Spinal Cord, Root, and Plexus Disorders Comlete

L I F E L O N G L E A R N I N G I N N E U R O L O G Y
SPINAL CORD, ROOT, AND PLEXUS

DISORDERS
Volume 14
Number 3
June 2008
FACULTY
NEERAJ KUMAR, MD, CHAIR

Associate Professor, College of Medicine, Mayo Clinic, Rochester, Minnesota;
Consultant, Department of Neurology, Mayo Clinic, Rochester, Minnesota
*
Dr Kumar has nothing to disclose.
JOSE BILLER, MD, FACP, FAHA, FAAN

Professor and Chairman, Department of Neurology, Loyola University Chicago,
Stritch School of Medicine, Chicago, Illinois
*
Dr Biller has nothing to disclose.
THOMAS COCHRANE, MD, MBA

Instructor in Neurology, Harvard Medical School, Boston, Massachusetts
*
Dr Cochrane has nothing to disclose.
JOHN K. FINK, MD
Professor, University of Michigan, Department of Neurology and Geriatric
Research, Education & Clinic Center, Ann Arbor, Michigan; Research Scientist, Ann
Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan
*
Dr Fink has received personal compensation from Athena Diagnostics, Inc.
Dr Fink has received royalty payments for atlastin and NIPA1 patents.
Dr Fink has nothing to disclose.
JEREMY L. FOGELSON, MD
Neurosurgery Resident, Mayo Clinic, Rochester, Minnesota
*
Dr Fogelson has nothing to disclose.
DAVID S. GELDMACHER, MD
Harrison Distinguished Teaching Associate Professor of Neurology, University of
Virginia, Charlottesville, Virginia
*
Dr Geldmacher has received personal compensation for activities with Eisai
Inc./Pfizer Inc, Forest Pharmaceuticals, Inc., Medical Care Corporation, Novartis
Pharmaceuticals, Inc., and Takeda Pharmaceuticals, Inc. Dr Geldmacher has
received grant or research support from Eisai Inc., Elan Pharmaceuticals, Inc.,
Myriad Pharmaceuticals, Inc., and GlaxoSmithKline.
Dr Geldmacher has nothing to disclose.
GREGORY GRUENER, MD, MBA

Professor of Neurology, Associate Chairman, Associate Dean of Educational
Affairs, Loyola University of Chicago, Stritch School of Medicine, Chicago, Illinois
*
Dr Gruener has received personal compensation for speaking engagements
with Medical Education Resources, Inc.
Dr Gruener has nothing to disclose.
WILLIAM E. KRAUSS, MD
Associate Professor of Neurological Surgery, Mayo Medical School, Rochester,
Minnesota
*
Dr Krauss has nothing to disclose.
Dr Krausss presentation includes figures of, but does not discuss, the
unlabeled use of cervical pedicle screws.
KERRY H. LEVIN, MD
Chairman, Department of Neurology, Director, Neuromuscular Center, Cleveland
Clinic; Professor of Neurology, Cleveland Clinic Lerner College of Medicine of
Case Western Reserve University, Cleveland, Ohio
*
Dr Levin has nothing to disclose.
DEVON I. RUBIN, MD
Associate Professor of Neurology, Director, EMG Laboratory, Mayo Clinic,
Jacksonville, Florida
*
Dr Rubin has received royalty payments for contributing to an EMG
educational CD-ROM from AAN Enterprises, Inc., and the American Association
of Neuromuscular and Electrodiagnostic Medicine.
Dr Rubin has nothing to disclose.
LUBDHA SHAH, MD
Assistant Professor, Radiology, University of Virginia Health System, