients
with a diagnosis of LSS and leg or low back pain with serial magnetic
resonance imaging and found that symptoms remained the same or improved
in 60% of patient, despite progressive anatomic changes. Interestingly, Haig et
al. [43] suggest that spinal stenosis is a fluctuating disease process with
potentially improving continuum, where anatomic and neurologic deficits do
not necessarily predict future function.

7. IMAGING STUDIES
According to current guidelines, the imaging studies provide the most
definitive diagnostic information for patients with suspicion of LSS [44]. In
clinical practice, imaging is not a routine part of initial patient evaluation but it
 Lumbar Stenosis 139

is rather reserved for diagnostic confirmation and procedural planning of

surgical candidates.

7.1. X-Rays (XR)

Plain anteroposterior (AP) lumbosacral radiographs demonstrate the

number of lumbar vertebrae and may disclose concurrent bony anomaly, such
as spondylolisthesis. Lateral films reveal the lumbar spine curvature and
the presence of static or dynamic instability and olisthesis. This is defined
as translation greater than 4 mm and degrees of angulation at the level of
olisthy greater than 10-12 [45]. Lastly, oblique views demonstrate the pars
interarticularis and any associated defects.

7.2.Computed Tomography (CT)

Reconstructed CT scan images in axial, sagittal and coronal planes can

confirm the diagnosis of LSS. In addition to demonstrating AP spinal canal
diameter, computed tomography can contribute to revealing disk disease
(degenerative disk, bulging annulus, herniated disk), hypertrophied ligaments,
facet arthropathy, ossification of the posterior longitudinal ligament (OPLL)
and ossification of the ligamentum flavum. (Figure 1c) CT myelograms are
rarely performed for LSS, as the combination of CT and MRI evaluation can
noninvasively establish the diagnosis in the majority of the cases. [44] On the
other hand, a CT myelogram may provide useful information in instances
when MRI evaluation is not available.

7.3.Magnetic Resonance Imaging (MRI)

MRI is considered the gold-standard noninvasive imaging modality for

soft-tissue structures assessment but not for bony pathology. It allows the
examination of the shape, the size and the anatomic association between
spinal, neural and vascular elements [44]. Nevertheless, a systematic review
found no difference in the accuracy between CT and MRI for the diagnosis of
LSS [46]. MRI is best utilized to demonstrate degenerative disk disease and
associated compressive changes of the nerve roots and the thecal sac,
140 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

hypertrophy or ossification of the posterior longitudinal ligament and

ligamentum flavum, olisthesis and other neural pathology [47] (Figure 2a).
In addition, increased fluid within the facet joints can be visualized on
routine axial MRI views [48] and it is positively correlated with sagittal spinal
instability documented by MRI and dynamic radiographs obtained at the L4-5
level. Three-dimensional enhanced MRI offer “myelographic” views that may
capture surgical findings in 82.6% of the time [49]. MRI has a sensitivity of
87-96% and specificity of 68-75% for the diagnosis of LSS [50]. Moreover it
has variability for assessment of the different spinal characteristics, with
central canal stenosis showing the highest reliability and foraminal stenosis
and subarticular zone stenosis the lowest reliability [51] (Figure 1b and 2b).
Regarding parameters that are used to quantify LSS, anteroposterior
diameter less than 10 mm and cross sectional area less than 70 mm2 of the
spinal canal are most commonly reported. [52] Moreover, developmental
spinal stenosis is defined as anteroposterior canal diameter of <20 mm at L1,
<19 mm at L2, <19 mm at L3, L4 <17 mm at L4, and <16 mm at L5 and S1
[53]. Lastly, according to a Delphi study, perineural intraforaminal fat and disc
protrusion are the most important diagnostic indicators of LSS [54].
Contrast-enhanced MRI is not a part of routine evaluation of a patient with
possible LSS but it can help differentiate between among tumors, scar,
arachnoiditis, demyelinating syndromes and infection [55].
Although spinal canal narrowing and neurovascular compression
visualization on imaging is needed for LSS diagnosis, it is not sufficient; many
asymptomatic lesions might be identified on MRI in the elderly population. An
old case series conducted in patients older than 60 years, showed that
herniated discs (36%) and lumbar stenosis (21%) were symptomatic in only
about one third of the subjects [47]. Therefore, abnormalities on MRI images
must always be correlated with age and any clinical signs and symptoms
before surgical intervention is contemplated.

8. MANAGEMENT
8.1. Non-Surgical

Non-surgical management is generally considered the first-line treatment

option for LSS. It includes lifestyle modification, physiotherapy, medication,
spinal injections and multidisciplinary rehabilitation. Corroborating
conservative treatment, a study in 1996 [56] compared Oswestry Disability
 Lumbar Stenosis 141

Index (ODI) and surgeons’ clinical assessment for 54 matched pairs of patients
with lumbar stenosis treated surgically (laminectomy) vs non-surgically and
found no statistically significant differences in the outcomes between the two
groups. There are very few high quality randomized clinical trials that have
investigated non-surgical management strategies for LSS. There is an ongoing
trial that has assigned patients with radiographically confirmed LSS into 3
groups, comparing usual medical care with individualized manual therapy and
rehabilitation exercise versus community based group exercise [57]. Another
study is assessing the effect of a pedometer-based physical activity promotion
and nutrition lifestyle intervention on overall health and quality of life of
patients with symptomatic LSS [58, 59].
Although there is a lack of consensus regarding treatment
recommendations, most patients who seek medical care are initially managed
conservatively and surgical management is recommended after failure of
conservative treatment [60].

8.1.1. Physiotherapy
Physiotherapy is a well-established and accepted treatment for LSS.
Physiotherapy-related options include [61]:

1. Aerobic exercise
2. Balance training
3. Flexion-based exercises
4. Spinal manipulation
5. Postural instruction
6. Body weighted supported treadmill ambulation
7. Muscle coordination training
8. Manual stretching of the back and hip musculature

Tomkins et al. carried out a telephone survey on patients diagnosed with

lumbar stenosis and found that the most common physical therapy treatments
used are massage (27%), strengthening exercises (23%), flexibility exercises
(18%) and heat/ice (14%) [62]. Unfortunately, there is paucity of studies
regarding the efficacy of physiotherapy for LSS. A recently published
systematic review of nonoperative treatments for patients with LSS and
neurogenic claudication found only low quality evidence from single small
trials, concluding that exercise might provide short-term benefit for leg pain
and function compared to no treatment [60]. Another systematic review by
Macedo et al. failed to reach conclusions regarding which physical therapy
142 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

treatment is superior for LSS [63]. The authors found that physiotherapy
modalities offer no additional benefit to exercise alone. Moreover, when
physiotherapy was compared to surgical intervention, surgery lead to better
long-term (2-year) outcomes for pain and disability but not for walking
distance. Lastly, a secondary data analysis of the Spine Patient Outcomes
Research Trial (SPORT) showed that physiotherapy was not associated with
improvement in pain and physical function after 1 year, although patients were
less likely to receive surgery within one year [64]. The most recent
randomized controlled trial was published in 2015 and compared standard
physiotherapy regimen of lumbar flexion, conditioning exercises and patient
education with lumbar decompression [65]. Interestingly, intention-to-treat
analysis revealed no difference between the two groups at one and two years.
Nevertheless, the results of the study are difficult to interpret as a high
proportion of the participants assigned to physiotherapy crossed over to
surgery.
In summary, physiotherapy for patients with LSS has not yet been
established as a successful alternative to surgical intervention. This can be
attributed to the fact that physiotherapy’s main role is to address the patient’s
symptoms and functionality, rather than the pathology itself. For example,
flexion exercises and other postural dynamic changes during physiotherapy
alter spinal canal diameter, thus relieving spinal compression. The
mechanisms underlying these effects remain to be determined and further
investigation is therefore warranted.

8.1.2. Medications
Various over-the-counter and prescription drugs can be used to treat LSS
symptoms. Despite their anti-inflammatory and analgesic properties, non-
steroidal anti-inflammatory drugs (NSAIDS) are no more effective than
acetaminophen in the treatment of LSS. The same holds true for opioids and
muscle relaxants as well; according to well controlled studies, they are not
more effective than acetaminophen and NSAIDS for pain control [66, 67]. The
role of long term opioids is still unclear [66]. Corticosteroids and
antidepressants are often prescribed for patients with LSS, but their efficacy is
not yet fully elucidated [69, 70].
Prostaglandins, gabapentin and vitamin B6 are some drugs that have been
in used small clinical trials and were found to improve pain and walking
distance [56, 65]. Prostaglandin (PG) E1 has been suggested to improve
symptoms in patients with LSS by vasodilation and improving blood flow to
cauda equina and nerve roots. In short term follow-up studies, PGE1 led to
 Lumbar Stenosis 143

improvement in pain, Japanese Orthopedic Association Score and walking

distance [68]. Calcitonin is no better than placebo and acetaminophen
(paracetamol) [59, 66].

8.1.3. Epidural Injections

Epidural injections are often used to help alleviate LSS symptomatology,
but the evidence surrounding the effectiveness of epidural injections is
controversial. Some studies have reported that epidural injections improve
pain, function and quality of life when compared to home exercise and
inpatient physical therapy alone [60]. However, other trials have failed to
show any benefit. A recent meta-analysis showed that epidural steroid
injections provide limited short-term and long-term pain relief and walking
distance improvement in LSS patients [68].
Local anesthetics may also be injected to assist with pain control in
patients with LSS. A systematic review of the literature of injections for
central LSS found that local anesthetics either alone or with steroids offer low
back and lower extremity pain relief [69]. There is lack of evidence to suggest
that epidural steroid injections are better than local lidocaine injections alone,
regardless of the mode of the epidural injection. One large, double-blind
controlled trial found no benefit of epidural injections with glucocorticoids and
lidocaine over lidocaine alone after 6 weeks of follow-up [70].
Steroid injections are not without risks. They are associated with
hyperglycemia, anxiety, sleeplessness, transient immunity suppression, and
they have even been associated with an increased rate of fungal meningitis
[71]. Steroid injections are contraindicated in the setting of an infection.
Despite these risks, in select patients with LSS, epidural injections may be a
good alternative for patients who do not have adequate symptom relief from
physiotherapy or oral medications.

8.2. Surgery

8.2.1. When to Operate?

Surgical intervention can be an appropriate treatment modality for patients
who have failed conservative medical management and who lack severe
comorbidities prohibiting intervention. In selected circumstances, surgery can
improve pain control and can potentially reverse existing neurological deficits.
Some studies have shown superiority of surgical intervention versus medical
management alone [23, 72, 73]. A randomized controlled trial of 94 patients
144 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

comparing nonsurgical (44 patients) and surgical (50 patients) interventions

for treatment of LSS, the surgical group reported a greater degree of back and
leg pain relief, and they demonstrated less overall disability compared to the
nonsurgical cohort [72]. This is consistent with multiple other studies that have
also reported improved pain relief and functional outcomes with surgical
patients [23, 73, 74]. Surgery for LSS consists of either decompression alone
or decompression with spinal fusion.

8.2.2. Laminotomy
Lumbar laminotomy is a procedure that involves removal of the inferior
portion of the rostral hemilamina and mesial one third of the ipsilateral facet
while simultaneously preserving the spinous process, interspinous ligament,
and lateral two thirds of the ipsilateral facet joint. Laminotomies may be
performed in a unilateral or bilateral fashion. One study followed 102 patients
who had underwent a unilateral laminotomy for an average of 5.6 years, and
92.2% noted sustained improvement post operatively [75]. Another study of
bilateral laminotomies showed a 76% incidence of good or excellent results
based on patient outcome questionnaires and a 71% of good or excellent
outcomes based on surgeon outcome measures [76]. Given the preservation
of the spinous process and interspinous ligaments, laminotomies may
help preserve spinal stability. One study compared clinical results and
postoperative stability of 41 patients treated by laminectomy with those of 26
patients who underwent bilateral laminotomy after a mean follow-up period of
3.7 years. The clinical outcomes were comparable (78 versus 81% good
outcome), but spinal instability was more frequent in the laminectomy group
[77].

8.2.3. Laminectomy without Fusion

Lumbar laminectomy is an effective and safe treatment for severe LSS. It
involves surgical removal of the entire dorsal spinous process, bilateral lamina,
and underlying ligamentum flavum. With this technique, compression of the
neural foramina can be palpated, and foraminotomies can easily be performed
if there is evidence of concurrent foraminal stenosis. There is class III
evidence to suggest that a decompression without fusion is acceptable in
patients without evidence of spinal instability [78]. One study of 500 patients
showed statistically significant differences in back pain, radiculopathy,
neurogenic claudication, motor deficits, and sensory deficits in patients who
underwent laminectomy for LSS [74]. The surgeon should carefully evaluate
 Lumbar Stenosis 145

the radiographic images in order to determine the level of diseased segments

and provide an adequate decompression.
Success rates associated with a decompressive lumbar laminectomy for
LSS range from 78 to 91% [79–82]. A prospective study found a success rate
of 78-88% at six weeks and 6 months, but this dropped to 70% at 1 year and 5
year follow up post operatively [82]. A second study of 50 patients with LSS
and degenerative spondylolisthesis demonstrated that a lumbar laminectomy
had 91% frequency of good to excellent results at three years and an 87%
success rate at six years [79]. Other studies have also found comparable
success rates (80% to 84%) following decompression alone for LSS [80, 81].

8.2.4. Laminectomy with Instrumented Fusion

In some series, the addition of instrumented fusion techniques following
decompressive laminectomy has been associated with improved outcomes. For
instance, one study of 50 patients with LSS and olisthesis compared
decompression alone (25 patients) to decompression with instrumented fusion
(25 patients) and found that the fusion cohort had improved outcomes
at 3 years. [83] Common indications for a fusion include presence of
spondylolisthesis, radiographic evidence of facet joint laxity at the site of
stenosis, scoliotic deformity, excessive kyphosis, and excessive surgical
removal of facet joint or ligaments that may result in iatrogenic spinal
instability.
Careful patient selection and extensive preoperative discussions are
essential as fusion procedures place patients at a greater risk for perioperative
morbidity and mortality compared to decompressive procedures alone [84,
85]. Deyo et al. report that fusion procedures in the elderly can have a twofold
increased mortality rate, a 20% increased perioperative morbidity rate, and that
patients were 5.6 times more likely to require a blood transfusion [84, 85].

8.2.5. Minimally Invasive Surgery

Minimally invasive spine surgery (MIS) techniques are becoming
increasingly popular in spinal surgery. Studies suggest that MIS
decompression techniques may be comparable to open decompression
procedures. One prospective study of 885 patients comparing the effectiveness
of MIS decompression versus traditional open laminectomy concluded that the
Oswestry Disability Index (ODI) in patient undergoing MIS decompression
was equivocal to that of the laminectomy cohort [86]. Multiple other studies
have also ascertained that MIS decompression procedures are associated with
146 Daniel Shepherd, Panagiotis Kerezoudis, Michelle J. Clarke et al.

significantly less blood loss, reduced hospital stays, and often have decreased
need for ancillary support upon dismissal [87, 88].
Certain patient populations, such as the geriatric patients or patients with
medical comorbidities that limit more invasive procedures, may have
increased benefit from MIS techniques. Multiple studies have shown MIS
decompression to be a safe and effective treatment strategy for LSS in elderly
patients and improve their quality of life [89–91].
Overall, MIS procedures have a similar complication profile when
compared to open approaches [87]. However, due to decreased
maneuverability, certain complications such as dural tears may be more
difficult to repair intraoperatively. Careful patient selection and adequate
surgical experience with MIS techniques is crucial to perform a safe and
effective minimally invasive lumbar decompression.

8.3. Surgical Failures and Operative Complications

Surgical failures in patients with LSS can usually be classified into two
broad groups: patients who did not get any pain relief following surgery (early
treatment failures), and those who initially experienced pain relief but later
developed recurrent symptoms (late treatment failures). One study showed that
most early treatment failures were secondary to either poor patient selection
(the absence of actual neurogenic claudication coupled with the absence of
severe stenosis on preoperative radiographic studies) or inadequate surgical
decompression [92]. Late treatment failures often occur due to recurrent
stenosis. Recurrent stenosis can occur either at or adjacent to the previously
operated level. In one series of 100 patients, 16 demonstrated recurrent
stenosis [93]. Most patients with recurrent stenosis respond to further surgery.
Similarly, lumbar decompression surgery both with or without fusion
techniques are associated with certain surgical risks. One of the more common
complications associated with spinal decompression surgery is durotomy. The
incidental durotomy rate with laminectomy procedures may be as high as 5 to
11% [74, 94–96]. A dural tear does predispose patient to subsequent
complications such as low pressure headaches, meningeal pseudocyst
formation, and dural-cutaneous cerebrospinal fluid (CSF) fistulas [97, 98].
Some studies suggest that an incidental durotomies during a first time lumbar
decompression did not adversely affect the long-term outcomes in affected
patients [99]. Other common surgical complications for surgery include
superficial and deep wound infections (0.9 - 5%) [100], and temporary
 Lumbar Stenosis 147

increased motor deficit (1-8%). Less common surgical complications include

direct neural injury, deep vein thrombosis, pulmonary embolism, and post-
operative visual loss secondary to posterior ischemic optic neuropathy [101,
102].

9. CONCLUSION
LSS is a common disease primarily affecting the elderly that is
characterized by degenerative changes causing progressive compression of
neurovascular structures, leading to debilitating symptoms of neurogenic
claudication and radiculopathy. Patients should be informed of the generally
favorable natural course of the disease and the expected benefits and risks of
each treatment option. Management strategies should be applied in a stepwise
fashion leading with initial conservative treatment options, including
physiotherapy, medications and epidural injections. Surgical intervention
should be considered in patients that fail conservative measures or develop
significant neurologic compromise, such as cauda equina syndrome.
Individualized decision making should consider the patient’s expectations
and goals. Minimally invasive spinal surgery represents a promising
surgical technique that offers optimal surgical outcomes while minimizing
complications. Future research should focus on defining the different
phenotypes within the broad spectrum of LSS pathophysiology with the goal
of enhancing personalized health care delivery.

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Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 8

LUMBAR DISC HERNIATIONS

Ajit Jada, MD, Roger Härtl, MD and Ali Baaj, MD*

New York-Presbyterian Hospital/Weill Cornell Medical Center, NY, US

ABSTRACT
Lumbar disc herniations occur with relatively high frequency such
that surgeons should be aware of prevention, management, and treatment
strategies. Clinical presentation including assessment of location,
morphology, symptoms, and imaging are crucial sources of information
in the determination of the necessity for surgery. Conservative
management may include one or a combination of medication, physical
therapy, and epidural steroid injections. If needed and depending on the
surgeon’s preference, minimally invasive microdiscectomies or
endoscopic procedures may be utilized to treat patients. Ultimately, the
ongoing debate between non-interventional and interventional approaches
to treatment requires surgeons to make final decisions tailored to each
patient.

Keywords: lumbar disc herniation, degenerative disc disease, adjacent level

disease, management of disc herniations

*
Corresponding Author address: New York-Presbyterian Hospital/Weill Cornell Medical Center
525 East 68 Street, Box 99, New York NY 10065. Email: [email protected].
158 Ajit Jada, Roger Härtl and Ali Baaj

INTRODUCTION
Degenerative disc disease and its sequelae, disc herniations, comprise the
most common cause for low back pain related physician office visits [1, 3]. In
addition, lumbar disc herniations (LDH) are a significant source of morbidity
and both operative and non-operative management of LDHs are associated
with rising health care costs.
This chapter discusses the epidemiology, anatomy, risk factors, clinical
features, and management and outcomes of lumbar disc herniations. The
emphasis of the chapter will be on management and outcomes. The
biomechanics and pathophysiology of disc disease are discussed in earlier
chapters.

EPIDEMIOLOGY
Low back pain is the most commonly reported type of pain and affects
approximately 29% of the adult population in the United States [1]. Total
medical costs for both the non-operaive and operative management of low
back pain in the U.S. ranges from $84 to $624.8 billion, with more recent
estimates of spending exceeding $100 billion annually [2, 24]. Furthermore,
degenerative disc disease and disc herniations comprise the most common
cause for low back pain related physician office visits [3]. Degenerative disc
disease comprises most of the back pain seen at visits, while disc herniations
result in more radicular pain at presentation.
From 1992 to 2003 there has been a 500% increase in lumbar spine fusion
surgery from $75 million to $482 million, respectively [23], with fusion
surgery from recurrent lumbar disc herniations contributing to this total. With
regard to lumbar disc herniation surgery alone, approximately 200,000 to
300,000 lumbar discectomies are performed annually in the U.S. [25-28].

Demographics

The highest prevalence of disc herniations are found in patients with an

age range of 30-50 years, with a male to female ratio of 2:1 [39, 42]. In
Western countries, the annual incidence of sciatica from lumbar disc
herniations is 5 cases per 1000 adults [41]. The lifetime prevalence of lumbar
 Lumbar Disc Herniations 159

disc herniation varies depending on the study but is commonly reported at

40% [43]. Furthermore, studies have reported a risk of approximately 3.6% in
patients younger than 35 and 22% in those aged 45 to 54 [40]. In patients
between 25 and 55 years 95% of herniated discs occur at the L4-5 and L5-1
levels, with younger patients having a predilection for herniations at L5-S1
(average age 39) whereas older patients (average age 42) had herniations at
L4-5 [46]. In patients over 55 disc herniations are more common above the
L4-5 level [44-46].
Sparse data exist on the frequency of lumbar disc herniations in patients <
21 years of age, with the most recent review citing only 1963 surgically treated
LDH patients below the age of 21 in the literature [49] with pediatric patients
constituting only 0.5-6.8% of all patients hospitalized for LDH [50, 51, 52].
Zitting et al. [53] performed an epidemiologic study following 12,058 Finnish
babies from birth up to 28 years of age. The authors found that none of the
subjects were hospitalized for LDH until the age of 15. The prevalence of
hospitalization from LDH increased to 0.1-0.2% by age 20, and by age 28,
9.5% of males and 4.2% of females were admitted to the hospital with a
diagnosis of LDH.

ANATOMY
In order to appreciate how lumbar disc herniations occur, the anatomy of
the lumbar spine needs to be briefly reviewed:
The lumbar spine has 2 basic functions, to house the spinal canal and to
provide mechanical support to the axial skeleton [12]. The lumbar spine
consists of 5 vertebral bodies, each containing 5 motion segments. The motion
segments consist of the intervertebral disc (IVD), vertebral body, pedicles,
apophyseal joints, lamina, and spinous process (Figure 1). The normal
physiologic movement of the spine is maintained by ligaments and joint
capsules. The major ligaments include the anterior longitudinal ligament
(ALL) which runs along the anterior border of the vertebral body and limits
extension, the posterior longitudinal ligament (PLL) which runs along the
posterior border of the vertebral body and limits flexion, the interspinous and
supraspinous ligaments, and the ligamentum flavum. The IVD has 3 structural
components which include the nucleus pulposis (NP), annulus fibrosus (AF),
and the vertebral endplate [12].
Intervertebral discs (IVD) are avascular fibro-cartilaginous pads that lie
between the vertebral bodies. During development, blood vessels enter the AF
160 Ajit Jada, Roger Härtl and Ali Baaj

and NP and remain patent until approximately 8 years of age, regressing over
the next two decades of life, leaving the IVD as the largest avascular structure
in the body [18-22].
The intervertebral discs serve to distribute loading forces evenly to the
vertebral bodies during loading [4]. The IVD consists of a soft nucleus
pulposus (NP) that is contained within a tough annulus fibrosus (AF). The NP
consists of cells derived from embryonic notochord [5-8] and as the NP
matures, chondrocyte-like cells remain in a highly hydrated gelatinous tissues
matrix which resists and redistributed spinal compressive loads [9].

Figure 1. Lumbar Disc Anatomy.

The extracellular matrix (ECM) of the NP consists of primarily water,

proteoglycans, namely aggrecan, and randomly oriented type II collagen, with
minor ECM contribution from minor collagens Types III, VI, IX, and small
proteoglycans [9]. The AF consists of both type I and type II collagen fiber
bundles arranged circumferentially into distinct laminate layers. Fibers in the
outer annulus form Sharpey’s fibers which are entrenched within the vertebral
bodies above and below the disc [9]. The inner annulus lacks the organized
lamellar structure that the outer annulus contains, and in the inner annulus,
Sharpey fibers combine with the cartilaginous endplate of the vertebral body
[17].
 Lumbar Disc Herniations 161

As we discuss disc herniations further in this chapter it is important to

correlate the anatomy of the lumbar spine with the pathology of disc
herniations. Of note, there is a transitional area in the posterolateral junction of
the disc which is the intersection of maximum and minimum concentrations of
the laminate layers which comprise the external layer of the AF. In the
posterolateral quadrant of the disc, there is also a change in the inclination of
the fiber bundles from 0 degrees parallel to as much as 90 degrees inclination
[10]. These structural phenomena may explain the high frequency of disc
herniations from the posterolateral quadrant where tensile strain is highest in
flexion and extension modalities [11].
The endplate consists of a cartilaginous bony components. The
cartilaginous endplate is usually less than 1 mm in thickness and overlies the
bony endplate. The bony endplate is thin sheet of bone which comprises the
cortical rim of the vertebral body [16]. Cranial endplates are thinner and
weaker than the caudal endplates, both of which are weakest in their central
regions [14, 15]. The avascular IVD receives nutrients from diffusion through
the capillary beds in the vertebral endplates.
The intervertebral disc is avascular and immunoprivileged, as a result the
IVD has no exposure to the immune system [18-22]. Thus when a disc
herniation occurs, it can elicit an inflammatory, auto-immune response [13].

Neuronal Innervation

The PLL, vertebrae, apophyseal joints, dura mater, and outer 1/3 of the
annulus are innervated by the dorsal ramus and sinuvertebral nerves branching
from the spinal nerve of the corresponding lumbar level [29-37]. Whereas, the
lateral and anterior annular areas are innervated by branches of the gray rami
communicans [37], the inner annulus and NP are not innervated [54]. The
somatic afferent information is collected in the dorsal root ganglia (DRG),
transmitted to the dorsal horn of the spinal cord and travels via the
spinothalamic tract to the thalamus and somatosensory and pain cortical areas.
Information from the grey rami communicans and autonomic afferents below
the level of L2 is collected at the level of the L2 DRG and transmitted to the
dorsal horn of the spinal cord and then relayed to the CNS.
162 Ajit Jada, Roger Härtl and Ali Baaj

DISC HERNIATIONS
Disc herniation occurs when a tear develops in the AF and the NP
extrudes through the tear. When the NP herniates, nerve injury may occur
from the NP pressing on adjacent nerve roots. Disc biomechanics are also
altered, with higher compression forces exerted on the annulus [38].
Furthermore, sclerotic changes in the endplates and osteophytes are sequelae
of long standing altered biomechanics secondary to disc herniations [38.]

Classifications of Disc Herniations

There are various classifications for disc herniations. They can be

described by either location (Figure 2) or morphology (Figure 3). With regard
to location, herniations are characterized as:

 Central
 Lateral Recess
 Foraminal
 Extra-foraminal
 Far Lateral (discussed later in the chapter)

From a morphology perspective, Spengler et al. [47] divided disc

herniations into:

 Protruded Disc (Disc bulge with an intact annulus fibrosus)

 Extruded Disc (Disc material that passes the annulus fibrosus but is
contiguous with the nucleus pulposus)
 Sequestered Disc (Disc material not contiguous with the nucleus
pulposus, otherwise characterized as a “floating fragment.”)
 Lumbar Disc Herniations 163

Figure 2. Disc Herniation Location.

Figure 3. Disc Herniation Morphology.

Other literature have described disc herniations as Contained or

Uncontained (Figure 4) [48]:

 Contained: The disc material has not passed beyond the PLL and is
subligamentous.
 Uncontained: The disc material has herniated beyond the PLL.
164 Ajit Jada, Roger Härtl and Ali Baaj

Figure 4. Contained and Uncontained Disc Herniations.

Onset of Herniation

Timing of onset of herniation is arbitrarily divided into acute or chronic.

Most authors refer to herniations as acute for up to 3 months and chronic
thereafter. From a surgical perspective, timing of herniation will factor into
outcomes, so this classification is of importance.

Symptomatology and Pain

After LDH, inflammatory factors, in addition to direct compression

on the nerve root; are suspected to play a role in the symptomatology of the
patient [59]. As previously discussed, the NP is contained within an
immunoprivileged environment, and when herniated out of the annulus, the
disc material causes an inflammatory cascade by the body. These findings
have been validated in animal and human studies from specimens obtained
 Lumbar Disc Herniations 165

intra-operatively [60-62]. This immunologic cascade involves inflammatory

cytokines including tumor necrosis factor-alpha, and IL-1 [63].

RISK FACTORS
Certain risk factors have been studied in the literature and there are
activities associated with an increased risk of LDH. A review of activities are
described below and the correlation with LDH is explained.

Sports

A retrospective study performed by Mundt et al. [65] analyzed 355

patients with disc herniations; both cervical and lumbar, that were between the
ages of 20 and 64 for 2 years. Subjects were questioned regarding their
participation in sports and control group of individuals free of disc herniations
was used to determine whether the frequency of exposures in the case group
was different from what would be expected in the subjects’ age group and sex.
The data showed that participation in recreational sports did not increase the
risk for low back pain and herniated discs, either cervical or lumbar, and even
offered a slight protective benefit against disc herniation.
There was an association with free weight lifting and increased risk of
cervical disc herniation, not lumbar disc herniation. This was the case for the
use of light weights, 3 sets of 10 repetitions, and heavy weights with 2 or more
repetitions. No increased risk of disc herniations were apparent for use of
weight lifting equipment, e.g., Nautilus, Universal Gym Equipment, etc. The
authors hypothesized the difference was related to lack of stability of free
weights and unequal distribution of weight to the cervical spine.
In another retrospective review of weight lifting as an independent risk
factor for LDH [66], the authors found that lifting with the knees straight and
back bent was consistently associated with LDH. This included lifting:
weights > 25lbs, children 10-24lbs, and children > 25lbs. These results are
correlated with biomechanical studies demonstrating increased intra-discal
pressures and intra-abdominal pressures associated with lifting with the knees
straight and back bent [67-70]
166 Ajit Jada, Roger Härtl and Ali Baaj

Driving

In older studies analyzing risk of disc herniation and driving, the data
showed that individuals who spent at least half of their day driving had a three-
fold increased risk of LDH as compared to non-drivers [71]. The risk was
found to be five-fold in truck drivers and two-fold in car drivers, and
correlated with the time spent driving [71]. Furthermore, the risk of LDH
appeared to be correlated with the amount of vibration transmitted to the spine,
road surface, speed of the vehicle, low seat position [71-75]. In addition,
animal studies have shown that vibration of the spine at 5 Hz can adversely
affect the intervertebral discs and facilitate degeneration [71, 76, 77].
However, the most recent literature published in the Lancet in 2002 [78]
was a retrospective cohort studying 45 male monozygotic twins and lumbar
disc disease associated with driving. The study group had 5.4 times more
driving exposure than their twin, control counterpart. With all other variables
controlled, driving exposure was not associated with accelerated lumbar
degeneration and structural abnormalities. This was measured through MRI
imaging of the lumbar spine and there were no significant differences in
disc signal, annual tears, disc bulges, herniations, disc height, or endplate
irregularities.

Smoking

Smoking has often been considered an independent risk factor for LDH.
There is some conflict in the literature whether smoking has a direct causal
effect on LDH, but there is a preponderance of evidence that demonstrates
smoking is a risk factor for LDH as well as recurrent disc herniations (RDH).
A study by Kelsey et al. demonstrated cigarette smoke is associated with
an increased risk of LDH by 20%, when 10 cigarettes are smoked per day for 1
year [79]. The Twin Spine Study [88] demonstrated a more modest effect on
lumbar degeneration. When comparing smokers to non-smokers, they found
an 18% increase in their lumbar disc degeneration score among twins, but less
than a 2% difference among all subjects when comparing smokers to non-
smokers, in their cohort.
A meta-analysis by Shiri et al. [80] demonstrated smoking was
independent risk factor for lumbar radicular pain and experimental studies
have shown smoking reduces perfusion around the intervertebral discs [80-
82] possibly exacerbating disc degeneration [83-86]. Furthermore, smoking
 Lumbar Disc Herniations 167

increases the production and release of inflammatory cytokines in

intervertebral discs [86, 87] also contributing to degeneration and pain.
Gill et al. compared the ligament healing process in passively smoking
mice with non-smoking mice and found decreased cellular density in the
healing ligaments of smoking mice. Furthermore, the smoke exposed mice
exhibited lower type I collagen expression in the injured ligament than their
non-smoking counterparts [159]. A study by Nemoto et al., exposed 4-week
old rats to passive smoking for 8 weeks. The authors found that the
intervertebral discs exhibited tears, cracks, and misalignment of the annulus
[160].

Diabetes

Diabetes has also been studied as an independent risk factor for LDH and
RDH. The studies have unequivocally shown that diabetic patients are at an
increased risk for both LDH and RDH [155, 161]. Robinson et al., compared
intervertebral disc tissue removed during surgery for LDH between diabetics
and non-diabetics [162]. The authors found that the proteoglycans of diabetic
patients are banded at a lower buoyant density, indicating a lowered
glycosylation rate and a lower number of sugar side chains per core protein.
Furthermore, in discs of diabetic patients, there was a slight increase in the
chain length of chondroitin sulfate. Further analysis of the glycosaminoglycan
chains showed a decreased amount of keratan sulfate, compared with that in
nondiabetic subjects. Thus, the authors concluded that discs in diabetic
patients have lower buoyant density and undersulfated glycosaminoglycans
which may lead to an increased susceptibility to lumbar disc herniation [162].

CLINICAL PRESENTATIONS OF LUMBAR DISC

HERNIATION
Patients may describe an incident attributable to a disc herniation such as a
fall, lifting a heavy object, or rotational forces e.g., golf swing. Patients with
LDH present with radicular pain more than axial low back pain, and axial back
pain alone is poor indication for microdiscectomy. Axial and mechanical low
back pain may indicate a more structural etiology for the pain, which would
168 Ajit Jada, Roger Härtl and Ali Baaj

require a fusion surgery. Further investigations with flexion extension studies

and even CT scans may be indicated.
The pattern of the radicular pain with LDH can correlate with the
dermatomal distribution of the nerve affected by the disc herniation. The
pain can be characterized as sharp, dull, or burning, and may be associated
with paresthesias and weakness. These symptoms can be exacerbated with
coughing, bending, or lifting [55].
The most common location of disc herniations, as previously described, is
the posterolateral quadrant of the disc. When a disc herniation occurs, it
commonly affects the traversing nerve root at that level. The traversing root
exits under the pedicle of the vertebral body below the level of the herniation.
For example, an L4-5 central disc herniation would usually compress the
traversing L5 nerve root, resulting in an L5 radiculopathy.

Physical Examination

The patient’s gait should be observed initially. In some cases, patients

may lean away from the side of the leg pain, which is indicative of a
paracentral herniation lateral to the nerve root. Whereas, with axillary
herniations patients may lean toward the side of the herniation. It is
hypothesized that flexion toward either side is an attempt to relieve tension on
the nerve root from the herniated fragment. A foot drop in a patient may be
associated with an L4 or L5 paresis.
The patient’s pelvic tilt with walking should also be assessed. A positive
Trendelenburg sign occurs with L5 nerve root compression resulting in
weakened hip abductors, gluteus medius, and gluteus minimus. As a result,
during gait, the pelvis will tilt downward on the unaffected side when the heel
plants on the affected side. Another common test used to elicit the patient’s
symptoms is the straight-leg raise or Lesegue test. If the patient develops
symptoms on the ipsilateral side with the straight leg raised to 30 degrees or
more the test is positive. If the patients develops symptoms on the contralateral
side the test is referred to as a crossed straight leg raise test. The straight leg
raise test has high sensitivity and low specificity for LDH, while the crossed
straight leg raise test has high specificity with low sensitivity for LDH [56]. If
patients present with bowel or bladder symptoms and/or loss of continence,
saddle anesthesia, and diminished genital sensation, this may be cauda equina
syndrome and warrants immediate decompression.
 Lumbar Disc Herniations 169

IMAGING
MRI is the preferred diagnostic modality for LDH. MRI enables
delineation of the soft tissue elements more than CT. One study correlated
clinical outcomes with the size of the herniated disc fragments on MRI [57].
The results demonstrated discs > 6mm were more likely to have a positive
straight leg raise on examination, and in the operative group, the larger discs
(>6mm) were predictive of improved surgical outcomes, whereas discs < 6mm
had fair and poor outcomes [57].
MRI is also the preferred diagnostic modality for post-operative imaging.
Studies have shown that post-op imaging should be delayed for 6 months in
order to fully assess the operative site, free from edema and hematoma [58].
Furthermore, post-operative scar tissue and fibrosis will enhance with
gadolinium contrast.
If the patient is unable to undergo an MRI, a CT myelogram provides
useful imaging to localize areas of stenosis and herniation.

TREATMENT OPTIONS
Natural History of Lumbar Disc Herniation

In order to understand and inform patients of the best treatment

paradigms, physicians should be knowledgeable about the natural course
of LDH. There are many studies in the literature, albeit with several
limitations, describing the natural history of LDH. The literature suggests
that larger disc herniations tend to resorb or regress more readily than smaller
disc herniations. Larger herniations penetrate the annulus or PLL thus
exposing disc material to the systemic circulation of the epidural space
eliciting an inflammatory response [92- 94]. Phagocytic mechanisms and
neovascularization of the outermost layer of herniated disc material result in
disc resorption [95- 97]. Also, degradation of proteoglycans in the NP results
in dehydration of the herniated disc fragment, followed by a decrease in
overall disc volume [98, 99].
A recent study by Kjaer et. al [89] followed patients for 8 years with LDH,
the majority of which were at L4-5 and L5-S1. The authors performed a
prospective population-based observational study on a Danish population. The
authors invited a random sample of 40 year olds to participate in the study,
170 Ajit Jada, Roger Härtl and Ali Baaj

thus this population did not necessarily have back pain or disc herniations. 412
participated and received a baseline MRI, a 4 year follow up MRI, and an 8
year follow up MRI. The data demonstrated that over 8 years for those patients
with LDH; 65% of herniations remained unchanged, 17.5% decreased, 12.5%
increased, and 5% had a fluctuating pattern.
Chun et. al, [90] performed a meta-analysis of the recent literature to
determine the probability of spontaneous disc regression among each type of
herniated disc in patients that underwent conservative management with: bed
rest, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), exercise,
physical therapy, and steroid injections. The authors found a spontaneous
regression rate of 96% for sequestered discs, 70% for extruded disc, 41% for
protrusions, and 13% for disc bulges. The rate of complete resolution was 43%
for sequestered discs and 15% for extruded discs.
Seo et. al., [91] reviewed volumetric changes in LDH using
three-dimensional measurements obtained from MRI. The authors
performed MRIs on initial visit and 6 months later in patients with LDH
who received conservative management. They found that the extent of
disc containment and migration, the initial size of the herniated disc, and the
degree of intactness of the posterior longitudinal ligament [PLL) were all
significantly correlated with resorption and increased disc volume. The risk of
volumetric increment in LDH appeared to be high in patients with small,
contained disc herniations. Furthermore, 88% of transligamentous-type LDH
patients exhibited resorption, compared with only 41.9% of those with
subligamentous-type LDH.
Another prospective study by Saal et al. [100] followed patients treated
conservatively for LDH for a mean of 25 months. Disc extrusions were
measured with MRI imaging at presentation and upon follow-up. The largest
disc extrusions were noted to decrease the most in size from initial visit to time
of follow-up.
The natural history of LDH:

 Phagocytic mechanisms, neovascularization of the outermost layer of

herniated disc material, and degradation of proteoglycans in the NP,
all result in decreased fragment size.
 Larger herniations tend to resorb more readily than smaller
herniations.
 Transligamentous herniations resorb more than subligamentous
herniations.
 Lumbar Disc Herniations 171

 Sequestered discs resorb more than extruded, protruded, or bulging

discs.
 Overall, most studies show that LDH tend to reduce in size over time
[90-93].

Non-Surgical/Conservative Management

The initial treatment of LDH is typically, conservative, non-surgical

management. However, conservative management is only applicable when
patients do not have progressive neurologic deficits, severe unremitting pain,
or cauda equina syndrome (discussed later in this chapter).

Medication

Initial management of LDH consists of treatment of the pain symptoms

with non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2
inhibitors (COX-2), narcotics, muscle relaxants, and modification of activities.
Clinicians must evaluate a patient’s past medical history before prescribing
NSAIDs and COX-2 inhibitors. These medications are typically
contraindicated in patients with a history of GI bleeding, peptic ulcers, and
renal disease. Acetaminophen has been shown to be efficacious in patients
with mild to moderate pain [102], but NSAIDs are typically the first line
medication of choice. Tramadol has also shown efficacy in pain control as
compared to placebos [103].

Physical Therapy

Physical therapy (PT) is often prescribed in conjunction with pain

medication. The focus of PT varies depending on practice preference, but the
program usually entails: core strengthening, paraspinal flexibility, extension
maneuvers, and stretching. PT has been shown to produce good and excellent
outcomes, less health care utilization, and increased return to work rates in
those patients that exhibit “centralization” [106- 110]. Centralization is
operationally defined as when a patient’s symptoms move distally from the
appendicular skeleton to a more central location in the axial lumbar spine with
specific end range extension movements of the lumbar spine [111].
172 Ajit Jada, Roger Härtl and Ali Baaj

Chiropractic manipulation is controversial for treatment of LDH, with no

evidence showing that chiropractic manipulation alters disc physiology. Also
of note, bed rest is not recommended for more than 2 days; with longer periods
of bed rest potentiating adverse effects [101].

Epidural Steroid Injections

Some practitioners will also initially recommend epidural (ESI) or

transforaminal (TFESI) steroid injections for pain relief. Studies have shown
the efficacy of ESI/TFESI in early relief of radicular pain from LDH when
compared to controls [104, 105]. It is important to note that patients without
prior surgery receive better pain relief from ESIs than those with prior surgery
[115]. Patients with prior microdiscectomies may have pain from epidural
scarring or fibrosis which an ESI will not ameliorate. Complications from ESIs
are rare but can include headaches (from intra-dural puncture), epidural
hematomas, arachnoiditis, meningitis, and retroperitoneal hematomas [102,
112, 113].
Contraindications to ESIs include:

 Patients that are on anticoagulants or have coagulopathies. There is a

substantial risk for epidural hematomas in these patients.
 The American Society of Regional Anesthesia recommends that
patients stop Ticlopidine for 14 days and Clopidogrel for 7 days prior
to ESI [114].
 Aspirin recommendations vary but most practitioners will hold the
ASA for 5 to 7 days [115].
 Uncontrolled diabetes is a relative contraindication, but can be
performed with increasing glucose medications prior to ESI and close
blood sugar monitoring afterward is recommended [115].
 Patients with systemic or local active infections [115].

SURGICAL MANAGEMENT
Several techniques are available for treatment of lumbar disc herniations
and ultimately, the decision on which technique to use lies with the surgeon
and which procedure he/she is most comfortable with. Though the techniques
 Lumbar Disc Herniations 173

vary, there are only a few conventions of LDH surgery and the objective of the
operation is the same; regardless of technique.
The objective of the surgery is to decompress the affected nerve root in an
atraumatic fashion and to maintain the stability of the axial lumbar spine i.e.,
maintain the structural integrity of the pars and lateral facet joints. If the
surgeon is too aggressive with bony removal of the lateral facets or pars, this
may result in overt or micro-instability which would necessitate a fusion
procedure in the future. Some surgeons will remove the entire disc at the
affected level, whereas the authors of this chapter prefer a more minimally
invasive approach and mostly perform fragmentectomies. The surgeon should
remember that minimizing scar formation during the procedure is always
essential in case reherniation does occur at a later point and re-operation is
necessary.

Figure 5. Laminectomy.

SURGICAL TECHNIQUES

The patient is brought to the operating room and general endotracheal

anesthesia is induced. The patient is typically intubated on a stretcher in the
174 Ajit Jada, Roger Härtl and Ali Baaj

operating room and flipped prone onto the surgical table. Different tables can
be used depending on the procedure and surgeon preference. The authors
prefer a Jackson (OSI) table with a Wilson frame attachment. However, an
Andrews frame can be attached to a standard Mizuho table to facilitate a prone
kneeling position. A C-arm or X-ray is then utilized to localize the appropriate
level.

Open Laminectomy and Disc Removal

Once prepped and draped, a 3-5 cm midline incision is made, which may
be longer for obese patients. The subcutaneous tissue is dissected down to the
spinous process in standard fashion and subperiosteal dissection technique
thereafter (Figure 5). At this point, the authors recommend the use of a
surgical microscope for improved visualization. The laminectomy is
performed in the standard fashion with care to preserve the lateral facets and
pars. Subsequently, the flavectomy is performed and epidural fat and thecal
sac can be seen. Of note, the wide interlaminar space at L5-S1 enables
adequate access to the disc without the need for a laminectomy. At this point,
the surgeon should find the exiting nerve root and carefully bipolar epidural
vessels as necessary. The medial facet is typically drilled in order to expose
the exiting nerve root. The surgeon then can mobilize the nerve root with a
Penfield
4 and then retract the nerve medially to expose the disc. If the disc herniation
is transligamentous, the fragment can be removed with a pituitary rongeur.
Whereas if the herniation is subligamentous, A No. 15 or No. 11 blade is used
to create a small annulotomy to remove the herniated fragment. The nerve root
is examined to ensure that it is decompressed. The area is irrigated and
meticulous hemostasis should be achieved. The wound is closed in a standard
fashion. Typically, a subcutaneous or epidural JP is not needed.

Microlaminotomy/Microdiscectomy (MID)

Microlaminotomy and Tubular Microdiscectomy are now considered the

gold standard operation for removal of lumbar disc herniations.
Microlaminotomy is performed with a 2-3 cm incision in the midline and the
 Lumbar Disc Herniations 175

subcutaneous dissection is carried out in the standard fashion of the open

laminectomy. Once the fascia is exposed, the subperiosteal dissection is
performed only on the side ipsilateral to the herniation. Most surgeons will use
a McCulloch or Caspar retractors at this point. There is no difference between
the open and microlaminotomy from this point forward and the discectomy is
performed in a similar fashion.

Figure 6. Microdiscectomy.

Tubular Microdiscectomy

The authors prefer the tubular microdiscectomy technique for LDH

operations (Figure 6). After intubation, the patient is positioned on a Jackson
table with a Wilson frame, with the tubular retractor arm placed opposite
the surgeon. Once localized and draped, a 1.5-2 cm incision is made on the
ipsilateral side of the herniation, 1 cm lateral to the midline. The subcutaneous
tissue is separated with monopolar cauterization down to the thoracolumbar
fascia. Once reached, the fascia is incised with a 15 mm blade and the dilator
176 Ajit Jada, Roger Härtl and Ali Baaj

tubes are introduced sequentially under fluoroscopic guidance, ultimately

docking a 15mm tube on the lamina overlying the disc space of interest. As a
technical note, the lamina of the superior vertebra typically overlaps in the
intervertebral disc space. The microscope is brought into the field and utilized
until completion of the procedure. The hemi-laminotomy is performed in the
standard fashion described above.

Endoscopic Surgery

Endoscopic spine surgery is a newer technique that has gained traction

with some surgeons (Figure 7). The technique can be performed from various
approaches, either transforaminally from a posterolateral or lateral approach,
and interlaminar from a posterior approach. The endoscopic technique allows
surgeons to perform these procedures under local anesthesia. Thus, patients
can be awake for the procedure and comment on if their radicular pain is better
during surgery.
Depending on surgeon preference, patients are positioned prone or lateral
on an x-ray permeable table with bolstering under the hips and thorax for
support in the prone position. For the transforaminal approach the appropriate
levels are localized and with the use of AP and Lateral fluoroscopy and an
atraumatic spinal needle is inserted into the appropriate disc space through
Kambin’s triangle, between the exiting nerve root and the traversing root.
Sequential reamers are used to enlarge the foramen and to remove the ventral
aspect of the superior facet. An 8-10 mm working cannula is then inserted over
the dilators and a drill is used to enlarge the foramen to expose the exiting
nerve root and the pedicle. Different degree endoscopes can be used to fully
visualize the exiting and traversing nerve roots for areas of compression. The
discectomy is performed in a similar fashion as described above, with the
exception of endoscopic instruments and visualization provided via endoscope
as opposed to microscopy. Again, the procedure can be performed with local
anesthesia, so the patient can comment on pain relief during the surgery. If the
patient still has pain after the fragment is removed, the surgeon can further
investigate the operative area for further disc material or other areas of nerve
root compression. For further elaboration on the technical aspects of the
procedure, Jasper et. al [116] provides a detailed case report of an endoscopic
transforaminal approach for removal of a lumbar disc herniation.
 Lumbar Disc Herniations 177

Figure 7. Endoscopic Spine Surgery.

Percutaneous Laser Disc Decompression

Percutaneous Laser Disc Decompression (PLDD) was approved by the

FDA in 1991 and is a relative new procedure for treatment of LDH.
Contraindications to the procedure are:

 Central stenosis
 Bony spurs that prevent percutaneous entry into disc space
 Sequestered fragments
 Ruptured PLL
 (relative contraindication) Neurologic deficit
 (relative contraindication) Significant facet arthropathy

This procedure can be performed under local anesthesia. After the patient
is anesthetized, he is flipped prone onto an open Jackson table or flat x-ray
permeable table. With fluoroscopy, an 18-gauage 7 inch needle is introduced
into the NP, parallel to the endplates, by means of a standard posterolateral
approach. The end point of the needle on AP projection should be halfway
between the lateral border of the spinous process and the medial border of the
pedicle (Figure 8). Lateral films should demonstrate the needle tip at the
junction of the posterior ¼ of the disc with the anterior ¾. There is variability
depending on technique after needle insertion. There is a LASE system, Laser
178 Ajit Jada, Roger Härtl and Ali Baaj

fiber or Modified Choy Technique, and rigid-scope endoscopic laser

technique. The modified Choy Technique is described below:
The technique involves inserting a Nd:YAG fiber through the needle tip
and subsequently removing the insertion needle. Typically, lesioning at 20W
with 5 seconds between 1-second pulses is used. The total energy used is 1000
J or up to 1500J is the patient is great than 165cm in height. The patient is able
to alert the physician if there is any new radicular pain during the ablative
period.
It is important to note that during the PLDD procedure there is no direct
visualization of the nerve roots, disc material, or thecal sac. The extent of
neurologic decompression cannot be determined by this procedure.

Figure 8. Percutaneous Laser Disc Decompression.

POST-OPERATIVE MANAGEMENT
The senior authors of the chapter typically discharge a patient the same
day after an uncomplicated discectomy. If the patient has significant co-
morbidities then the patient will be admitted for overnight observation. Post-
operatively, patients are instructed to not lift objects more than 5 lbs and to
limit bending and lifting for 4 weeks. Patients will normally return to work,
depending on the type of occupation, after 1 week and will start rehabilitation,
if needed, after 4 weeks.
 Lumbar Disc Herniations 179

There is varying data on the efficacy of early rehabilitation. A Cochrane

database review by Oosterhuis [132] demonstrated that exercise programs
starting 4-6 weeks post-op seem to lead to a faster decrease in pain and
disability as compared to no treatment, with small to medium effect sizes.
Also, high intensity programs lead to a slightly faster decrease in pain and
disability versus low intensity regimens. Of note, the quality of the studies
reviewed in the analysis varied drastically. Large randomized controlled trials
are still needed on the subject.

NON-OPERATIVE TREATMENT VERSUS

OPERATIVE TREATMENT
There have been several trials delineating outcomes of patients that
underwent non-operative vs operative management of lumbar disc herniations.
Much of the data presented demonstrates that there is a role for surgical
intervention for the treatment of LDH and radiculopathy. Operative patients
have earlier recoveries than would have otherwise occurred spontaneously.
One classic study was performed by Weber [117]. The study performed
was a prospective, randomized study analyzing surgery vs non-operative care.
The patients were placed into 3 study groups: one group had definitive
indications for surgery, another group had no indications for surgery, and the
last group could be treated with or without surgery. The last group was
randomly assigned to operative or non-operative management.
The data demonstrate that at 1 year good results occurred in 33% of the
non-operative group vs. 66% in the operative group; at 4 years, 51% of the
non-operative group reported good results vs. 66% in the operative, and at 10
years 55% of the non-operative group reported good results vs. 57% in the
operative group. The study demonstrates that initially, the operative group did
better than the non-operative group, but over a 10 year period the outcome
data appeared to converge [117].
The MAINE lumbar study was a long term prospective cohort analyzing
507 patients with LDH referred to a neurosurgeon or orthopaedic surgeon
[118]. Of the 507 patients 275 were treated surgically and 232 non-surgically.
At 1 year follow-up 71% of surgically treated patients reported that their
predominant symptom was better or completely gone compared with 43%
non-surgically treated patients. At 10 years, 69% of patients initially treated
with surgery reported improvement in their predominant symptoms versus
180 Ajit Jada, Roger Härtl and Ali Baaj

61% treated non-surgically [119]. Also, 56% of surgical patients vs 40% non-
surgical reported that their low back pain and leg pain were completely gone
and were more satisfied with their current status (71% vs. 56%). [119].
However, at 10 years, there were no differences in work or disability status
between both groups.
The spine patient outcomes research trial, (SPORT) is another large,
recent, trial comparing operative vs. non-operative patients with LDH [120-
122]. The trial was conducted in 11 states at 13 medical centers and included
men and women who had symptoms and confirmatory signs of lumbar
radiculopathy that persisted for at least six weeks, who had disc herniation at a
corresponding level and side on imaging, and who were considered surgical
candidates were eligible. Participants were offered enrollment in one of 2
groups, a randomized trial or an observational cohort prospective randomized
[501 participants) and observational cohorts [743 participants) at 13 spine
clinics in 11 US states. Interventions were standard open discectomy versus
usual non-operative care which entailed active physical therapy,
education/counseling with home exercise instruction, and non-steroidal anti-
inflammatory. Main outcome measures were changes from baseline in the SF-
36 Bodily Pain (BP) and Physical Function (PF) scales and the modified
Oswestry Disability Index (ODI - AAOS/Modems version) assessed at 6
weeks, 3 and 6 months, and annually thereafter [120-122].
In the observational cohort, at 3 months, those patients who chose surgery
had larger improvements in the primary outcome measures of bodily pain
(mean change: surgery, 40.9 vs non-operative care, 26.0; treatment effect,
14.8; 95% confidence interval, 10.8-18.9), physical function (mean change:
surgery, 40.7 vs non-operative care, 25.3; treatment effect, 15.4; 95% CI, 11.6-
19.2), and Oswestry Disability Index (mean change: surgery, −36.1 vs non-
operative care, −20.9; treatment effect, −15.2; 95% CI, −18.5. to −11.8).
These differences narrowed somewhat at 2 years. At 4 years, the
combined data, in both randomized and observational cohorts, those patients
who underwent surgery for LDH had greater improvement than non-operative
patients in all primary and secondary outcome measures except work status
[122]. In the 8 year follow-up, combining the randomized and observational
cohorts demonstrated a significant improvement in pain, function, satisfaction,
and self-rated progress over 8 years in the surgical cohort vs the non-operative
one [126].
Finally, looking at cost-effectiveness data from the SPORT analysis [125],
the authors noted that surgery was more initially more costly than non-
operative management, however health outcomes in the first 2 years were
 Lumbar Disc Herniations 181

better with surgical management. Furthermore, when looking at costs per

quality-adjusted life years (QALY) gained with surgery as compared to non-
operative management, the totals were $34,355 vs $69,403 for surgery and
non-operative management, respectively. Thus, surgery is ultimately a more
cost-effective treatment modality than conservative management for the
treatment of symptomatic LDH patients [125].
Key Points:

 Most LDH respond well to conservative management within the first

3 months of symptom onset.
 Patients with progressive neurologic deficits or cauda equina are
absolute indications for surgery.
 The ideal surgical patient for LDH is one with severe unilateral
radicular pain who has tried and failed conservative management and
whose imaging correlates with the clinical findings.
 Discectomy in patients appears to provide faster symptomatic relief in
appropriately selected patients as opposed to the natural history of the
disease.
 Over the course of several years the differences between outcomes in
the operative patients and non-operative patients narrows, but surgical
patients still report better outcomes than non-operative patients.
 Improvement in back pain, paresthesias, and weakness, are less
reliable outcomes than improvement in radicular pain.
 Surgical management of LDH is more cost-effective than non-
operative management for treatment of symptomatic LDH patients.

SURGICAL OUTCOME DATA

Outcomes for surgical intervention have been well documented and
produce reliable results as demonstrated in the non-operative vs. operative
treatment section of the chapter. Also described earlier in the chapter, a study
performed by Carragee et. al [57], found that operations on larger discs
(>6mm) produced better results than patients with disc < 6mm. However, disc
size is a less reliable predictor of outcome in the non-operative group. In
another study by Knop-Jergas [123] found that patients with paracentral and
intraforaminal discs had the best outcomes with 80% of patients yielding good
or excellent results.
182 Ajit Jada, Roger Härtl and Ali Baaj

The post-hoc analysis of the SPORT data [124] found that patients with
lateral disc herniations had the greatest improvement from surgery vs non-
operative management. Furthermore, the data demonstrated that the level of
disc herniation or morphology did not influence outcome in either the surgical
or non-surgical groups.
Of note, social and psychological factors have a strong influence on
outcomes after LDH surgery. A study by Sorensen found that the outcome of
LDH surgery could be predicted correctly in 86% of patients based on pre-
operative psychological assessment [127]. Another study analyzing personality
factors and results of LDH surgery found that patients that were self-confident,
concerned with their illness, only mildly depressed, optimistic regarding their
outcome, and able to withstand setbacks without resorting to emergency
reactions had good outcomes [128]. An analysis performed by Johansson
[129] found that low expectations for work return within 3 months after
surgery was also significantly predictive for residual leg pain.

Return to Play Outcomes

A study from the Professional Athlete Spine Initiative (PASI) in 342

players with LDH from baseball, football, hockey, and basketball returned to
play 82% of the time with 81% of surgically treated patients returning to play
for an average of 3.3 more years [130]. Another recent study by Minhas et al.
[131], studied 61 players in the NBA with an LDH. 34 players underwent
discectomy, 27 were managed conservatively. Return to play did not differ
between the groups, player efficiency in the operated group was lower than the
non-operative group in the first year post-op, but no difference was seen 2 and
3 years after surgery [131]. In another recent study by Watkins [133]
determining return to play in MLB, NBA, NFL and NHL athletes after lumbar
discectomy, found no significant differences in return to play after level of
surgery. Although, L5-S1 discectomies were the most common procedure and
L3-4 discectomies were the least common. No discectomies were performed at
L1-2, or L2-3. This study accounted for off-seasons in the individual sports
and found that 89.3% returned to play after surgery with an average off time of
5.8 months. Furthermore, 50% of players returned to sport at 3 months, 72% at
6 months and 84% at 12 months [133].
 Lumbar Disc Herniations 183

Key Points:

 > 6mm disc herniations produce better post-operative outcomes than

disc herniations < 6mm.
 Paracentral and intra-foraminal disc herniations produce good post-
operative outcomes, whereas patients with lateral disc herniations do
better with surgery as opposed to non-operative treatment.
 Location of disc herniation does not influence post-surgical outcome
 Social and psychological factors do influence post-operative
outcomes, namely depression and desire to return to work.
 50% of athletes will return to play at 6 months and 84% at 1 year post
lumbar discectomy.
 The athlete may not be at his peak performance during the 1st year
post-op, but will return to his baseline during subsequent years.

COMPARISON OF DIFFERENT SURGICAL TECHNIQUES

There is debate in the literature regarding which procedure yields the best
outcomes when comparing standard open discectomy (SOD), minimally
invasive lumbar discectomy (MLD), tubular microdiscectomy (MTD),
endoscopic discectomy (ED) and percutaneous laser disc decompression
(PLDD). The authors of the chapter have a personal preference for the tubular
microdiscectomy technique.
A study by Ryang et. al [134] compared standard open discectomy (SOD)
versus tubular/trocar microdiscectomy (MTD). The authors found small, non-
significant, differences that favored MTD over SOD in regard to decreased
operative time, blood loss, and complication rate. However, at follow up of 16
months, there were no differences in clinical outcomes as measured by CAS
pain, Oswestry Disability Index (ODI), or SF-36 scales [134]. Another
randomized prospective trial comparing SOD vs MLD found that: size of
incision, and length of hospital stay were greater in the SOD group, and
operative time was greater in the MLD group. Overall patient outcome was
comparable between the 2 groups [135].
A meta-analysis of the literature comparing minimally invasive (MIS)
techniques (MLD and MTD) versus SOD for LDH found moderate-quality
evidence that failed to show an advantage of MIS techniques over SOD in
terms of short and long-term pain outcomes. There was also low-quality
184 Ajit Jada, Roger Härtl and Ali Baaj

evidence that suggested higher rates of nerve root injury, durotomy, and re-
operation with the minimally invasive techniques when compared to the
standard open surgery [136]. However, the authors did not consider blood loss,
radiation exposure, operating time, and muscle injury when performing the
meta-analysis [136].
Arts et al., performed a double-blind randomized controlled trial
comparing MTD versus MLD for LDH in 328 patients. They found no
significant differences in clinical or functional outcomes for either group. The
study followed patients for 2 years and noted small differences with MTD
patients reporting more leg pain and low back pain, however the differences
did not achieve statistical significance or clinical relevance [137].
However, when considering the complications associated with obese
patients MIS procedures afford benefits over SOD. In a retrospective review
Tomasino et al. [138], studied 115 obese and nonobese patients that underwent
a 1 level lumbar laminectomy or microdiscectomy via MTD. The outcomes
were comparable between both groups and when compared to SOD, MTD
offered smaller incisions, and decreased operative time, blood loss, and length
of stay [138].
Another recent study comparing microsurgical, endoscopic, and
endoscopically assisted discectomies in both a randomized prospective cohort
and a retrospective cohort found all procedures were effective in relieving
acute radicular symptoms. The study found no significant differences in
outcome at 1 year follow-up. However, recurrent disc herniation occurred
more frequently after endoscopic discectomy as compared to MTD and MLD
[140].
In another prospective randomized study comparing full-endoscopic
interlaminar and transforaminal lumbar discectomy versus conventional MLD,
the authors found no difference in clinical outcomes between both groups and
similar recurrent disc herniation rates (6.2%). The authors reported benefits of
ED over MLD and MTD to include: expanded fields of view, shorter operative
times, reduced anatomic trauma, and facilitation of revision operations.
Possible disadvantages of ED over MLD and MTD include the limited
possibility of extending the approach in the event of unforeseen complications,
and in the trans-foraminal technique, there is an elevated risk of exiting nerve
root injury. Furthermore, the learning curve is steeper in the ED technique as
compared to the MIS techniques [141].
Percutaneous laser discectomy was compared to conventional MLD for
treatment of sciatica in a randomized controlled trial performed by Brouwer et.
al, [142]. The goal of the study was to demonstrate non-inferiority of PLDD to
 Lumbar Disc Herniations 185

MLD. 115 surgical candidates with sciatica from a disc herniation smaller than
one-third of the spinal canal were included. Patients were randomly assigned
to either the PLDD (n = 57) or MLD (n = 58) group. It is important to note that
the following patients were excluded from the study: patients with cauda
equina syndrome, previous spinal surgery at the same disc level, lytic or
degenerative spondylolisthesis, sequestered disc herniation, disc height less
than 7 mm, and patients with central canal stenosis. The results showed non-
inferiority of PLDD compared to MLD at 52 weeks using the Roland-Moriss
Disability Questionnaire. There was a higher speed of recovery in favor of
MLD and the number of reoperations was significantly less in the MLD group
(38% vs 16%).
Minimally invasive and endoscopic techniques are technically demanding
and require significant expertise. There is a well-documented learning curve
associated with these procedures [139, 141], however; the benefits over
standard open techniques include: decreased blood loss, operative time,
incision length, and length of stay [134-138]. The differences between the MIS
and ED techniques are negligible and preference should depend on the
surgeons comfort with the procedure and their level of training. PLDD has
limited indications and may provide benefit for some patients with small disc
bulges or herniations that are in direct continuity with the NP.

Comparisons of the different procedures, with the exception of the PLDD,

are provided in Table 1 and 2. Table 3 demonstrates comparisons between
open discectomy versus microdiscectomy, and microdiscectomy versus tubular
microdiscectomy.
Key Points:

 Standard open discectomy has similar patient outcomes when

compared to minimally invasive techniques e.g., tubular
microdiscectomy, microdiscectomy, and endoscopic techniques.
 MIS techniques compared to open techniques offers decreased blood
loss, operative time, incision size, and length of stay.
 Differences in outcomes between MLD, MTD, and ED are negligible.
 PLDD has very limited proven indications: only for small disc bulges
or protrusions.
 PLDD has been associated with a higher need for re-operation.
Table 1. Comparison of Operative Techniques
 Table 1. (Continued)

The “+” symbol indicates the strength of association of a particular feature with the type of surgery. The more “+” symbols, the stronger the
association.
Reprint from: [174] Härtl R. Andreas K. Minimally Invasive Spine Surgery—Techniques, Evidence, and Controversies. 2012 ed. Switzerland,
Davos Platz: Thieme; 2012. p. 294.
Table 2. Comparison of Operative Techniques
The “+” symbol indicates the strength of association of a particular feature with the type of surgery. The more “+” symbols, the stronger the
association.
Reprint from: [175] Härtl R. Andreas K. Minimally Invasive Spine Surgery—Techniques, Evidence, and Controversies. 2012 ed. Switzerland,
Davos Platz: Thieme; 2012. p. 295.
 Table 3. Evidence based Results of 3 prospective trials comparing standard discectomy vs. microdiscectomy, and
microdiscectomy vs. microsurgical tubular discectomy

Evidence-based results of three prospective trials comparing standard discectomy, microdiscectomy, and microendoscopic discectomy
techniques.
S: statistically significant, NS: not statistically significant, VAS: visual analog scale.
a) Katayama Y, Matsuyama Y, Yoshihara H (2006). Comparison of surgical outcomes between macrodisectomy and microdisectomy for
lumbar disc herniation: a prospective randomized study with surgery performed by the same spine surgeon. J Spinal Disord Tech;
19(5):344-347.
b) Porchet F, Bartanusz V, Kleinstueck FS (2009). Microdiscectomy compared with standard discectomy: an old problem revisited with new
outcome measures with the framework of a spine surgical registry. Eur Spine J; 18 Suppl 3:S360-S366.
c) Arts MP, Brand R, Akker ME, et al. (2009). Tubular discectomy vs conventional microdiskectomy for sciatica: a randomized controlled trial.
JAMA; 302(2):149-158.
Reprint from: [176] Härtl R. Andreas K. Minimally Invasive Spine Surgery—Techniques, Evidence, and Controversies. 2012 ed. Switzerland,
Davos Platz: Thieme; 2012. p. 307.
 Lumbar Disc Herniations 191

EXTRA FORAMINAL (FAR LATERAL) DISC HERNIATIONS

Extra foraminal or, far lateral, lumbar disc herniations (FLLDH) account
for 2.6 to 11.7% of all lumbar disc herniations resulting in nerve root
compression [143-146], the majority of which occur at L4-5 [148, 151]. Far
lateral disc herniations are classically lateral to the neural foramen (Figure 2).
Of note, these herniations compress the exiting nerve root as opposed to the
descending nerve root which is typically compressed by central disc
herniations. Accessing FLLDH without destabilizing the lumbar spine or
injuring the nerve root is challenging. Earlier techniques to approach FLLDH
required a unilateral facetectomy, which ultimately resulted in fusion surgery
for these patients [147].
Standard open techniques can be used without a facetectomy to access the
far-lateral herniations. However, as described by Virk et al., [148] standard
open techniques require long midline incisions (4-8cm) and wide sub-
periosteal dissections resulting in significant muscle retraction and post-
operative morbidity. To minimize muscle trauma with open techniques, the
Wiltse paraspinal muscle-splitting approach has been used with success.
Weiner et al., [149] accessed far lateral herniations using the Wiltse technique
and followed patients for an average of 5.5 years after surgery. They found
that 85% of patients were satisfied with their post-op results, pain was
eliminated in 60% of patients, while 50% reported still having some degree of
low back pain.
Liu et at., [150] performed an investigation using ED, MTD, and a
minimally invasive transforaminal lumbar interbody fusion (TLIF), techniques
for treating FLLDH. The authors characterized the herniations as type I
(foraminal), type II (extra-foraminal), and type III (mixed). The authors found
ED was associated with the shortest operation time and simplest anesthesia
and least trauma, especially for type I herniations. MTD was particularly
useful for type II herniations and TLIF produced the best outcomes for type III
herniations because the authors need to remove the ipsilateral facet joint to
access the herniations.
The authors prefer to approach FLLDH using MTD as described by Virk
and Elowitz (Figure 9) [148]. The authors describe their approach by making a
2 cm incision, 2 cm lateral to midline, ipsilateral to the pathology. The
thoracolumbar fascia is opened with a stab incision (1 cm) by scalpel or bovie
electrocautery. The initial dilator is introduced through the fascial incision and
docked on the lateral aspect of the pars interarticularis under fluoroscopic
192 Ajit Jada, Roger Härtl and Ali Baaj

guidance. K-wires and Steinmann pins are not used in order to lower the risk
of durotomy or nerve root injury. Serial dilation occurs until an 18 mm tubular
retractor placed. An operative microscope is utilized to identify the bony
landmarks; defined medially as the lateral aspect of the pars and caudally by
the inferior facet. The lateral pars is drilled to maximize medial exposure. The
ligament is opened to expose Kambin’s triangle. The nerve root is gently
retracted supero-laterally to remove the extruded disc. The authors reported
excellent results with complete resolution of symptoms in all patients; with
none returning after 6 week follow up with recurrent or new symptoms or the
need for re-operation or fusion [148].

Figure 9. Virk and Elowitz Approach.

 Lumbar Disc Herniations 193

Key points:

 Surgery for far lateral disc herniations is more complicated than other
types of LDH.
 Care must be taken to preserve the bony architecture to prevent
instability.
 If the facet joint must be taken, fusion surgery is indicated and
produces good outcomes.
 MIS techniques produce excellent results and most surgeries can be
performed by MTD without destabilizing the lumbar spine.

RECURRENT DISC HERNIATION

Recurrent disc herniation (RDH) is defined as reherniation of disc material
at the level of a prior lumbar discectomy. The frequency of RDH herniations
varies in the literature, but rates are generally reported as 5 to 15% [152-156].
Patients who have RDH may present with the same symptomatology as their
initial herniation. It is important to distinguish whether the recurrence of
symptoms is due to scar tissue or RDH. As described previously in this
chapter, post-operative scar tissue and fibrosis will enhance with gadolinium
contrast, whereas RDH will not.
A prospective study was performed by McGirt et al. [157] studying
whether aggressive disc space removal was associated with increased risk of
RDH. The study observed 100 patients which underwent lumbar discectomy
surgery that were followed for 2 years. 11 patients experienced RDH. The
authors found that patients experiencing symptomatic RDH requiring re-
operation had a greater mean annular defect area and lower percentage of their
disc volume removed (46 +/- 18 vs. 32 +/- 14mm2). Furthermore, larger
annular defects were associated with earlier symptomatic reherniation (4
months after surgery). Thus, the authors concluded that large annular defects
with less aggressive disc space removal is associated with increased risk of
reherniation. It was also demonstrated that aggressive disc space removal was
associated with loss of disc height, which ultimately, may exacerbate lumbar
disc degeneration. Conversely, Thorne et al., [158] found no correlation
between amount of disc removed and risk of RDH. McGirt et. al., [157]
explained the contradiction stating that it is the residual proportion of disc left
194 Ajit Jada, Roger Härtl and Ali Baaj

after discectomy, rather than absolute volume removed, that carries prognostic
significance of RDH.
Another retrospective review by Moliterno et. al [162] noted a recurrence
rate of 9.5% in patients undergoing MTD for LDH, with the most common
level involved being L5-S1. The mean length to recurrence was 12 weeks and
lower body mass index (BMI) was significantly associated with recurrence. A
recent large meta-analysis investigated age, gender, BMI, smoking, level of
herniation, herniation type, and BMI as of risk factors for RDH. The authors
found that smoking, lumbar disc protrusion without a herniated fragment, and
diabetes were all correlated with RDH [161]. Interestingly, obesity was not
correlated with increased risk of RDH.
The authors of this chapter evaluate each patient on a case-by-case basis
but generally recommend fusion surgery when more than 2 discectomies are
performed at the same level for RDH.

Annular Repair

As described above, large annular defects are associated with reherniation

and progressive disc degeneration. Newer techniques and research have
focused on annular repair and biologic glues to prevent RDH after discectomy.
A large prospective, randomized, multicenter trial studying annular repair
in lumbar discectomy found that using the Xclose annular repair system
(Anulex Technologies, Minnetonka, MN) reduced RDH at 3 and 6 months
post op [172]. There was also a trend toward reduced risk of RDH through 2
years, but these values did not achieve significance.
Yu et al. [169], performed a comprehensive review of the literature on
techniques available for annular and disc repair. The authors found that
approaches involving mechanical treatments such as suturing, i.e., Xclose, and
annulopasty, failed to improve annular healing strength in long-term clinical
trials [170-172].
In contrast to mechanical AF repair, Grunert et al., reported promising
data from their current trials on biologic glue for AF repair. They successfully
demonstrated the in vivo efficacy of riboflavin cross-linked high-density
collages gels to facilitate annular repair in a needle-punctured rat-tail model.
Their results demonstrated preservation of NP size, hydration and prevention
of further degeneration [173].
Key Points:
 Lumbar Disc Herniations 195

 Large annular defects and less aggressive disc removal may be

associated with increased risk of RDH.
 Volume of disc material removed is associated with decreased disc
height and possibly increased degeneration.
 Smoking, disc protrusion, and diabetes were correlated with increased
risk of RDH.
 Lower BMI may be a risk factor for RDH.
 Annular repair is a promising new technique to prevent RDH.
 The authors recommend fusion surgery when more than 2
discectomies are performed at the same level for RDH.

CAUDA EQUINA SYNDROME

Cauda equine syndrome (CES) is caused by compression of the lumbar
and sacral roots which results in bowel or bladder incontinence and/or saddle
anesthesia. There can be associated weakness in the lower extremities,
paresthesias in a dermatomal distribution, and absent/decreased reflexes [163].
Acute CES is usually caused by LDH where the herniated fragment occupies
the whole canal [164]. CES is more common with a central disc herniation, but
can occur with lateral or paracentral herniations as well [166, 167]. When
acute CES occurs, it is a surgical emergency and immediate imaging should be
performed followed by surgical decompression. MRI is the standard for
imaging, however a CT with contrast can be performed if the patient cannot
undergo an MRI.
The data has shown that CES should be treated within 48 hours as
opposed to later than 48 hours, due to improved outcomes in resolution of
sensory and motor deficits, rectal function, and urinary function [165].
Furthermore, studies have also shown the presence of preoperative chronic
low back pain is associated with poorer outcomes in urinary and rectal
function and older patients are less likely to fully regain sexual function after
surgery [165]. Post-void residual should be measured in CES patients pre-
operatively and should be followed post-operatively as well.
There is considerable debate in the literature on which surgical technique
is optimal for decompression in patients with CES. Either MIS or open
techniques can be employed and studies have demonstrated that either
technique is appropriate and result in comparable outcomes [163, 167, 168].
Some studies favor MIS techniques over SOD for CES, with improved VAS,
196 Ajit Jada, Roger Härtl and Ali Baaj

ODI, and Frankel scores in MIS techniques [168]. Ultimately the type of
surgical approach should be determined by the experience of the surgeon and
the nature of the injury resulting in CES.
Key Points:

 CES is a surgical emergency.

 MRI is the optimal imaging modality.
 CES surgery should be performed within 48 hours of presentation.
 Open or MIS techniques can be used for decompression.

CONCLUSION
Given their prevalence, lumbar disc herniations present challenges and a
set of options for conservative and surgical remedy. Although it is not
essential to know the details of every procedure outlined here, spine surgeons
must possess mastery of several different techniques while also generally
aware of alternatives.

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 9

LUMBAR DEGENERATIVE
SPONDYLOLISTHESIS

Sam Cartmell, B. A., Eric S. Sussman, MD

and John K. Ratliff*, MD
Stanford University School of Medicine,
Department of Neurological Surgery,
Stanford University School of Medicine, Stanford, California, US

ABSTRACT
Lumbar Degenerative Spondylolisthesis (LDS) is a common
condition affecting the lumbar spine characterized by chronic arthritis and
bony remodeling of the facet joints. Epidemiologic studies have revealed
that LDS is a relatively common condition among older patients, and may
be asymptomatic in many affected individuals. While conservative
treatment measures are often utilized initially, the mainstay of
management for persistently symptomatic LDS is surgical
decompression. Despite a number of recent well-designed randomized
clinical trials, there remains no consensus regarding the optimal method
of surgical treatment, including whether or not lumbar spinal fusion
provides added clinical benefit beyond decompression alone. This chapter
reviews the epidemiology and clinical presentation of LDS, as well as the

*
Corresponding Author address Correspondence to: John K. Ratliff ([email protected]),
Department of Neurosurgery. Stanford University School of Medicine. 300 Pasteur Drive,
R281. Stanford, CA 94303-5327.
212 Sam Cartmell, Eric S. Sussman and John K. Ratliff

existing evidence for the range of surgical treatments that have been
utilized in patients suffering from this condition.

Keywords: lumbar disc degeneration, decompression, fusion,

spondylolisthesis

INTRODUCTION
Spondylolisthesis (Greek spondylos “vertebrae” + oliothesis “dislocation,
slipping”) is defined as the anterior translation of one vertebral body relative to
the next caudad vertebrae. Spondylolisthesis has numerous etiologies, and
most commonly affects the lumbar spine. Since the first description of this
clinical syndrome in the late 18th century, several classification systems have
been proposed. The most widely used schema is the Wiltse Classification
system, which identifies five forms of spondylolisthesis based on the location
and character of the defect (Table 1). Type 1, or dysplastic spondylolisthesis,
is due to congenital abnormalities of the superior sacral and/or inferior L5
facet. Type II, or isthmic spondylolisthesisis is due to a defect in the pars
interarticularis, and is further divided into three subtypes: IIa due to a stress
fracture of the pars, IIb due to elongation of the pars, and IIc due to acute or
traumatic fracture of the pars. Type III, or degenerative spondylolisthesis, is
due to intersegmental instability at the location of the facet joints secondary
to chronic arthritis and bony remodeling. Type IV, or traumatic
spondylolisthesis, is due to fractures of elements of the neural arch aside from
the pars. Finally, Type V, or pathological spondylolisthesis, is due to
generalized or localized destruction of the posterior elements, as may occur in
the setting of underlying malignancy, infection or another secondary process
(Wiltse, Newman, and Macnab 1976). Another important schema is the
Meyerding Classification system, which assigns a grade (I–IV) based on the
extent of anterior migration of the cephalad vertebral body on the caudad
vertebral body (Meyerding 1933) (Table 2). This chapter will focus on Wiltse
Type III spondylolisthesis, or lumbar degenerative spondylolisthesis (LDS).

Epidemiology and Risk Factors

Given the underlying degenerative etiology of this disease, LDS typically

occurs in older patients. It rarely occurs before age 40, and the prevalence
 Lumbar Degenerative Spondylolisthesis 213

increases in a stepwise fashion from the 5th to the 7th decade of life. There is a
distinct female gender predominance, with some sources citing a six-fold
increased incidence in females. In addition, black individuals are affected as
much as three times as frequently as Caucasians (ROSENBERG 1976;
Jacobsen et al. 2007; Kalichman, Kim, et al. 2009).
The majority of available epidemiologic data regarding LDS comes from
two large longitudinal regional health studies. A cross-sectional analysis of a
subgroup of patients from the Framingham Heart Study investigated the
relationship between lower back pain and LDS. Among 188 patients aged 40-
80 who underwent CT imaging to assess for aortic calcification, 13.6% had
radiographic evidence of LDS on CT imaging, with a 1:3 male-to-female ratio.
The vast majority of these patients were classified as Meyerding Grade I (0-
25%) (Kalichman, Kim, et al. 2009). In a cohort of patients from the
Copenhagen Osteoarthritis Study, approximately 2.7% of males and 8.4% of
females demonstrated radiographic evidence of LDS, for an overall prevalence
of 6.3% (Jacobsen et al. 2007).
A variety of risk factors for LDS have been identified. Chief among these
risk factors is increased age, which is consistent with the known chronic
degenerative etiology of this subtype of spondylolisthesis (Herkowitz 1995).
Both the Framingham and Copenhagen cohorts discussed above identified a
significant association between LDS prevalence and age, with a peak
prevalence in the 7th decade of life (Kalichman, Kim, et al. 2009; Jacobsen et
al. 2007). Other epidemiologic studies have reaffirmed that LDS is most
prevalent in geriatric patients, with an overall prevalence of roughly 29% in
white women over the age of 65 (Vogt et al. 1998).

Table 1. Wiltse Classification

WILTSE CLASSIFICATION
Type Nature of Defect
Dysplastic (I) Congenital abnormality of Sacrum/arch of L5
Isthmic (II) Lesion of Pars Interarticularis
Degenerative (III) Long-standing intersegmental instability
Traumatic (IV) Fractures in areas other than pars
Pathological (V) Generalized or localized bone disease
214 Sam Cartmell, Eric S. Sussman and John K. Ratliff

Table 2. Meyerding Classification. Slippage refers to [Extent of migration

of rostral body] / [A/P length of caudal vertebral body] * 100. Although
Grade V was not part of Meyerding’s original classification, providers
may refer to it when using this system

MEYERDING CLASSIFICATION
Grade Slippage
I <25%
II 26-50%
III 51-75%
IV 76-100%
V >100% (Spondyloptosis)

As mentioned previously, it is well-established that women are at an

increased risk for LDS. Estimates vary, but have placed the overall male-to-
female ratio in the range of 1:3 – 1:6 (Jacobsen et al. 2007; Kalichman, Kim,
et al. 2009; Rosenberg 1975). It has been speculated that this gender difference
may be due to hormonal effects on the laxity of the joint. Indeed, LDS is more
common among patients who have undergone oophorectomy (Imada, Matsui,
and Tsuji 1995); however, the data concerning the effect of parity on LDS are
equivocal (Jacobsen et al. 2007; Sanderson and Fraser 1996). Interestingly, the
gender disparity in LDS appears to be dependent on the spinal level, such that
women are significantly more likely to have slips of L3 and L4 vertebral
bodies, but not of L5 (Jacobsen et al. 2007).
With regard to the racial differences mentioned previously, an early study
of 200 patients and 20 cadavers noted the prevalence of LDS among black
patients was roughly three times that of white patients (Rosenberg 1975).
Whether other ethnicities are also at higher risk of LDS is not yet known, but a
recent study examining variation in lumbar facet orientation among several
Asian ethnic groups found no association with ethnicity (Williams et al. 2016).
Numerous anatomic and biomechanical risk factors have also been identified,
including decreased disc height, increased lumbar index, hyperlordotic sagittal
balance, sagittally-oriented facet joints, and ligamentous laxity (Bird et al.
1980; Grobler et al. 1993; BODEN et al. 1996; Love, Fagan, and Fraser 1999;
I.-R. Chen and Wei 2009; Fujiwara et al. 2001; Dai 2001; Kalichman, Suri, et
al. 2009; Devine, Schenk-Kisser, and Skelly 2012; Jacobsen et al. 2007). A
wide range of other variables, including physical activity, occupation, BMI,
and smoking have been examined in relation to LDS, but evidence supporting
the role of these factors is equivocal or absent. While some studies have
 Lumbar Degenerative Spondylolisthesis 215

reported increased prevalence of LDS among those with higher levels of

physical activity (Denard et al. 2010; Mariconda et al. 2007) and professional
seniority among taxi drivers (J.-C. Chen et al. 2004), others have found no
association with physical activity or occupation (Jacobsen et al. 2007). BMI
and smoking have been consistently reported to be unrelated to LDS incidence
(Devine, Schenk-Kisser, and Skelly 2012), with the exception of a single
study, which noted a correlation between BMI and LDS incidence only among
women (Jacobsen et al. 2007).

Clinical Presentation and Natural History

There is significant variation in the predominant clinical features and the

severity of symptoms among patients with LDS. Patients may be
asymptomatic despite radiographic spondylolisthesis, whereas other patients
may present with significant neurogenic claudication, characterized by leg
pain, weakness and/or paresthesias associated with back extension and
ambulation (Porter 1996; Katz and Harris 2009). Isolated back pain is a less
common manifestation of LDS (Kalichman, Kim, et al. 2009).
Observation of patients who elected for conservative rather than operative
management offers insight into the natural history of LDS. In one such cohort
of 145 patients followed for a minimum of 10 years, Matsunaga et al. noted
radiographic progression (≥5% increase in degree of slip) in roughly a third of
patients. A relationship between radiographic progression and changes in
clinical symptoms was not present, but initial clinical presentation may offer
insight into subsequent disease course. That is, 76% of those without
neurologic symptoms on initial presentation remained symptom-free on
follow-up, whereas 83% of patients with neurogenic claudication or
vesicoureteral dysfunction experienced further decline in their symptoms in
the absence of surgical intervention (Matsunaga, Ijiri, and Hayashi 2000). An
earlier report from a similar cohort of 40 patients followed for a minimum of 5
years indicated that severity of radiographic disease on initial presentation did
not predict subsequent progression (Matsunaga et al. 1990). Instead, factors
deemed important in progression related to the presence of mechanical stress
and stability of the intervertebral joints. Among the earlier cohort, repetitive
occupation-related anterior flexion of the spine was present in 75% of those
that progressed as opposed to 10% of those that did not. In addition to
mechanical factors, general joint laxity was observed in 65% of all patients,
and no progression of disease was noted in patients who showed evidence of
216 Sam Cartmell, Eric S. Sussman and John K. Ratliff

spur formation, subcartilaginous sclerosis, increased intervertebral disk

narrowing, or ossification of the ligaments (Matsunaga et al. 1990). Longer-
term follow up similarly revealed that no patients with significant narrowing
of the intervertebral disk demonstrated radiographic progression of disease,
whereas 96% of those without disc-space narrowing did progress (Matsunaga,
Ijiri, and Hayashi 2000). This suggests that while disk degeneration may be an
important step in the initial pathogenesis of LDS, subsequent degeneration and
narrowing may be a mechanism of natural re-stabilization. Re-stabilization
may also help to resolve symptoms, as the degree of intervertebral disk
narrowing correlated with a decrease in the severity of lower back pain
(Matsunaga, Ijiri, and Hayashi 2000).

Pathophysiology and Biomechanics

LDS results from the degeneration of the facet joints without an associated
defect or disruption in the neural arch (Watters et al. 2009). As described
previously, a variety of anatomic and morphologic factors have been
implicated in LDS, including decreased disc height, increased lumbar index,
hyperlordotic sagittal balance, sagittally-oriented facet joints, and ligamentous
laxity. The diagnosis of LDS is typically made radiographically when a
vertebral body is seen to have migrated greater than or equal to 5% anterior to
the vertebral body below (Denard et al. 2010). Importantly, the extent of
migration rarely exceeds 25-30% in LDS (Herkowitz 1995). In contrast to
isthmic (Type II) spondylolisthesis, which typically affects the L5-S1
interspace, LDS occurs at the L4-5 interspace in the majority of patients
(Kalichman, Suri, et al. 2009).
Patients with LDS typically have chronic and often diffuse degenerative
spine disease – including intervertebral disc bulging, ligamentum flavum and
facet joint hypertrophy and prominent osteophyte complexes – which results in
a baseline narrowing of the spinal canal (Figure 1). Spondylolisthesis further
decreases the cross-sectional area of the canal, and also compromises the
neural foramina, where spinal nerves traverse to exit the spinal canal (Katz and
Harris 2009). Biomechanically, lumbar extension as seen with standing
upright and ambulation results in a decrease in the cross-sectional, mid-sagittal
and sub-articular diameters of the canal, as well as neuro-foraminal narrowing.
This narrowing may lead to compression of peri-medullary venous complexes,
which in turn causes venous engorgement and ischemia (OLMARKER,
RYDEVIK, and HOLM 1989; OLMARKER et al. 1989; OLMARKER et al.
 Lumbar Degenerative Spondylolisthesis 217

1991; Porter 1996). This is the likely pathophysiologic mechanism underlying

the typical neurogenic claudication experienced by LDS patients, as described
above.

Figure 1. Various Types of Disc Degeneration.

Treatments

Treatment options for patients with LDS span the gamut, from
conservative non-operative therapy to multi-level decompression and
instrumented fusion operations. With the exception of the Spine Patient
Outcomes Research Trial (SPORT), the literature is largely lacking in well-
designed randomized controlled trials of LDS treatment. Thus, the literature
reviewed here is predominantly Class II and III.

Non-Operative

Non-operative therapy for LDS consists of activity modification, anti-

inflammatory medication, physical therapy, or corticosteroid injections. It is
well accepted that these conservative interventions should be offered to most
218 Sam Cartmell, Eric S. Sussman and John K. Ratliff

patients as an initial treatment; however, there are no clear guidelines that

specify the precise regimen or duration of conservative management.
In the absence of a well-validated program, a reasonable approach to non-
operative management includes patient education on ergonomic lifting
technique and lifestyle modification to minimize inappropriate or excessive
mechanical stress on the lumbar spine. Physical therapy is also an essential
component of non-operative management and should focus on stabilization of
the trunk and lumbar spine. In particular, flexion-based exercises, as well as
those targeting deep abdominal muscles, are preferred over extension-based
exercises (Gramse, Sinaki, and Ilstrup 1980; Sinaki et al. 1989; O'Sullivan et
al. 1997). Sparse evidence exists to support the benefit of lumbar orthotics in
LDS patients, however this may be attempted in conjunction with other
conservative measures described above (Spratt et al. 1993). Symptomatic
relief and pain control may be achieved with use of NSAIDs or epidural
corticosteroid injections; however, no evidence exists to suggest these
measures address the underlying cause or reverse the course of the disease
(van Tulder et al. 2000; Cuckler et al. 1985; Kraiwattanapong et al. 2014).
These measures may be most appropriate in patients who present without
neurologic signs or symptoms, as the majority of these patients will not
experience disease progression.

Operative

In the case of debilitating or persistent symptoms despite the above

mentioned conservative measures, surgical intervention should be strongly
considered (Kovacs, Urrútia, and Alarcón 2011). In fact, while operative
treatment has not been found to be uniformly superior to non-operative
treatment (Garet et al. 2013), the SPORT Trial did report substantially
improved outcomes with regard to both pain and function at 2- and 4-year
follow-up in the surgical arm (Weinstein et al. 2009; Weinstein et al. 2007).
Unfortunately, the methodology of the SPORT Trial did not standardize the
surgical arm of the study, and thus did not provide Class I evidence regarding
the optimal surgical intervention for LDS patients. The spectrum of surgical
options, and the available evidence for each, will be discussed in the following
sections.
 Lumbar Degenerative Spondylolisthesis 219

Indications for surgical treatment are not clearly defined, but a general
consensus is that surgery is appropriate in patients who continue to experience
debilitating symptoms after 3-4 months of non-operative treatment (Steiger et
al. 2014). Patients with predominantly leg pain secondary to LDS-associated
stenosis may experience better symptomatic relief from surgery as compared
with those patients presenting with predominantly back pain (Pearson et al.
2011). As with all surgical procedures, the indications for surgery must be
considered in the context of operative risk, which was estimated to be 9.2% in
one relatively recent series of 10,242 patients with either Type II or Type III
spondylolisthesis. Importantly, the rate of surgical complications in this study
– which included durotomy, wound infection, hardware infection or failure,
neurological sequalae, and mortality - was noted to increase with increasing
Meyerding grade (Charles A Sansur et al. 2010).

Surgical Decompression

At the time of this publication, the cornerstone of operative management

for LDS is surgical decompression, either with or without fusion.
Laminectomy is the most commonly performed decompressive procedure in
these patients, and allows for decompression of the central canal, lateral
recesses and neural foramina (Figure 2). However, fenestrated procedures,
including laminotomy and foraminotomy, may be considered to preserve the
integrity of the posterior elements and thereby minimize the stress on adjacent
levels (Eismont, Norton, and Hirsch 2014). Several studies, including a meta-
analysis of 11 papers, have demonstrated satisfactory outcomes in roughly
70% of patients treated with decompression without fusion (Mardjetko,
Connolly, and Shott 1994; Epstein 1998; Kristof et al. 2002). Despite this, the
general bias in spinal surgery has been one of increasing complexity of
operative intervention and increased utilization of surgical fusion (Deyo et al.
2010), and the operative management of LDS patients has not been immune to
this trend. Nonetheless, it is important to note that decompression without
fusion is a valid surgical option in LDS patients, particularly in those with a
“stable” slip and minimal translation and/or angulation, as well as in elderly
patients in whom the increased morbidity and mortality of fusion procedures
cannot be justified (Epstein 1998; Rudolf A Kristof et al. 2009; Joaquim et al.
2015).
220 Sam Cartmell, Eric S. Sussman and John K. Ratliff

Figure 2. Relative Locations of Disc Herniation.

Fusion

The role of fusion in LDS treatment remains controversial. In theory,

fusion may prevent progression of the inherent instability associated with
spondylolisthesis and subsequent decompression (Resnick et al. 2014). In one
of the first studies to tackle the question of fusion and decompression versus
decompression alone, Herkowitz and Kurz enrolled 50 patients in a
prospective, randomized trial and found the addition of fusion led to a
significant improvement clinical outcomes and reduction in pain (Herkowitz
and Kurz 1991). A more recent meta-analysis examined the role of fusion and
similarly found superior clinical outcomes in patients who underwent fusion
(Martin et al. 2007). Although instrumented fusion has not been shown to
further improve clinical outcomes, the use of instrumentation does lead to a
more robust and durable fusion, making this the standard of care when a fusion
is desired (Fischgrund et al. 1997; Gibson and Waddell 2005; Kimura et al.
2001; Eismont, Norton, and Hirsch 2014).
Two recent randomized controlled trials published in the New England
Journal of Medicine provide conflicting Class I evidence regarding the benefit
of lumbar spinal fusion in patients with LDS (Försth et al. 2016; Ghogawala
 Lumbar Degenerative Spondylolisthesis 221

et al. 2016). In both studies, patients aged 50-80 with degenerative

spondylolisthesis and symptomatic lumbar spinal stenosis were randomized to
either decompressive laminectomy alone, or laminectomy with fusion. The
Swedish Spinal Stenosis Study (Försth et al. 2016) included both spinal
stenosis patients with LDS and those without LDS, however the stratification
of these two subgroups allowed for the selective analysis of the LDS cohort. In
the Ghogawala et al. study, laminectomy plus fusion was associated with a
statistically significant improvement in overall physical health-related quality
of life as compared with laminectomy alone, and this difference remained
significant at four-year follow-up. In contrast, the Swedish Study did not
identify a difference between the two groups with regard to patient-reported
outcome measures or 6-minute walk test at two-year follow-up. Importantly,
the fusion technique was not specified or standardized in the Swedish
Study, but was instead left to the discretion of the surgeon. In contrast, all
patients randomized to the fusion arm in the Ghogawala Study underwent
posterolateral instrumented fusion. In both studies, the fusion group was
associated with longer operating times and increased intra-operative blood
loss.
As with most aspects of surgical management of LDS, there is no
consensus regarding the optimal technique of surgical fusion in this patient
population. A stratified subgroup analysis of the SPORT data found no
significant difference in clinical outcome between those patients treated by
conventional posterolateral fusion versus those who underwent anterior and
posterior (360˚) fusion operations (Abdu et al. 2009). Interbody fusions –
including anterior lumbar interbody fusion (ALIF), posterior lumbar interbody
fusion (PLIF), and transforaminal lumbar interbody fusion (TLIF) – have been
utilized in LDS patients (Figure 3). According to one study, 76% of LDS
patients treated with ALIF had a positive outcome at 10 years (Takahashi et al.
1990). A separate study showed that ALIF compared favorably with posterior
decompression (Satomi et al. 1992). PLIF and TLIF have similarly been
shown to be effective treatments of LDS (Yan et al. 2008), and have the
additional benefit of avoiding morbidity associated with the anterior approach.
However, a notable complication of the interbody fusion technique is the
development of adjacent segment disease (ASD), which can require surgical
revision. Of note, some surgeons advocate for a reduction of the
spondylolisthesis at the time of decompression and fusion, however the
evidence for this technique is inconclusive (Watters et al. 2009).
222 Sam Cartmell, Eric S. Sussman and John K. Ratliff

Figure 3. Interbody Fusion Approaches.

Alternative Surgical Approaches

Classic operative management of LDS consists of the above-described

procedures, but other techniques have been attempted experimentally in the
setting of LDS. Minimally invasive surgery (MIS) in the treatment of LDS
aims to achieve similar clinical outcomes while avoiding complications related
to extensive muscular and ligamentous dissection. The feasibility of a
percutaneous microendoscopic approach (Figure 4) was demonstrated in the
early 2000’s in cadaver studies, and some of the first human MIS surgeries for
LDS were described shortly thereafter (S. Palmer, Turner, and Palmer 2002;
Guiot, Khoo, and Fessler 2002). Due to the relatively recent development of
these techniques, long-term follow up studies are still needed to determine
efficacy relative to traditional open approaches. Nonetheless, a handful studies
indicate a minimally invasive approach to decompression alone achieves
positive clinical outcomes in the treatment of LDS (Jang et al. 2012; Kelleher
 Lumbar Degenerative Spondylolisthesis 223

et al. 2010; Mori et al. 2016). Moreover, because MIS minimizes the risk of
direct destabilization, it has the theoretical advantage of preserving the re-
stabilization process observed in the natural history of LDS, and may therefore
reduce the need for fusion in some patients (Mori et al. 2016).
That being said, minimally invasive approaches may also be employed for
performance of fusion procedures, as in the case of an MIS-TLIFrr. Kim et al.
examined MIS-TLIF in 44 patients, 19 of whom had LDS. At 5-year follow
up, statistically significant improvements in back and leg pain were observed
(Kim, Jung, and Lee 2012). Two other studies compared minimally invasive
TLIF to open TLIF and reported shorter hospital stays and decreased blood
loss with similar long-term outcomes with the MIS approach (Jang et al. 2012;
Wong et al. 2014).
In light of the well-described drawbacks of fusion procedures, there has
been a concerted effort to develop novel surgical techniques that achieve
similar stabilization without causing the adjacent segment disease or motion
limitation characteristic of spinal fusion. Disk arthroplasty, or total disk
replacement (TDR) is intended primarily for use in patients with discogenic
back pain, and became FDA approved for this indication in the mid-2000s. It
has been suggested that TDR is contraindicated in patients with LDS >3mm
due to additional destabilization caused by obligatory discectomy (Berg et al.
2009). Nonetheless, a pilot study of seven subjects suggested that TDR may be
an effective approach for treating the symptoms of LDS, and there is some
evidence to support the role TDR for symptomatic treatment in patients with a
spondylolisthesis <3mm (Hähnle et al. 2008; Berg et al. 2009).

Figure 4. Percutaneous Microendoscopic Approach.

224 Sam Cartmell, Eric S. Sussman and John K. Ratliff

Figure 5. Comparison of “Open” TLIF to MIS-TLIF.

CONCLUSION
LDS is a common condition characterized by anterior migration of the
lumbar vertebral body due to gradual destabilization of the intervertebral
joints, occurring most often at the L4 vertebral body. LDS almost exclusively
affects patients older than 40 years of age, is more common in women, and
occurs with a higher incidence in black patients. The clinical presentation of
LDS may be asymptomatic, but low back pain and neurogenic claudication are
the most common symptoms, when present. Natural history studies have
demonstrated that the majority of patients who present without neurologic
symptoms will experience no further neurologic decline, whereas those
presenting with neurologic symptoms can be expected to undergo further
clinical deterioration.
Strong evidence exists to suggest that patients with persistent symptoms
referable to LDS experience better clinical outcomes with surgical
management, as compared with patients treated conservatively. While many
surgical options exist, the cornerstone of surgical management is
decompression. The addition of lumbar spinal fusion may be considered to
provide further stabilization, however the existing evidence is ambiguous
regarding the clinical benefit of this procedure. There is also no consensus in
the literature to support a particular fusion technique in this patient population.
 Lumbar Degenerative Spondylolisthesis 225

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In: Intervertebral Disc Degeneration ISBN: 978-1-63485-829-8
Editors: A. L. Ho and A. M. Desai © 2017 Nova Science Publishers, Inc.

Chapter 10

EMERGING TREATMENTS FOR

INTERVERTEBRAL DISC DISEASE

Gregory D. Arnone1, MD, Shivani Rangwala2, BS

and Ankit I. Mehta1,*, MD
1
Department of Neurosurgery University of Illinois at Chicago,
Chicago, IL, US
2
University of Illinois at Chicago, Chicago, IL, US

ABSTRACT
Degenerative disc disease (DDD) is a significant component of spine
disorders and low back pain, and the prevalence of disc disease is
increasing with an aging population. While current treatment modalities,
ranging from conservative approaches to surgical interventions, are
continually evolving, new therapies for intervertebral disc disease are
also in development. Increased research on the cellular mechanisms
underlying DDD have led to novel cell-based treatments which aim to
delay rates of degeneration [1, 3]. Most of these cellular therapies remain
in the research phase. Recent innovations in engineering have also
pioneered several types of surgical constructs that improve the durability
of treatment, while minimizing device-associated complications. Several
examples include hybrid materials for intervertebral cages, zero-profile
implants, expandable cages, sagittal correction implants, and disc

*
Correspondence to: Ankit I. Mehta ([email protected]), Department of Neurosurgery, University
of Illinois at Chicago, 912 S. Wood St., M/C 799, 60612, Chicago, IL, US.
236 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

arthroplasty. Finally, surgical techniques have been refined and adapted

to allow less invasive modalities such as endoscopic and percutaneous
techniques to reach adequate treatment effect with less risk of adverse
event and further degeneration of the incident and adjacent spinal
segments. This chapter highlights several emerging non-surgical and
surgical treatments for intervertebral disc disease.

Keywords: intervertebral disc disease, degenerative disc disease, treatment,

emerging therapy, surgical treatment, nonsurgical treatment

INTRODUCTION
In 2005, the estimate health care expenditure for spine pathology was $86
billion, which amounts to 9% of total health care spending [1]. The annual
prevalence of chronic low back pain among the adult population ranges from
15% to 45%, with a point prevalence of 30% [2]. Degenerative disc disease
(DDD) is a significant component of spine disorders and low back pain, and
the prevalence of disc herniation or secondary spinal stenosis increases with an
aging population. Traditional treatment modalities range from conservative
approaches to surgical intervention. Still, more work needs to be done to
improve the quality of life for patients with DDD, as well as to address the
underlying pathologial processes leading to intervertebral disc degeneration.
To that effect, increased research on the cellular mechanisms underlying
degenerative intervertebral disc disease have led to novel cell-based treatments
which aim to delay rates of degeneration [1, 3]. Although most of these
cellular therapies remain in the research phase, recent innovations in
engineering have also pioneered new treatment modalities which improve
surgical constructs, improve the durability of treatment, and minimize
complications. Finally, surgical techniques have been refined and adapted to
allow less invasive modalities to reach the same treatment effect with less risk
of adverse event and further degeneration of the incident or adjacent spinal
segments. This chapter highlights several emerging non surgical and surgical
treatments for intervertebral disc disease.
 Emerging Treatments for Intervertebral Disc Disease 237

EMERGING NONSURGICAL TREATMENT

The Concept of Directional Exercises

Low back pain is a common chief complaint seen in the physician’s

office, for which conservative management is the first line treatment. Recent
studies show 64% of patients who present with low back pain initially still
report pain symptoms at 12 months [4]. An obvious reason for poor treatment
efficacy is prescribing general physical therapy for a multifactorial pathology.
The optimal conservative treatment is based on the etiology of the back pain,
and can take several attempts before clinical improvement is achieved. The
McKenzie method, also known as Mechanical Diagnosis and Therapy (MDT),
offers clinicians an evidence based assessment tool to evaluate and treat low
back pain with specific directional exercises [5].
First described in 1981, the McKenzie method is a clinical tool that
objectively assesses back pain to provide more directed conservative therapy.
The assessment tool requires the physician to conduct a thorough history and
physical exam with the goal of categorizing the level of physical impairment
to three treatment groups: derangement, dysfunction and postural syndromes
[5]. Patients are placed into one of these groups, and then further subclassifed
based on their response to active, repetitive movements, which either increase
or decrease their pain. Clare et al. observed that therapists specifically trained
in the McKenzie method are able to reliably classify patients with cervical and
lumbar pain into sub groups [6]. Specific movements are isolated to determine
“directional preference”—position in which the pain is decreased, centralized
or resolved [5]. Therapy is then guided based on the “directional preference”
of patients. A systematic review of 6 studies determined the efficacy of MDT
therapy for patients experiencing low back pain and who identified a specific
directional preference, mainly at short term and intermediate follow up
intervals [4]. Unfortunately, there is mixed evidence on MDT treatment
efficacy compared to other physical therapy treatment modalities and this
warrants further study [4, 5]. Still, this methodology holds promise in
improving back pain symptoms through specific goal directed physical
therapy.
238 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

Biological Therapies- Disc Repair and Regeneration

The normal intervertebral disc consists of an outer fibrous ring (annulus

fibrosus-AF) surrounding an inner, gelatinous core (nucleus pulposus-NP), and
a cartilaginous cap covering the superior and inferior surfaces (Figure 1) [1].
The AF has greater collagen content arranged concentrically at varying
degrees, creating a strong structural support. The inner nucleus pulposus is a
hydrophilic core composed of a greater proteoglycan (primarily aggrecan)
matrix with loosely arranged collagen fibrils. Degenerative disc disease is a
pathological, accelerated process of the normal age related changes to the
intervertebral disc. One understanding of disc degeneration is based on gradual
loss of water content from the central core causing it to lose its biomechanical
properties and be more susceptible to mechanical stress. At the cellular level,
there is accelerated cellular senescence compounded with increased local
inflammatory response that compromises extracellular matrix integrity [3].
Understanding the biomechanical properties and cellular composition of the
normal disc will allow for development of treatment targets for degenerative
disc disease. Biological therapies are focused on the repair and regeneration of
disc components (Figure 2). Cell based therapies aim to replace the
chondrocyte- like cells of the NP and fibroblast-like cells of the AF [8].

Figure 1. Intervertebral Disc Anatomy.

 Emerging Treatments for Intervertebral Disc Disease 239

Figure 2. Biologic- and Cell-Based Therapies for IVD.

Disc innervation is restricted to the periphery and there no specific

vascular supply exists for each disc—thus, each disc relies on diffusion of
nutrients and oxygen from surrounding vertebrae. For this reason, the chemical
milieu of each disc is low in oxygen and glucose, and fairly acidic -
characteristics which present potential challenges to biological therapies [1, 7].
Risk factors for degeneration of the intervertebral disc are multifactorial, and
there is increasing evidence on the genetic basis of disc degeneration from
several twin studies [1]. Genetic analysis of specific receptors and
extracellular matrix components are an active area of research focus. Finally,
tissue engineering is being explored as another potential avenue through which
disc regeneration may be prevented or reversed.

Cell-Based Therapies

Stem Cells, Chondrocytes, Intervertebral Disc Cells

The NP has low cell density and limited regenerative capacity, making
disc degeneration at this level rather structurally compromising. Mesenchymal
stem cells (MSC) are a natural option for cell based therapy for IVD
degeneration due to their regenerative capacity. Studies with rabbit cell
cultures that combined MSC and NP cells yielded greater cell proliferation,
growth factor production and proteoglycan synthesis than NP cells alone [9].
A significant challenge to larger human trials is viability of stem cells in the
hypoxic, acidic and nutrient deprived IVD environment [3].
240 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

Figure 3. Chondrocyte Insertion into Disc Space.

Chondrocytic cell types are also being investigated as a potential for

restorative capacity in IVD degeneration. Early trials in canine models showed
disc chondrocytes could be viably transplanted into damaged IVDs and
sucessfully persist in the environment, as well as produce an ECM and
collagen network similar to the normal IVD tissue. Human trials have also
shown promise in chondrocyte therapy. As part of the EuroDisc trial, Meisel et
al. demonstrated a reduction in low back pain at 2 years (compared to control
population) for patients receiving autologous disc derived chondrocyte
transplant after discectomy. For the trial, harvested chondrocytes were
cultured ex vivo, then inserted into the disc space and successfully shown to
remain viable after transplantation, produce sufficient ECM and maintain disc
dimensions on follow up imaging (Figure 3). Primary outcomes were assessed
using the Oswestry low back pain disability questionnaire modified according
to Hudson-Cook (OPDQ). The transplant group showed a sustained decrease
in the total sum score and disability index of the OPDQ at 2 years, while the
improvement in the control group leveled off after an initial effect from
surgery. On evaluation of secondary MRI criteria, the transplant group was
found to have significantly higher residual fluid content of their treated disc
and discs at adjacent levels when compared to control [10]. Chondrocytic cell
therapy shows promising results for regeneration of the IVD in symptomatic
patients and continued study is warranted.

Biomolecular Therapy

Platelet Rich Plasma

Platelet rich plasma (PRP) is an autologous plasma formulation that is rich
in platelets and their associated growth factors. This concentrated formulation
 Emerging Treatments for Intervertebral Disc Disease 241

makes the substance a source of multipotent stem cells with the potential to
differentiate into targeted tissue types [3]. The use of PRP for the treatment of
DDD has limited clinical evidence supporting its use, but animal studies
showed promising results. In a rabbit model, introducing PRP into the
intradiscal space yielded increased expression of collagen II and
proteoglycans, decreased apoptotic cells and gross disc improvement on MRI
relative to control disks [3]. Outside of the scope of intervertebral disc
degeneration, there have been reported human trails with PRP assisted tissue
regeneration with clinical success. Pak et al. reviewed 13 human studies that
successfully regenerated cartilage with adipose tissue derived stem cells in
human trials, 11 of which added autologus PRP to the treatment. PRP
enhanced tissue regeneration by providing a source of growth factors for stem
cell differentiation and a scaffold for new cartilage formation [11].

Gene Therapy
Identifying genes responsible for disc degeneration or regeneration and
creating ways to target those genes is central to the conept of gene therapy.
Vectors for gene delivery include viral and non viral options. Several animal
studies with viral vectors have shown successful results, but human studies are
still pending. In a rabbit model, TGF-β1 gene transfer via an adenovirus vector
results in 5x increase in IVD expression of the gene and increased
proteoglycan production relative to control discs [3]. TGF-β1 is a growth
factor whose expression promotes cell growth and proliferation, making it
crucial in IVD regeneration (Figure 4).

Figure 4. Role of TGF-β and ADAMTS5.

242 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

Gene therapy in other animal models have focused on stimulating other

growth factors, inhibiting matrix metalloproteases (which play a role in the
degradation pathway) and promoting transcription factors. A mouse model
showed the role of ADAMTS5 in degradation of the NP which led to
researchers designing small interference RNA targeting ADAMTS5. In a
rabbit model, application of siRNA for ADAMTS5 yielded preservation of NP
cells [12]. Several in vitro studies in human cells showed promising results;
however, until an optimal viral vector for gene transfer is identified and an
appropriate method for transferring vectors to target cells is developed,
progress towards clinical application is limited at this time [3].

Immune Therapy
Growing research suggests a role of intervertebral disc immune imbalance
in degnerative disc disease. The physical breakdown of the AF leads to NP
herniation and exposure to immune cells. This process starts a cascade of local
inflammatory response at the site of herniation, which may exacerbate IVD
symptoms [13]. Further, there is some evidence to suggest decrease in FasL
expression in pathological NP tissue, which will augment the local immune
response after disc herniation [14, 15]. Immunotherapy techniques to control
the disc environment used in conjunction with surgical discectomy could
improve post operative quality of life and pain management; this is an area
that warrants further investigation [13].

Nucleus Pulposus Prosthesis and Tissue Engineering

The NP core loses its mechanical properties with age as the tissue
loses water content and degenerates. Hydrogels and scaffolds that can be
injected into NP space to replace and regenerate local tissue are currently
under investigation (Figure 5). Tsaryk, et al. demonstrate extracellular matrix
production and chondrogenesis of multipotent stem cells and nasal
chondrocytes in vitro and in vivo with a collagen- low molecular weight
hyaluronic acid hydrogel loaded with TGF-β3 releasing microspheres [16].
Aside from hydrogel based NP replacement, nanofiber scaffolds also promote
MSC differentiation into NP-like cells. Specifically, in vitro studies showed a
combination of TGF-β1 and hypoxic growth conditions promoted maximal
cell differentation on electrospun nanofiber scaffolds [17]. Much of this NP
regeneration investigation is meant to promote healing and growth after
nucleotomy of a degenerating disc or for early cases of degenerative IVD.
 Emerging Treatments for Intervertebral Disc Disease 243

Injection of cell free polyglycolic acid-hyaluronon scaffold in the disc space

after nucleotomy yielded greater tissue repair and collagen type II production
compared to nucleotomy alone in rabbit models [18]. Endres et al. used this
cell free implant for its porous nature, which promotes local cell migration and
differentiation. Hydrogel based NP replacement requires cell implantation
with growth factors to promote differentiation because gel alone cannot
promote cell regeneration [16, 18].
Tissue engineering attempts to regenerate intervertebral disc tissue are still
in pre-clinical stages. Based on preliminary investigation, successful scaffold
constructs must have good porosity, mechanical strength properties similar to
natural IVDs and be composed of non-toxic material to promote stem cell
proliferation in vivo [19]. Xu et al. describe development of a biphasic
scaffold which successfully cultured IVD-like tissue in vivo mouse models
[20]. The success of this project holds promise for future in vivo three
dimensional scaffolding techniques, which could replace degenerative IVD.

Figure 5. Hydrogel and Scaffold Injections.

EMERGING SURGICAL TREATMENT

When conservative and nonsurgical measures for DDD fail, surgery
remains an effective and safe option for select patients. Surgical options for
244 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

treatment of DDD range from disc removal and fusion to percutaneous and
minimally invasive techniques. Improvements in each modality have led to a
number of emerging products and techniques available to treating physicians.

Developments in Intervertebral Cages for Fusion Surgery

For patients with failed decompressive surgery, recurrent disc herniation,

impending deformity, or loss of intervertebral disc height, removal of the
interverebral disc and fusion of the adjacent vertebral segments may offer the
best surgical option for treatment of their disease. In such cases, a support
between the adjacent vertebral segments is used to preferentially maintain the
disc height, prevent instability, and promote bony fusion. Several generations
and designs of intervertebral cages using a variety of biocompatible materials
have been developed and used in clinical practice. The most popular
geometrical design is wedge-shaped, mimicking the end plate geometry and
allowing for maximal end plate contact and incresaed implant stability in
flexion, extension, and rotation. At the same time, these implants should
maintain vertebral column height and restore normal lordosis. These concepts
generally apply to both cervical and lumbar pathology, though several
important differences in surgical technique and biomechanics of each region
have led to cages designed specific to each location.

Cervical Implants

Hybrid Cages
The most common biomaterals used in cervical intervertebral implants are
titanium and polymer materials, namely poly-ether-ether-ketone (PEEK).
Although controversy exists regarding which material is superior, studies have
shown that long-term subsidence rates may be higher with titanium implants
when not used in conjunction with anterior plating [21]. PEEK as a material
has a Young’s modulus that is between cancellous and cortical bone and
therefore is thought to decrease the rate of subsidence particularly in
osteoperotic bone (Table 1) [22]. Recently, hybrid titanium/PEEK cages have
been developed in an attempt to take advantage of the preferential
characteristics of each materal: titanium has optimal surface characteristics
and bioactivity, while the elastic modulus and radiolucency of PEEK allow for
less stress shielding and easier x-ray visualization of fusion. Available
 Emerging Treatments for Intervertebral Disc Disease 245

examples include the A-Spine Asia Co. Combo Cervical Disc Cage (A-SPINE
Asia, Taiwan) (Figure 6), and Orthofix CONSTRUX® Mini PTC™ Spacer
System (Orthofix, USA); these hybrid implants have yet to be rigorously
tested in the clinical arena.

Zero-Profile Implants
While standard interbody cervical fusion surgery includes concomitant
placement of an anterior plate with screws, new options of low-profile plating
systems have emerged. Integrated designs may address the difficulties with
placing the anterior plate and quell the adverse effects of plating, namely
adjacent segment degeneration and postoperative dysphagia. The designs
currently available on market are the ZERO-P® VA stand-alone Spacer
(DepuySynthes, USA) (Figure 7), the PEEK Prevail® Cervical Interbody
Device, the COALITION® integrated plate and spacer system (Globus
Medical, USA), and the ROI-C® Cervical Cage (LDR Holding Global
Corporation, France). A recent meta analysis comparing the ZERO-P® system
to anterior plating showed reduced operation time and blood loss, significant
improvement of postoperative Japanese Orthopedic Association (JOA) score,
reduction of postoperative Neck Disability Index (NDI) and Visual Analog
Scale (VAS) scores, and decresaed incidence of postoperative dysphagia at
early and late follow-up using the low profile implant. Important to note,
however, is that the two procedures had a similar fusion rate, and that anterior
plating promoted better sagittal alignment [23].

Lumbar Implants
A multitude of lumbar intervertebral cage designs are available for clinical
use, tailored to the goals of treatment and specific needs of the surgery. Cages
for anterior lumbar interbody fusion (ALIF) are similar to those used in
cervical spine surgery, given the common anterior approach to the vertebral
column and generally full exposure of the width of the disc space. Threaded
cylindrical cages, titanium mesh cages, wedged structural allograft, kidney-
shaped cages, and bullet shaped cages represent various design iterations over
the course of the history of intervertebral cage development. Threaded
cylindrical designs were shown to have inferior lateral and axial torsional
resistance [24] and may be prone to subsidence when not supplemented with
anterior plating or posterior fixation [25]. Those designs have largely been
replaced by flat or convex shaped grafts with teeth to engage the endplates.
Going further, several new cage designs for ALIF procedures are now
available that incorporate the use of multiple materials as well as plate and
246 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

plateless designs, similar to those of anterior cervical implants. Plateless

designs eliminate the need for extensive anterior exposure in cases where illiac
vessels make are difficult to mobilize on the face of the vertebral bodies.

Figure 6. A-Spine Asia Co. Combo Cervical Disc Cage.

Figure 7. ZERO-P® VA stand-alone Spacer.

For patients undergoing posterior and posterolateral approach to lumbar

interbody fusion, access to the disc space is obscured due to the thecal sac and
cages have evolved to aid the proper placement. Kidney-shaped cages which
cover a large surface area can be placed transforaminally and steered into
proper position with inserter attachments at one end and implant curves that
follow the end plate geometry. Some studies have shown biomechanical
advantages with placement of the graft along the anterior border of the
endplates, though subsequent testing has challenged the necessity of anterior
graft positioning [26]. Additionally, when used in conjunction with posterior
 Emerging Treatments for Intervertebral Disc Disease 247

stabilization, stability seems to be consistent across all modern cage designs

[27]. Nonethelesss, the kidney shape facilitates selective positioning of the
graft across the width of the entire vertebral body, especially in combination
with a transforaminal technique, and allows the surgeon greater control of the
final construct.

Titanium Implants
Several materials have been examined for use in lumbar intervertebral
implant design. Titanium was a popular initial choice in intervertebral cage
design due to its widespread use as implant material in other procedures. Later,
titanium use was largely supplanted by PEEK cages due to the latter material’s
biomechanical similarities to bone (more comparable Young’s modulus of
elasticity) with presumed less stress shielding. The radiolucency of PEEK also
allows better visualization of bony fusion on x-rays. Despite the attractive
qualities of PEEK, in vivo studies have not convincingly demonstrated
superiority of PEEK implants in fusion surgeries [28], and titanium use has
seen a re-emergence in many surgeons’ practice. Unlike polymer implants, the
surface of titanium can be modified to produce a micron-scaled roughed
surface, a property which increases osteoblast maturation and induces a more
osteogenic environment compared to that of PEEK materials [29, 30].
Additionally, these micro surface textures improve surface area contact
between bone and implant during fusion [31]. To improve osteoinduction with
polymers, these materials are often used in conjunction with biological agents,
namely bone morphogenic protein (BMP), which are associated with various
other risks [32]. Furthermore, PEEK materials are generally contraindicated in
cases of infection and thus, titanium is favored for surgical management of
discitis when medical therapy fails and the disease process renders the disc
unsalvageable. Again, hybrid PEEK lumbar intervertebral implants with a
surfaced titanium coating are now becoming available, though further testing
is warranted to determine the true clinical benefits of the combination
materials.

Lateral Interbody Implants

In addition to anterior and posterior approaches to the spine, direct lateral
interbody fusion (DLIF) or extreme lateral interbody fusion (XLIF)
approaches offer additional fusion options (Figure 8). Lateral approaches to
the lumbar spine generally facilitate placement of a larger interbody graft and
allow for coronal as well as sagittal correction. For patients with adequate
bone quality, the large interbody graft may provide equivalent stability to
248 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

posterior fusion techniques, while avoiding disruption or destabilization of the

posterior column and musculature [33]. Laterally inserted grafts also allow for
correction of coronal deformity, though only modest correction is observed in
the sagittal plane [34, 35]. Sagittal correction may be further augmented in
combination with the use of anterior longitudinal ligament release and lordotic
cages [36, 37]. Inability to access the neural elements for direct decompression
limits the use of these approaches as standalone procedures, although an
adequate indirect decompression through distraction of the disc space with a
large graft is achievable [38]. The lateral approach to the vertebral column can
also be useful in reoperations, avoiding the posterior scar tissue. Lateral access
to the spine does requires a learning curve, however, and complications related
to violation of the lumbar plexus as well as the genitofemoral nerve as it
traverses the lateral spine border through the psoas muscle must be avoided
[39]. Neurostimulation of the psoas muscle is critical in this approach but
stimulation is limited for purely sensory nerves. Similarly, risk of vascular
injury to the great vessels must be weighed against the potential benefits of
this approach.

Expandable Cages

Given geometric contraints of posterior or minimally invasive anterior and

lateral exposures, expandable cages have been developed which facilitate safe
placement of the graft through less retraction of soft tissue and neural
elements, less bony removal and destabilization, and less endplate destruction
during positioning. Once seated, the cage can be expanded against the
endplates to ensure for enough load bearing to prevent dislodgement of the
graft and generate higher endplate forces (that promote fusion) than static
grafts [40]. Overdistraction remains a concern, with potential deleterious
effects related to increased subsidence, though further investigation is needed
to better characterize this risk [41, 42]. Such implants are perhaps most useful
in more extensive procedures that span more than one disc space (such as
corpectomies), but nonetheless, remain a viable option for single level fusions
as well. Newer implants have incorporated the kidney-shaped cages with
expandable technology (Stryker Acculif), optimizing the advantages of each
design.
Laterally expandable cages are also gaining popularity as techniques shift
toward more minimal exposures. These implants can be placed during
minimally invasive procedures and expanded in-situ, without sacrifice of graft-
 Emerging Treatments for Intervertebral Disc Disease 249

endplate surface area contact. Prelminary biomechanical data suggests that

these mini-expandable cages provide comparable stability in fusion
procedures, and may also reduce supplemental fixation burden, facilitating
minimally invasive single-position surgery [43].

Figure 8. Lateral Body Fusion.

Sagittal Plane Correction Implants

Recent literature on spine surgery outcomes have placed an emphasis on

the concept of proper sagittal vertebral alignment of the spine, inclduing its
relationship to the pelvis (sagittal balance) (Figure 9). These spinopelvic
parameters have subsequently been shown to correlate with level of patient
disability and serve as important predictors of quality of life improvement in
people undergoing spinal fusion surgery for adult spinal deformity [44-50]. As
such, implants have been developed that facilitate the restoration of this
sagittal alignment, adding height preferentially at the anterior spinal column,
improving lumbar lordosis (Figure 10). A multitude of lordotic cage designs
are now available from various vendors worldwide. The effectiveness of
sagittal correction with lordotic cages varies across studies, and additional
methods such as rod bending and compression across the fusion are often
employed to increase lordosis [51, 52]. For multilevel TLIF surgery, the effect
of lordotic cages may compound, offering a correction in the sagittal plane of
greater than 5 degrees per level and possibly avoiding a more extensive and
risky osteotomy operation [53]. An important caution with hyperlordotic
designs is unequal loading of the endplate that may increase the chance of
graft subsidence.
250 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

Disc Arthroplasty

The concept of disc arthroplasty replaces a degenerated disc with a

prosthetic that most closely mimicks a physiologic state and preserves disc
joint function. To that effect, one would hope to alleviate pain, eliminate the
prospect of disc recurrence, and maintain or restore intervertebral disc height.
Importantly, and unlike fusion procedures, arthroplasty maintains range of
motion and flexibility, and prevents non-physiologic loading of adjacent
segments that leads to adjacent segment degeneration. Despite the theoretical
advantages of disc arthroplasty, the progress in development and acceptance of
near-physiologic implants has been slowed by some early clinical setbacks and
the high cost of implants. Several generations of implants have been developed
for use in the cervical and lumbar spine.

Figure 9. Sagittal Balance.

Figure 10. Implants for Sagittal Alignment.

 Emerging Treatments for Intervertebral Disc Disease 251

Cervical Disc Arthroplasty

Dr. Ulf Fernstrom performed the first cervical disc arthroplasty (CDA)
surgeries in patients in 1966, though this series met with generally poor results
[54], and discectomy with subsequent fusion became the standard treatment
for cervical degenerative disc disease. Over the past three decades, however,
development of cervical disc prostheses have evolved, with numerous
currently available models, including the Bryan disc (Medtronic Sofamor
Danek, Memphis, TN, USA), Prestige disc (Medtronic Sofamor Danek,
Memphis, TN, USA), porous coated motion (PCM) disc (NuVasive, San
Diego, CA, USA), ProDisc-C disc (Synthes Spine West Chester, PA, USA),
Mobi-C disc (LDR Spine, Austin, Texas, USA), and Kineflex-C disc
(SpinalMotion, Mountain View, CA, USA). These designs vary in their
materials and composition but are all conceptualized with the similar
biomechanical goal of preserving motion and loading at the disc segement.
Based on a meta-analysis of studies with 4–6 years of follow-up, patients who
underwent single level disc arthroplasty showed preservation of segmental
motion, a lower rate of reoperation, and greater improvements in NDI score,
neck and arm pain scores, and SF 36 Health Survey physical component score
than those who underwent ACDF. In a 7-year followup comparing single level
disc replacement with the ProDisc-C implant to ACDF, patients treated with
arthroplasty had lower rates of subsequent surgery, while clinical outcomes
between the groups were similar [55]. Over the 7 year study period, disc
arthroplasty was also shown to be less costly than ACDF [56]. In a separate
analysis comparing single level cervcial disc arthroplasty to ACDF,
arthroplasty was associated with cost savings throughout a 3-year follow up
period due to lower readmission rates, fewer mechanical complications, and
lower reoperation rates [57].
Two level disc arthroplasty was later compared to two level ACDF in a
prospective study that included 24 centers across the United States,
randomizing 330 patients to CDA with the Mobi-C device, or ACDF with
corticocancellous allograft and anterior cervical plating. The authors
concluded that at 48 months, the arthroplasty group had statistically significant
improvements in NDI scores, SF-12 PCS scores, patient satisfaction,
subsequent surgery rates, adjacent-segment degeneration, and overall success
compared to the fusion group [58]. Additional cost analyses on the same
patient cohort showed a greater improvement in quality of life at a lower total
cost over an initial 24 month and subsequent 5 year study period, supporting
the cost effectiveness of two level arthroplasty compared to ACDF [59, 60].
252 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

The use of cervical disc prosthesis implants are favored in cases of single-
level disease, primary anterior or disc related pathology, preserved disc height,
preserved segmental motion, absence of significant facet arthropathy, and
normal sagittal alignment [61]. Practitioners should continue to exercise
caution whenever adopting new technology and techniques. In a review of the
literature on CDA vs ACDF, Alvin et al. found significant descrepancy in
reported incidence of complications, namely adjacent segment disease and
heterotopic ossification, for studies in which the authors had stated conflict of
interest. Important to note, however, is that quality of life outcomes in all of
these studies were unaffected by reported conflicts of interest [62]. Disc
arthroplasty therefore remains a favorable option for select patients, and future
data will determine the long-term complications, benefits, and cost-
effectiveness of this technique.

Lumbar Disc Arthroplasty

The first lumbar disc implant, the SB Charite (Depuy), was developed in
the 1980’s. Early problems with migration, fatigue of the implants, and
increased facet joint loading [63] led to a number of revisions and model
updates. Simultaneously, a slew of other companies developed lumbar
prosthetic disc implants, two of which are currently FDA approved: the
Prodisc L (Synthes Spine, PA, USA) (Figure 11), and Charite (DePuy Spine,
Inc., Raynham, MA, USA). These implants, however, have not caught vast
clinical usage due to ongoing questions regarding the durability of outcome
results of arthroplasty. A recent review of the California Office of Statewide
Health Planning and Development discharge database demonstrated that total
disc arthroplasty is not associated with lower rates of repeat lumbar surgery
compared with lumbar fusion beyond one year [64]. A cochrane review of
total disc replacement for lumbar degenerative disc disease concluded that
short-term patient outcomes were equivalent to fusion surgery though
prevention of adjacent level disease and facet joint degeneration was not
properly assessed, cautioning the surgical community to be prudent about
adopting lumbar disc replacement technology on a large scale [65].
Furthermore, mid to long-term results for multilevel lumbar disc arthroplasty
show worse results in conjunction with higher complication rates, limiting the
use of current designs for multilevel disc disease [66]. Nonetheless, continued
long-term data will better define the complications associated with and
indications for lumbar disc arthoplasty.
 Emerging Treatments for Intervertebral Disc Disease 253

Figure 11. Prodisc Lumbar Disc Implant.

Endoscopic Techniques

Microscopic discectomy has largely supplanted open discectomy as the

initial treatment of choice for refractory lumbar HNP and radiculopathy. The
microscopic approach has equivalent success to open surgery, in addition to a
low complication rate [67]. This procedure is also frequently done on an
outpatient basis, and is often favored by patients. Spinal fusion surgeries have
also been adapted with these less invasive approaches, with good outcomes
and lower complication rates [68]. Moving toward the trend of less invasive
techniques, endoscopic procedures have been developed through the same
concept of less disruption of normal anatomy while achieving the same goals
of neural decompression. Some of the earliest endoscopic techniques were
developed by Dr. Parvis Kambin for percutaneous removal of the posterior
third of the nuclues pulposus as a technique for indirect decompression [69].
In the modern era, endoscopic procedures are now described for anterior and
posterior approaches to the cervical and lumbar spine. While these techniques
have been refined for the past three decades, they are associated with
additional learning curve [70] and require specialized training and familiarity
with endoscopic instruments, adding a level of complexity to the procedure.
While certainly not as abundant as microdiscectomy for treatment of disc
254 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

disease, endoscopic approaches may play a larger part in resident training and
surgical armamentarium in the future, and warrant further discussion.

Endoscopic Discectomy

Cervical Anterior
While ACDF is the mainstay operation for cervical degenerative disc
disease, patients with maintenance of disc height and paracentral disc
pathology may be good candidates for a less invasive discectomy without
fusion. Access to the anterior cervical spine for open procedures carries risk of
retraction injury. Furthermore, violation of the anterior longitudinal ligament
(ALL) and entire disc space necessitates fusion after decompression; therefore,
an anterior transdiscal endoscopic technique that avoids excessive tissue
retraction and fusion offers many advantages. This anterior trasnsdiscal
endoscopic approach can be performed percutaneously and safely [71].
Additionally, though some loss of disc height may be noted postoperatively,
preservation of sagittal alignment and range of motion with good clinical
outcomes is experienced in most cases [71, 72]. Important to note is that
lateral disc pathology and primarily radicular symptoms are the main
predictors of good outcomes with an anterior endoscopic transdiscal approach,
and careful patient selection is critical [73].
Furthermore, indications for endoscopic anterior cervical approaches are
being expanded, and a transcorporal endoscopic approach has recently been
described for disc fragments that migrate superiorly or inferiorly away from
the disc space behind the vertebral body; this may offer an alternative to a
more invasive corpectomy and fusion surgery, though the technique is not yet
proven [74]. Microendoscopic techniques for anterior discectomy with fusion
have also been developed [75]. In a single-center prospective, randomized
study, a microendoscopic group demonstrated a significantly improved early
postoperative course with less laryngopharyngeal complications, and marked
reduction in postoperative pain, analgesic use, and hospital stay compared to
conventional ACDF [76].

Posterior
For patients with lateral disc herniation and radiculopathy, posterior
microscopic foraminotomy and discectomy have become a viable alternative,
eliminating the need for fusion in ACDF and maintaining the bony integrity of
the posterior column by avoiding full laminectomy. Similarly, an endoscopic
 Emerging Treatments for Intervertebral Disc Disease 255

approach to these procedures is feasible, with outcomes equivalent to ACDF

[77]. A main advantage of these approaches over conventional laminectomy is
avoidance of progressive kyphotic deformity due to minimal disruption of the
posterior elements. In a group of patients 24-46 months following posterior
endoscopic foraminotomy, Kim et al. found that measures of cervical
curvature, disk height, and segmental angle were not worsened [78].

Lumbar
Two main techniques for posterior endoscopic lumbar decompression
have evolved: percutaneous endoscopic transforaminal discectomy (PETD),
and percutaneous endoscopic interlaminar discectomy (PEID). PETD involves
a posterolateral, transforaminal approach to the pathology using Kambin’s
triangle [79] (Figure 12), and is preferable for soft unilateral disc herniations
with sciatica in the absence of severe neurologic deficit. PEID, on the other
hand, involves a more posterior interlaminar projection and is advantageous in
cases with a significant amount of canal compromise, extended disc migration,
narrow neural foramen, or a high iliac crest [80]. The disadvantage of this
approach is a higher risk of dural tear compared with microdiscectomy or open
procedure, and thus, it is the less favored technique [81].

Figure 12. Kambin’s Triangle Trajectory.

PETD can be used effectively for nerve root decompression in treating

lateral recess stenosis, as well as for removal of herniated disc fragments [82].
PETD may also be a useful technique for recurrent disc herniation, and in a
review assessing efficacy compared to redo open discectomy, had decreased
256 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

operative time, blood loss, and lower complication rates with similar effect on
relief of back and leg pain [80]. Furthermore, in experienced hands, the lateral
endoscopic approach can be done under a local anesthetic with results
equivalent to microdiscectomy [83-86]. One lingering concern over
endoscopic approaches is the tendency toward higher rates of recurrent disc
herniation [87, 88]. Furthermore, exiting nerve root injury leading to transient
postoperative dysesthesia can be seen in 1 to 8.9 percent of cases, and can
deter inexperienced surgeons from utilizing the technique [89]. Despite some
limitations, endoscopic procedures are being expanded for spinal fusion as
well [90], and endoscopic techniques in general may prove to be useful tools
as more surgeons become familiar with the instruments and technique, and
more training programs nationwide incorporate the technique into resident
traning.

Percutaneous Techniques

Bridging the gap between so called “conservative” options which target

symptom relief, and “surgical” options which aim to remove the pathologic
process, are a variety of percutaneously performed procedures developed to
address disc pathology. Similar to more invasive surgical procedures, they
address the degenerated disc disease, though are done percutaneously via
minimal access and are associated with less incisional pain and disruption of
normal anatomy. Important to note is that these procedures are not appropriate
for extruded fragments, or facet and ligamentous hypertrophy. Additionally,
despite fluoroscopic guidance, the procedure itself is essentially “blind” and
drawbacks include inability to directly visualize the normal anatomy to protect
it, and inability to evaluate the progress and completion of decompression in
real time.

Nucleotomy
Nucleotomy procedures involve fluoroscope-guided introduction of a
percutaneous instrument inserted into the intervertebral disc. These
percutaneous procedures have been described in the literature for its
application to disc herniations in both cervical [91] and lumbar regions [92].
Various techniques can then be used to decompress the nucleus pulposus,
ranging from percutaenous laser disc decompression (PLDD), radiofrequency
ablation, and intradiscal electrothermal therapy (IDET), to intradiscal
placement of chemically engineered products (chemonucleolysis) such as
 Emerging Treatments for Intervertebral Disc Disease 257

alcohols (DiscoGel®; Gelscom SAS, Caen, France), collagenase (WeiBang

Biopharm, Liaoning, China), and oxygen-ozone (O2-O3) therapy [93]. (Figure
13) Symptom relief is dependent on an indirect effect by decreasing the
intradiscal pressure and, therefore, concern over efficacy and durability of
these procedures has prevented their adoption by many surgeons. In a
prospective randomized trial for patients with sciatica and relatively small disc
herniations, 44% of patients who had a technically successful PLDD required
additional surgical intervention (re-operation) in the first year [94].
Furthermore, a systematic review of lumbar disc nucleoplasty concluded that
there was only limited to fair evidence for nucleoplasty in managing radicular
pain due to contained disc herniation; patients with contained disc herniation
and maintained disc height may benefit most from percutaneous interventions
[95].

Figure 13. Percutaneous Procedure Techniques.

Automated Percutaneous Lumbar Discectomy and Dekompressor

Instruments for mechanical percutaneous disc decompression have also
been developed. The Dekompressor® system (Stryker Spine, Allendale, NJ)
utilizes an Archimedes’ screw design to decompres the nucleus, while an
automated percutaneous lumbar discectomy (APLD) system is designed with a
suction/cutting probe to achieve the same result. Some authors have even
258 Gregory D. Arnone, Shivani Rangwala and Ankit I. Mehta

described combined techniques such as APLD in conjunction with oxygen-

ozone therapy to promote proteoglycan hydrolysis and fibrosis within the
nucleus pulposus, leading to further disc volume reduction after mechanical
decompression [96]. Similar to nucleotomy procedures, however, there exists
only limited evidence for these techniques, and many of the same drawbacks
pertaining to limited indications, and questionable efficacy and durability
persist [97, 98].

CONCLUSION
As life expectancy of the general population increases, the medical
community can inevitably expect to see a higher number of patients with disc
disease, and a longer duration of disc disease in individual patients. Therefore,
a long-term treatment plan is necessary, preferably one that prevents or
reverses the degenerative process itself and improves the quality of life for
patients. In parallel, surgical tools and technique must continue to be refined
with the goal of providing the least invasive and least disruptive, but robust
and durable surgery. In these efforts, it is the responsibility of the physician to
scrutinize and study each emerging therapy with proper due diligence, keeping
the best interest of the patient always at the forefront.

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EDITOR’S CONTACT INFORMATION

Dr. Allen Ho
Stanford University School of Medicine
300 Pasteur Drive, R281,
Stanford, CA 94303-5327
[email protected]
 INDEX

angulation, 139, 219

A anisotropy, 46
ankylosing spondylitis, 131
acetaminophen, 142, 143
ankylosis, 4, 114
acetylcholinesterase, 20, 199
anterior cervical disketomy and fusion
achondroplasia, 131
(ACDF), 64, 71, 72, 73, 76, 106, 108,
acid, 43, 239, 242, 259
109, 110, 111, 114, 117, 119, 123, 251,
acquired lumbar stenosis, 129
252, 254
adenovirus, 241
antibody, 23, 259
adipose tissue, 241
antidepressants, 142
adjacent level disease, 157, 252
antigen, 23, 259
adolescents, 149, 198, 200
anti-inflammatory drugs, 152
adults, 148, 149, 158, 196
anti-inflammatory medications, 10, 70
advancements, 8, 10, 109
anxiety, 143
adverse effects, 109, 172, 245
apoptosis, 3, 8, 10, 19
adverse event, xi, 114, 236
appendicular skeleton, 171
aging, ix, xi, 15, 19, 31, 37, 52, 54, 55, 58,
arachnoiditis, 140, 172
60, 128, 131, 235, 236
arteries, 115
aging population, xi, 235, 236
arteriovenous malformation, 138
air embolism, 115
arthritis, x, 114, 211, 212
alcohol abuse, 22
arthrodesis, 109, 154
algorithm, 103
arthroplasty, xi, 73, 81, 83, 106, 114, 122,
anaesthesiologists, 91
123, 126, 223, 236, 250, 251, 252, 262,
analgesic, 134, 142, 254
263
anatomy, vii, 1, 4, 38, 88, 95, 100, 108, 158,
articular cartilage, 46
159, 161, 197, 198, 253, 256, 261
Asia, 233, 245, 246
anchoring, 42
assessment, ix, x, 14, 24, 25, 31, 87, 89, 90,
anesthetics, 143
139, 140, 149, 150, 151, 157, 182, 202,
angina, 22
208, 237, 262, 266
angiogenesis, 203
270 Index

asthma, 22 body weight, 46

asymptomatic, x, 7, 19, 70, 140, 151, 211, bone, 7, 14, 42, 69, 72, 79, 86, 93, 99, 109,
215, 224 110, 111, 116, 118, 119, 124, 126, 136,
athletes, 182, 183, 206 161, 197, 213, 244, 247, 260, 261
atrophy, 69 bone form, 111
attachment, 174 bowel, 89, 107, 168, 195
autoantibodies, 13 brachioradialis, 107
automobiles, 202 brain, viii, 17, 19
autonomy, 131 branching, 161
avoidance, 91, 99, 103, 114, 255 breakdown, 2, 43, 242
axial skeleton, 159 breastfeeding, 22
bursitis, 138

B
C
back pain, vii, x, xi, 2, 15, 22, 24, 28, 29,
31, 32, 54, 89, 127, 128, 129, 138, 144, cadaver, 80, 222, 261
150, 151, 152, 158, 165, 167, 170, 180, calcification, ix, 7, 15, 53, 69, 87, 90, 101,
181, 184, 191, 195, 196, 198, 199, 204, 108, 135, 136, 213
206, 213, 215, 216, 219, 223, 224, 235, calcium, 42, 111, 119, 149
236, 237, 240, 258, 263 candidates, 139, 180, 185, 254
behavioral assessment, 199 capillary, 161
bending, ix, 37, 40, 46, 49, 50, 130, 168, capsule, 52
178, 249 carbon, 260, 261
beneficial effect, 131 cardiac output, 91
benefits, 88, 137, 147, 184, 185, 247, 252 cardiovascular disease, 22
benign, 136 cartilage, 5, 21, 25, 30, 40, 42, 45, 48, 241
benzene, 23 cartilaginous, viii, 18, 40, 41, 42, 48, 49,
bias, 97, 100, 219 159, 160, 161, 238
bilateral, 39, 79, 128, 129, 133, 134, 144, cascades, 3
153, 262 cation, 19
biochemistry, 38 Caucasians, 213
biocompatibility, 110 cauda equina syndrome, 147, 149, 168, 171,
biocompatible materials, 244 185, 209
biomechanics, vii, 19, 49, 158, 162, 244, causal relationship, 7
260 cauterization, 175
bleeding, 22 cell culture, 239
blood flow, 142 cell death, 9, 13
blood supply, 6, 9 ceramic, 111
blood transfusion, 145 ceramic materials, 111
blood vessels, viii, 18, 19, 20, 29, 159, 198, cerebrospinal fluid, 146
203 cervical herniated disc, 106
body mass index (BMI) , viii, 17, 18, 194, cervical laminectomy, 117
195, 214 cervical radiculopathy, 84
 Index 271

cervical spondylosis, ix, 63, 64, 71, 75, 80, complement, 108
84 complexity, 2, 219, 253
cervical spondylotic myelopathy, ix, 63, 64, compliance, 8, 13
65, 66, 70, 77, 80, 81, 86, 121, 260 complications, xi, 74, 75, 94, 97, 99, 102,
cervical stenosis, ix, 63, 64, 65, 66, 68, 69, 110, 111, 112, 116, 119, 120, 146, 147,
74, 77, 107, 125 148, 150, 154, 184, 207, 219, 222, 235,
Chad, 149 236, 248, 251, 252, 254, 261, 262, 263,
challenges, 100, 120, 196, 239 264, 265
chemical, 198, 239 composition, ix, 37, 38, 42, 43, 46, 47, 197,
Chicago, 235 238, 251
childhood, 15, 137 compression, x, 8, 13, 19, 40, 44, 45, 46, 49,
children, 165, 200 50, 65, 66, 67, 69, 71, 74, 75, 76, 77, 78,
China, 257 81, 88, 90, 106, 107, 109, 112, 113, 116,
chondrocyte, viii, 18, 19, 20, 25, 30, 32, 43, 117, 118, 127, 134, 140, 142, 144, 147,
160, 238, 240, 259 148, 162, 164, 168, 176, 191, 195, 199,
chondroitin sulfate, 167 209, 216, 249
chronic obstructive pulmonary disease, 22 computed tomography, 68, 139, 208
chylothorax, 112 conditioning, 142
cigarette smoking, 106, 166, 202, 209 configuration, 2, 46
circulation, 169 confounding variables, 262
classification, 24, 66, 164, 212, 214, 259, congenital lumbar stenosis, 129
262 connective tissue, 38
claudication, 22, 129, 130, 132, 134, 138, consensus, xi, 141, 211, 219, 221, 224
141, 144, 146, 147, 148, 152, 215, 217, Consensus, 205
224 consent, 22
clinical application, 13, 242 contour, 260
clinical assessment, 141 contradiction, 193
clinical presentation, xi, 70, 211, 215, 224 control group, 165, 240
clinical symptoms, 70, 107, 215 controlled studies, 142
clinical syndrome, x, 127, 128, 212 controlled trials, 179, 217, 220, 263
clinical trials, xi, 141, 142, 194, 204, 211 controversial, 2, 136, 143, 172, 220
Clinical validation, 150 controversies, 204
clonus, 107 coordination, 141
closure, 76, 100, 115 correlations, 21, 24, 28, 31, 89, 165, 193,
cluster type chondrones, 18, 26 215, 262
clusters, 21, 26 cortex, 93
CNS, 161 cortical bone, 5, 116, 244
collagen, 5, 7, 8, 19, 25, 40, 41, 42, 43, 45, cosmetic, 112
46, 47, 50, 51, 135, 160, 167, 210, 238, cost, vii, 111, 114, 128, 180, 181, 196, 206,
240, 241, 242 250, 251, 252, 263
color, 118 cost effectiveness, 206, 251
common symptoms, 129, 224 cost saving, 251
community, 141, 150, 198, 252, 258 costotransversectomy, 87, 94, 95, 102
272 Index

coughing, 130, 168 demographic characteristics, 198

counseling, 180 demyelination, 69
covering, 238 Denmark, 202
cracks, 19, 29, 167 deposition, 8, 149
cranium, 90 depression, 136, 183
creep, 49 depth, 8, 53, 69, 100
cross-sectional study, 262 destruction, 23, 212, 248
CSF, 69, 99, 100, 146 diabetes, 22, 167, 172, 194, 195
CT scan, 133, 139, 168 diabetic patients, 167
cyclooxygenase, 171 diffusion, 5, 15, 40, 42, 48, 161, 239
cyst, 11, 138 dilation, 192
cystoscopy, 131 disability, x, 69, 127, 131, 142, 144, 179,
cytokines, viii, 9, 10, 17, 19, 20, 29, 43, 180, 206, 240, 249, 262
165, 167 disc replacement, 73, 106, 108, 114, 119,
cytoskeleton, 21 122, 251, 252, 263
discitis, 9, 12, 15, 205, 247
discomfort, 108
D discs, viii, ix, 2, 3, 5, 6, 7, 8, 9, 10, 13, 15,
18, 22, 30, 31, 32, 38, 40, 45, 49, 52, 53,
daily living, 67
54, 63, 64, 69, 71, 88, 89, 90, 91, 97, 99,
database, 179, 252, 263
103, 121, 128, 135, 140, 159, 160, 165,
decompression, xi, 9, 22, 71, 72, 74, 75, 79,
166, 167, 169, 170, 171, 181, 197, 198,
80, 81, 82, 85, 106, 109, 112, 113, 114,
200, 201, 202, 203, 209, 240, 241
115, 118, 136, 137, 142, 144, 145, 146,
disease progression, 67, 75, 218
150, 153, 154, 168, 177, 178, 183, 195,
diseases, 14, 22, 64, 200, 260, 262
196, 207, 211, 212, 217, 219, 220, 221,
disk disease, 14, 115, 139
222, 224, 226, 227, 228, 229, 230, 231,
dislocation, 212
248, 253, 254, 255, 256, 257, 265, 266
disorder, 22, 84, 137
defects, 139, 193, 194, 195
displacement, 44, 46, 106
deficiency, 8, 15
distribution, 7, 24, 27, 42, 106, 107, 109,
deficit, 21, 89, 108, 147, 177, 255
130, 165, 168, 195, 259
deformation, 8, 44, 47
dizygotic, 9
degenerate, 6, 52, 54
dizygotic twins, 9
degenerative conditions, 64, 88
DNA, 9
degenerative disc disease, vii, viii, xi, 9, 12,
dorsal horn, 161
15, 17, 18, 19, 20, 24, 38, 54, 124, 138,
drainage, 100
157, 158, 235, 236, 238, 251, 254, 263
drugs, vii, 1, 142, 204
Degenerative Spondylolisthesis, vi, x, 7,
dura mater, 161, 199
132, 134, 145, 149, 185, 211, 212, 221,
durability, xi, 235, 236, 252, 257, 258
225, 226, 227, 228, 229, 230, 231, 232,
dysphagia, 109, 111, 119, 245
233
degradation, 19, 169, 170, 242
dehydrate, 50
dehydration, 19, 51, 169
 Index 273

ethnic groups, 214

E ethnicity, 214
etiology, viii, 7, 10, 17, 18, 106, 155, 167,
East Asia, 135
212, 213, 237
ECM, 160, 240
everyday life, 138
ectoderm, 3
evidence, x, xi, 65, 66, 70, 78, 128, 130,
edema, 69, 111, 169
137, 141, 143, 144, 145, 147, 166, 172,
education, 134, 142, 180, 218
183, 204, 206, 212, 213, 214, 215, 218,
EIT, 150
220, 221, 223, 224, 237, 239, 241, 242,
elaboration, 176
257, 258, 266
elderly population, vii, 137, 140
evoked potential, 91, 136
electrocautery, 191
evolution, 20, 22, 25, 124
electromyography, 136
excision, 86, 116
ELISA, 30
exercise, 130, 134, 141, 142, 143, 170, 179,
elongation, 212
180, 218, 237, 252
embryogenesis, 20
exertion, 129
embryology, 3
expertise, 137, 185
emergency, x, 128, 182, 195, 196
exposure, vii, 1, 54, 95, 110, 112, 113, 118,
emerging therapy, 236, 258
136, 161, 166, 184, 192, 242, 245
EMG, 136
extracellular matrix, 5, 7, 9, 10, 13, 19, 25,
employment, 67
26, 30, 32, 38, 42, 43, 160, 197, 238,
encoding, 19
239, 242
endocrine, 20, 22
endoderm, 3
endonuclease, 9 F
endoscope, 176
endothelial cells, 7, 20, 30 Fabrication, 260
endothelial dysfunction, vii, 1, 7, 14 fascia, 113, 115, 117, 175, 191
energy density, 51, 52 fat, 11, 113, 140, 174
engineering, xi, 235, 236, 243 fear, 91
enrollment, 180 female rat, 158, 213, 214
environment, 30, 43, 53, 164, 239, 240, 242, fiber, 3, 5, 6, 8, 20, 25, 29, 30, 40, 41, 46,
247 47, 49, 51, 53, 54, 160, 161, 178, 260,
environmental factors, 9 261
enzymes, 19 fibrin, 155
epidemiologic, 159, 201, 202, 213 fibroblast growth factor, 20
epidemiology, xi, 158, 211, 258 fibroblasts, 5
epidural hematoma, 172 fibrosis, 3, 4, 8, 50, 106, 108, 135, 169, 172,
equilibrium, 47 193, 258
equipment, 120, 165 films, 69, 139, 177
ESI, 108, 172 Finland, 199
esophagus, 113 fistulas, 146
ethanol, 23 fixation, 77, 78, 79, 109, 111, 115, 117, 123,
ethics, 21 245, 249, 262
274 Index

flexibility, 2, 141, 171, 250 germ layer, 3

fluid, 8, 42, 45, 46, 49, 50, 99, 136, 140, Germany, 23, 24
151, 155, 240 gestation, 3
Food and Drug Administration (FDA), 177, GI bleeding, 171
223, 252, 263 glial cells, 20
football, 182 glucocorticoid, 143, 153
foramen, 66, 90, 93, 106, 107, 113, 118, glucose, 172, 239
176, 191, 255 glue, 99, 155, 194
foraminotomy, 76, 80, 83, 85, 86, 106, 112, glycosaminoglycans, 45, 46, 167
115, 117, 118, 119, 124, 219, 254, 264 glycosylation, 167
force, 10, 46, 88, 261 grading, 67
formation, 3, 53, 78, 100, 109, 131, 135, gravitational force, 2
146, 173, 216, 241, 259 growth factor, viii, 3, 17, 18, 19, 20, 30,
fractures, 22, 136, 149, 197, 212 203, 239, 240, 241, 242, 243, 259
fragments, 22, 25, 30, 108, 136, 169, 177, guidance, 176, 192, 256
254, 255, 256 guidelines, 137, 138, 218
France, 245, 257
functionalization, 260
fusion, ix, xi, 9, 10, 13, 53, 64, 71, 72, 73,
H
75, 76, 79, 80, 81, 82, 83, 84, 85, 87, 99,
healing, 167, 194, 209, 210, 242
101, 102, 108, 109, 110, 111, 113, 114,
health, vii, 131, 141, 147, 149, 158, 171,
115, 117, 119, 121, 122, 123, 124, 125,
180, 196, 213, 236
135, 137, 144, 145, 146, 153, 154, 158,
health care, 147, 158, 171, 236
168, 173, 191, 192, 193, 194, 195, 211,
heart failure, 22
212, 217, 219, 220, 221, 222, 223, 224,
height, 19, 40, 64, 107, 110, 111, 112, 113,
225, 226, 227, 228, 229, 231, 232, 233,
131, 166, 178, 185, 193, 195, 208, 214,
244, 245, 246, 247, 248, 249, 250, 251,
216, 244, 249, 250, 252, 254, 255, 257
252, 253, 254, 256, 260, 261, 262, 263,
hematoma, 72, 120, 169
264, 265
hematomas, 110, 172
hemostasis, 118, 174
G hepatitis, 22
hernia, 125, 201
gadolinium, 169, 193, 200 herniate, 19, 135
gait, 66, 67, 107, 137, 168 herniated, 25, 30, 31, 32, 66, 69, 71, 76, 87,
ganglion, 19, 20, 30 88, 89, 90, 91, 97, 99, 103, 106, 108,
gastrulation, 3 120, 121, 122, 135, 139, 140, 159, 163,
gel, 210, 243 164, 165, 168, 169, 170, 174, 194, 195,
gene therapy, 241 199, 200, 201, 202, 203, 204, 205, 255,
gene transfer, 241, 242 259, 262, 266
general anesthesia, 265 herniated nucleus pulposus, 203, 205, 259
genes, 19, 20, 241 high blood pressure, 22
genetic predisposition, vii, viii, 1, 17, 18 hip fractures, 110
geometry, 244, 246, 262 histochemistry, 199
 Index 275

histogram, 26, 27 implants, xi, 235, 244, 246, 247, 248, 249,
histology, 7, 54, 203 250, 252, 260, 261
history, 2, 15, 31, 132, 134, 138, 169, 170, improvements, 180, 223, 251
171, 181, 203, 204, 215, 223, 224, 237, in vitro, 7, 10, 49, 242, 260
245, 264 in vivo, 45, 49, 194, 210, 242, 243, 247, 260
HIV/AIDS, 22 incidence, 106, 129, 144, 158, 200, 213,
homogeneity, 46 215, 224, 245, 252
hospitalization, 159, 200, 202 indentation, 108
Hunter, 149, 228 indirect effect, 257
hyaline, 5, 25, 42, 48 individuals, x, 70, 106, 152, 165, 166, 211,
hybrid, xi, 235, 244, 247 213
hydrogen peroxide, 23 induction, 91, 92
hydrolysis, 258 infection, 12, 72, 111, 114, 120, 131, 137,
hydroxyapatite, 111, 126 140, 143, 212, 219, 247
hydroxylapatite, 121 inferiority, 184
hyperesthesia, 66 inflammation, 107, 108, 134
hyperglycemia, 143 inflammatory cells, 30, 200, 201
hypertrophy, ix, 7, 11, 63, 64, 65, 131, 136, inflammatory disease, 22
140, 216, 256 inflammatory mediators, 8, 19
hypothesis, viii, 14, 18, 21, 30, 31 inflammatory responses, 200
hypoxia, 259 informed consent, 21
hysteresis, 49, 50 inhibition, 197
injections, x, 10, 108, 127, 140, 143, 147,
153, 157, 170, 172, 204, 205, 217, 218
I injury, ix, 37, 38, 39, 50, 52, 70, 76, 100,
109, 112, 113, 115, 136, 137, 147, 162,
iatrogenic, vii, 1, 10, 75, 76, 145
184, 192, 196, 200, 248, 254, 256
ibuprofen, 108
insertion, 116, 177, 178
ideal, 30, 91, 100, 110, 118, 181
insulin, 20
identical twins, 12
integrity, 8, 47, 51, 173, 219, 238, 254
identification, viii, 18, 20, 106
interface, ix, 25, 37, 42
idiopathic, 66
interference, 242
IFN, 19
intervention, x, 71, 88, 128, 141, 143, 147,
IL-17, 19
152, 218, 219
IL-8, 10, 19
intervertebral disc, vii, viii, ix, xi, 1, 2, 4, 6,
iliac crest, 109, 124, 255
7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 19, 20,
images, 23, 90, 91, 95, 107, 139, 140, 145
22, 23, 29, 30, 31, 32, 37, 38, 40, 41, 53,
imaging modalities, 68
54, 63, 64, 66, 86, 107, 109, 125, 128,
immobilization, 70
131, 159, 160, 161, 166, 167, 176, 197,
immune response, 161, 242
198, 199, 200, 201, 202, 203, 204, 208,
immune system, 161
209, 210, 216,235, 236, 238, 239, 241,
immunity, 143
242, 243, 244, 250, 256, 259, 264, 266
immunohistochemistry, 23
invaginate, 3
immunotherapy, 259
276 Index

inversion, 107 Limbus Vertebral Fractures, 136

ions, 5 liver, 97
ipsilateral, 93, 144, 168, 175, 191 local anesthesia, 143, 176, 177, 256, 265
ischemia, 216 localization, 91, 112
Islam, 155 longevity, 110
issues, 110 longitudinal study, 202
lordosis, 65, 71, 75, 111, 115, 129, 244,
249, 261
J lumbar degenerative disc disease (LDDD),
viii, 17, 18, 21, 252
joints, x, 2, 8, 12, 39, 52, 95, 113, 120, 128,
lumbar disc degeneration, 13, 14, 166, 193,
129, 136, 140, 159, 161, 173, 211, 212,
199, 202, 212
214, 215, 216, 224
lumbar disc herniation, x, 9, 14, 15, 21, 153,
157, 158, 159, 165, 167, 172, 174, 176,
K 179, 190, 191, 196, 200, 203, 205, 206,
207, 208, 209, 265, 266
keratin, 43 lumbar laminectomy, 145, 153, 184
kidney, 245, 247, 248 lumbar radiculopathy, 149, 180
knees, 130, 165 Lumbar spinal stenosis (LSS), x, 127, 128,
kyphosis, 72, 74, 75, 99, 111, 112, 113, 114, 129, 131, 134, 135, 136, 137, 138, 139,
115, 116, 117, 145 140, 141, 142, 143, 144, 145, 146, 147,
148, 149, 150, 151, 152, 153, 221
lumbar spine, x, 11, 22, 23, 39, 49, 90, 99,
L
128, 132, 133, 134, 139, 149, 150, 151,
labeling, 9 153, 154, 158, 159, 161, 166, 171, 173,
Laminectomy, 75, 79, 80, 81, 82, 85, 115, 191, 193, 198, 199, 203, 205, 207, 209,
116, 117, 119, 131, 135, 137, 141, 144, 211, 212, 218, 247, 250, 253
145, 146, 148, 149, 153, 154, 155, 173, lumbar stenosis, 128, 136, 140, 141, 153,
174, 175, 184, 219, 221, 226, 227, 254 154, 155
Laminotomy, 93, 144, 153, 176, 219 lymph, 198
lateral extracavitary, 87, 94, 99, 102
learning, 5, 98, 184, 185, 207, 248, 253 M
Lebanon, 87
lesions, 90, 100, 136, 140, 197 macrophages, 19
leucocyte, 197 magnetic resonance imaging (MRI), 2, 5, 9,
life expectancy, 258 11, 12, 13, 14, 21, 22, 23, 64, 65, 68, 69,
lifetime, 158 78, 79, 107, 108, 125, 132, 133, 134,
ligament, 40, 46, 64, 69, 80, 81, 82, 109, 138, 139, 140, 149, 151, 166, 169, 170,
116, 117, 118, 119, 125, 135, 136, 139, 195, 196, 200, 201, 203, 208, 240, 241
140, 144, 149, 159, 167, 170, 192, 199, majority, 6, 65, 99, 136, 139, 169, 191, 213,
209, 248, 254, 261 216, 218, 224
ligand, 259 malignancy, 212
light, 23, 24, 165, 223, 259
 Index 277

management, vii, ix, x, 70, 71, 77, 80, 87, migration, 3, 74, 111, 114, 170, 197, 212,
88, 91, 102, 103, 117, 127, 134, 137, 214, 216, 224, 243, 252, 255
140, 141, 143, 148, 149, 157, 158, 170, mildly depressed, 182
171, 179, 180, 181, 182, 204, 205, 208, military, 117
211, 215, 218, 219, 221, 222, 224, 237, mineralization, 7
247, 258 MLD, 183, 184, 185
management of disc herniations, 157 MMP-3, 9
manipulation, 90, 91, 136, 141, 172 models, 20, 240, 242, 243, 251
marrow, 6, 14 modifications, 24, 103, 109
Maryland, 63 modulus, 8, 44, 45, 46, 47, 51, 244, 247
mass, 50, 75, 79, 115 molecular weight, 242, 259
materials, xi, 111, 135, 235, 245, 247, 251 molecules, 29, 43
matrix, 5, 7, 10, 13, 14, 24, 25, 29, 38, 43, monocyte chemoattractant protein, 201
45, 51, 79, 124, 160, 238, 242 monozygotic twins, 166
matrix metalloproteinase, 13, 14 morbidity, vii, ix, 72, 87, 97, 103, 110, 111,
matter, 22, 206 118, 124, 145, 158, 191, 219, 221
mean arterial pressure, 91, 103 morphology, x, 20, 157, 162, 182, 200, 206
measurements, 25, 45, 69, 95, 170 morphometric, 30
mechanical properties, 242 mortality, 103, 109, 145, 154, 219
mechanical stress, 43, 44, 80, 106, 108, 215, multiples, 5
218, 238 multipotent, 20, 241, 242
medial collateral, 209 muscle relaxant, 142, 171
median, 25, 27, 28, 31 muscle strength, 130
medical, 71, 83, 108, 129, 138, 141, 143, muscles, 39, 66, 113, 114, 116, 218
146, 148, 158, 171, 180, 247, 258 myelogram, 69, 139, 169
medical care, 129, 138, 141 myocardial infarction, 22
medical history, 171
Medicare, 128, 154
medication, x, 134, 140, 157, 171, 217
N
medicine, 13
narcotic, 118
meninges, 107
narcotics, 91, 171
meningitis, 143, 153, 172
National Basketball Association, 206
mesoderm, 3, 20
NDI, 245, 251
meta-analysis, 114, 143, 148, 150, 152, 166,
necrosis, 7, 111
170, 183, 194, 207, 209, 219, 220, 245,
neovascularization, 54, 169, 170
251, 263, 264
nephropathy, 138
Metabolic, 8
nerve, viii, ix, 17, 18, 19, 20, 25, 26, 29, 30,
metabolism, 8
31, 32, 53, 54, 65, 66, 71, 76, 77, 79, 88,
methodology, 218, 237
93, 106, 107, 109, 112, 113, 115, 117,
microcirculation, 6, 14
118, 120, 130, 137, 139, 142, 161, 162,
microscope, 23, 24, 120, 174, 176, 192, 207
164, 168, 173, 174, 176, 178, 184, 191,
microspheres, 242, 259
192, 198, 199, 200, 204, 248, 255
278 Index

nerve fibers, viii, 18, 19, 20, 25, 29, 30, 32, operations, 110, 114, 121, 154, 175, 181,
53 184, 217, 221
nerve growth factor, viii, 17, 18, 19, 20 opioids, 142
neuralgia, 100 organs, 29, 54
neurofilaments, 21, 30 ossification, 3, 64, 74, 80, 81, 82, 108, 109,
neurogenic claudication, 129, 132, 134, 141, 114, 117, 119, 125, 135, 139, 140, 149,
144, 146, 147, 148, 152, 215, 217, 224 216, 252
neurologic symptom, 65, 215, 224 Ossification of Ligamentum Flavum (OLF),
neuronal and endothelial proliferation, 18 135, 136
neuronal cells, 21 Ossification of the Posterior Longitudinal
neurons, 20, 30 Ligament (OPLL), 64, 69, 74, 76, 82,
neuropathy, 22, 147, 155 135, 136, 139
neurosurgery, vii, 80, 82 osteomyelitis, 9, 12
neutral, 75, 76, 115 osteoporosis, 99, 114
neutrophils, 19 osteotomy, 116, 249
New England, 121, 220, 226, 227, 232 outpatient, 198, 253
NFL, 182 oxygen, 7, 239, 257, 258, 266
nicotine, 7, 11, 12, 13, 202 ozone, 257, 258, 266
nitrous oxide, 7
nodes, 42
non-smokers, 166
P
non-steroidal anti-inflammatory drugs, 142,
Pacific, 233
170, 171
pain, viii, ix, x, 2, 18, 19, 20, 21, 22, 28, 29,
nonsurgical treatment, 135, 149, 152, 205,
30, 31, 32, 38, 65, 68, 70, 71, 79, 89, 94,
236
100, 106, 107, 108, 109, 114, 117, 119,
normal aging, 19, 54, 128
120, 127, 128, 129, 130, 131, 135, 141,
North America, 15, 58, 62, 81, 83, 102, 122,
142, 143, 146, 150, 158, 161, 166, 167,
128, 138, 232, 233
168, 171, 172, 176, 178, 179, 180, 181,
notochord, 3, 20, 41, 160
182, 183, 184, 191, 204, 206, 215, 218,
NSAIDs, 108, 170, 171, 218
219, 220, 223, 236, 237, 240, 242, 250,
nucleus, 3, 4, 5, 7, 8, 10, 19, 20, 25, 26, 30,
251, 254, 256, 257, 258, 259
40, 41, 42, 45, 49, 50, 114, 135, 159,
pain management, 108, 242
160, 162, 197, 238, 256, 257, 259, 260
pallor, 130
nutrient, viii, 5, 7, 8, 11, 15, 17, 18, 40, 42,
parallel, 31, 47, 161, 177, 258
43, 45, 48, 161, 239
paralysis, 112
nutrition, 141, 152
paresis, 168
nutritional status, vii, 1
paresthesias, 66, 78, 110, 119, 168, 181,
195, 215
O parity, 214
participants, 142, 180
obesity, 194 pathogenesis, 14, 84, 136, 216
oophorectomy, 214 pathogens, 9
 Index 279

pathology, vii, 40, 65, 68, 71, 72, 77, 89, 98, porosity, 243
107, 109, 112, 115, 132, 137, 139, 142, posterior cervical decompression and
149, 151, 161, 191, 197, 198, 236, 237, fusion, 64
244, 252, 254, 255, 256 post-hoc analysis, 182
pathophysiological, 65 potential benefits, 248
pathophysiology, vii, 2, 11, 13, 14, 15, 31, prescription drugs, 142
38, 106, 147, 158, 197, 204 preservation, 68, 73, 75, 114, 115, 144, 194,
pathways, 4, 18, 242 242, 251, 254
PCM, 45, 251 prevention, x, 155, 157, 194, 252
pelvis, 168, 249 primary function, 38
penetrance, 11 principles, 109
peptic ulcer, 171 probability, 170, 203
perfusion, 6, 91, 166 probe, 113, 257
peripheral vascular disease, 129 prognosis, 14, 106, 109
permeability, 45, 46, 49, 50, 51 pro-inflammatory, viii, 17, 19, 20, 29
personality, 182 project, 243
personality factors, 182 prolapse, 49, 202, 209
PGE, 19 proliferation, viii, 7, 18, 19, 29, 54, 135,
phenotype, 19, 197, 147, 259, 260 239, 241, 243
Philadelphia, 101, 102, 105, 258, 259 prosthesis, 114, 123, 251, 252
phosphate, 111, 119 protection, 113
physical activity, 131, 141, 214 proteins, 10, 13, 43
physical health, 221 proteoglycans, 5, 8, 19, 41, 42, 43, 45, 50,
physical therapy, x, 141, 143, 152, 157, 170, 160, 167, 169, 170, 241
180, 217, 237 proteolytic enzyme, 29
physicians, 169, 244 pseudocyst, 146
physiology, 172, 197 pulmonary embolism, 147
pilot study, 204, 223 pyogenic, 15
placebo, 143
plants, 168
platelets, 240
Q
platysma, 113
quality of life, x, 114, 127, 137, 141, 143,
playing, 30
146, 149, 154, 206, 221, 236, 242, 249,
pleura, 94
251, 252, 258
plexus, 5, 248
query, 83
PMMA, 91
questionnaire, 137, 240
polyether, 111
polymer, 244, 247
polymer materials, 244 R
polymorphisms, 14
polypeptide, 54 racial differences, 214
population, vii, 19, 129, 131, 150, 154, 158, radial distribution, 42
169, 199, 203, 221, 224, 236, 240, 258 radiation, 184
280 Index

radiculopathy, 2, 65, 78, 100, 107, 108, 114, risk factors, 106, 158, 165, 194, 198, 201,
115, 129, 132, 144, 147, 168, 179, 203, 202, 209, 213, 214
204, 253, 254 RNA, 10, 242
randomized controlled clinical trials, x, 127 ROI, 245
reactions, 182 Romania, 17
real time, 256 root, 19, 20, 30, 54, 65, 66, 71, 76, 77, 79,
receptors, 10, 14, 30, 54, 239 88, 93, 106, 107, 108, 109, 113, 115,
recognition, 112 117, 118, 131, 139, 142, 161, 164, 168,
recommendations, 134, 141, 172 173, 174, 176, 178, 184, 191, 192, 195,
reconstruction, 79 200, 204, 255
recovery, 69, 119, 131, 185 roughness, 260
recreational, 165 routes, 9
recurrence, 193, 194, 209, 250
reflexes, 78, 107, 108, 130, 195
regeneration, 10, 238, 239, 240, 241, 242,
S
243, 259
sacrum, 39, 89
regenerative capacity, 239
saddle anesthesia, 168, 195
regression, 71, 170, 203
safety, 204
rehabilitation, 38, 112, 140, 178, 179
SAS, 227, 257
reinforcement, 8
scar tissue, 131, 169, 193, 248
relaxation, 49
schema, 212
relevance, 184
sciatica, 24, 28, 29, 151, 158, 184, 190, 199,
reliability, 140, 148
200, 202, 205, 207, 208, 255, 257, 266
relief, 109, 129, 143, 144, 146, 172, 176,
sclerosis, 216
181, 218, 219, 256, 257
Scoliosis, 99, 137, 150, 262
repair, 100, 146, 194, 195, 210, 238, 243,
scope, 178, 241, 258
259
secondary data, 142
repetitions, 165
secretion, 30
requirements, 6, 118
sedentary lifestyle, 131
researchers, 242
seeding, 9
resection, 76, 94, 100, 113, 136, 149
senescence, 19, 238
resistance, 245
sensation, 67, 68, 128, 168
resolution, 107, 170, 192, 195
sensitivity, 140, 168
response, 9, 10, 49, 51, 169, 237, 238, 242
sensory symptoms, 106
responsiveness, 11
serum, 7
restoration, 72, 110, 249, 261
shape, 5, 30, 39, 43, 45, 139, 247
rheumatoid arthritis, 67
shear, ix, 8, 10, 37, 44, 45, 47, 49, 50, 199
riboflavin, 194
shock, 50, 130
risk, xi, 9, 22, 65, 70, 99, 100, 106, 111,
showing, 11, 12, 48, 133, 134, 140, 172,
119, 120, 135, 145, 158, 159, 165, 166,
262
167, 170, 172, 184, 192, 193, 194, 195,
side chain, 43, 167
198, 201, 202, 209, 213, 214, 219, 223,
signals, 69
236, 248, 254, 255, 265
 Index 281

signs, 9, 65, 67, 69, 70, 77, 106, 107, 118, stem cell differentiation, 241, 259
128, 131, 140, 180, 204, 218 stem cells, 239, 241, 242
simulation, 51 stenosis, ix, 7, 63, 64, 65, 66, 68, 69, 70, 71,
siRNA, 242 74, 75, 76, 77, 107, 109, 112, 113, 119,
skin, 112, 130 125, 128, 129, 133, 134, 135, 136, 140,
smoking, viii, 7, 13, 17, 18, 166, 167, 194, 141, 144, 145, 146, 147, 148, 152, 153,
202, 209, 214 154, 155, 169, 177, 185, 219, 221, 255,
software, 24 265
solid matrix, 8, 51 sterile, 23
solid phase, 50 sternocleidomastoid, 113
solution, 23, 100, 106 sternum, 88, 99
spasticity, 107 steroids, 108, 143
specialists, 100 stimulation, viii, 9, 18, 20, 248
spending, vii, 158, 236 straight leg raising test, 130
spinal canal narrowing, x, 11, 127, 128, 140 strategic planning, 88
spinal cord, 38, 64, 65, 66, 67, 69, 71, 74, stratification, 221
75, 76, 77, 78, 79, 80, 81, 84, 88, 90, 91, stress, 13, 44, 46, 51, 52, 109, 114, 212,
106, 109, 115, 116, 161 219, 244, 247
spinal fusion, xi, 109, 137, 144, 154, 211, stress fracture, 212
220, 223, 224, 249, 256 stretching, 141, 171
spinal stenosis, ix, x, 19, 63, 65, 71, 127, structural changes, 19
128, 129, 132, 134, 136, 138, 140, 147, structure, ix, 4, 5, 26, 37, 38, 40, 42, 43, 47,
148, 149, 150, 151, 152, 153, 154, 155, 48, 49, 51, 54, 160, 197
221, 236 subcutaneous tissue, 174, 175
spine, vii, ix, xi, 2, 23, 37, 38, 39, 40, 41, subgroups, 221
52, 54, 63, 64, 65, 69, 70, 71, 75, 76, 78, subluxation, 52
80, 88, 90, 95, 99, 100, 102, 105, 106, substrates, 260
109, 111, 114, 116, 117, 120, 128, 131, success rate, 119, 145, 198
132, 134, 136, 145, 149, 151, 155, 159, sulfate, 43, 167
165, 166, 171, 176, 180, 190, 196, 201, suppression, 29, 143
202, 206, 210, 215, 216, 218, 235, 236, surface area, 24, 25, 26, 28, 31, 246, 247,
245, 247, 249, 254, 261, 262, 264 249
spondylolisthesis, vi, x, 7, 22, 131, 132, surgical intervention, vii, xi, 23, 128, 137,
134, 135, 137, 139, 145, 149, 153, 154, 140, 142, 143, 179, 181, 215, 218, 235,
185, 211, 212, 213, 215, 216, 219, 220, 236, 257
221, 223, 225, 226, 227, 228, 229, 230, surgical removal, 144, 145
231, 232, 233 surgical technique, xi, 99, 102, 147, 195,
stability, 45, 68, 73, 75, 76, 99, 109, 113, 223, 236, 244
115, 144, 165, 173, 215, 244, 247, 249, surgical treatment, xi, 70, 74, 102, 103, 108,
260 150, 151, 153, 154, 211, 219, 236, 260,
stabilization, 109, 116, 137, 150, 216, 218, 262
223, 224, 247 survival, 20
statistics, 196 susceptibility, 167
282 Index

swelling, 8, 45, 46, 48, 50, 51 Thoracic disc herniations, ix, 87, 88, 97, 98,
Switzerland, 187, 189, 190, 210 100, 102, 103
symptomatic treatment, 223 thoracic herniated disc, 87, 88, 89, 91, 99
symptoms, viii, ix, x, 2, 18, 21, 24, 28, 31, thoracic surgeon, 98
32, 63, 65, 66, 67, 71, 72, 75, 76, 77, 78, thoracotomy, 87, 102
88, 105, 106, 107, 108, 114, 117, 128, thorax, 176
129, 131, 132, 135, 137, 138, 140, 142, thrombosis, 147
146, 147, 148, 157, 168, 171, 179, 180, tissue, 8, 12, 19, 21, 25, 26, 30, 31, 32, 46,
184, 192, 193, 199, 204, 215, 218, 219, 47, 49, 50, 51, 53, 54, 68, 94, 99, 106,
223, 224, 237, 242, 254 107, 108, 112, 113, 116, 118, 139, 167,
syndrome, 107, 147, 195, 204, 209 169, 193, 200, 203, 239, 240, 241, 242,
Synovial Cysts, 136, 137, 149 243, 248, 254, 259, 260
synthesis, x, 105, 239 tissue engineering, 239
syringomyelia, 69 titanium, 111, 119, 244, 245, 247, 260, 261
TLR, 10
TNF-α, 10, 19, 20
T tobacco smoke, 202
total energy, 178
T cells, 19
trachea, 113
Taiwan, 245
training, 141, 185, 253, 256
tantalum, 111
training programs, 256
target, 113, 118, 241, 242, 256
transcription, 242
tau, 24, 28
transcription factors, 242
techniques, x, xi, 76, 91, 93, 98, 99, 100,
transduction, 45
101, 102, 111, 114, 116, 118, 128, 145,
transforming growth factor (TGF), 3, 4,
146, 172, 183, 184, 185, 190, 191, 193,
241, 242, 259
194, 195, 196, 201, 222, 236, 242, 243,
translation, 52, 75, 139, 212, 219
244, 248, 252, 253, 254, 255, 256, 258,
transmission, 42, 111
265
transpedicular, 87, 92, 93, 95, 97, 101, 229,
technology, 109, 248, 252
260
temperature, 130
transplant, 240
tendon, 46, 54, 108
transplantation, 13, 240, 259
tensile strength, 5, 43, 45, 109
transport, 45, 49
tension, 65, 76, 168
transportation, viii, 17, 18
territorial, 24
trauma, 70, 109, 131, 136, 184, 191
testing, 51, 91, 128, 246, 247
treatment, vi, vii, ix, x, xi, 7, 11, 21, 38, 60,
thalamus, 161
70, 71, 74, 75, 81, 82, 85, 89, 98, 102,
therapeutic targets, viii, 1
103, 105, 106, 108, 112, 114, 119, 120,
therapeutics, 15, 259
122, 125, 127, 135, 137, 140, 141, 142,
therapy, 13, 14, 106, 108, 110, 141, 149,
143, 144, 146, 147, 148, 149, 150, 151,
152, 171, 217, 218, 236, 237, 239, 240,
152, 153, 154, 157, 169, 171, 172, 177,
242, 247, 256, 258, 259
179, 180, 181,183, 184, 196, 197, 198,
therapy interventions, 152
200, 204, 205, 206, 207, 209, 211, 217,
 Index 283

218, 219, 220, 222, 223, 225, 227, 229, vein, 147
230, 231, 232, 233, 235, 236, 237, 238, vertebrae, ix, 37, 38, 39, 40, 90, 139, 161,
241, 243, 244, 245, 251, 253, 258, 259, 212, 239
260, 262, 263, 264, 265, 266 vertebral artery, 115
trial, 22, 122, 123, 134, 137, 141, 142, 143, vertebrates, 38
151, 152, 153, 180, 183, 184, 190, 194, vessels, 6, 7, 174, 246, 248
204, 205, 206, 207, 208, 220, 240, 257, vibration, 108, 166
263, 264, 266 viral vectors, 241
triggers, 19, 20 viscoelastic properties, 41, 45
tropism, 10, 13 visual field, 24, 26
truck drivers, 166 visualization, 23, 95, 111, 112, 113, 140,
tuberculosis, 22 174, 176, 178, 244, 247
tumor, 69, 138, 140, 165, 201 vitamin B6, 142
tumor necrosis factor, 165, 201 Vitamin C, 8, 15
twins, 14, 166 volumetric changes, 170, 203

U W

United States (USA), 24, 123, 158, 196, walking, x, 68, 127, 128, 129, 131, 137,
245, 251, 252 142, 143, 148, 168
Washington, 14, 105, 198
water, 5, 8, 38, 42, 43, 45, 50, 51, 100, 160,
V 238, 242
weakness, 66, 78, 89, 106, 107, 108, 129,
Valencia, 83
132, 168, 181, 195, 215
validation, 204, 262
Western countries, 158
variables, 166, 214
wires, 91, 192
variations, vii, 1, 7, 38, 46, 47
wound healing, 115
vascular bundle, 100
wound infection, 146, 219
vascular wall, 7
vasodilation, 142
vector, 241, 242 X
VEGF, 30, 203
vehicles, 201 x-rays, 68, 90, 91, 247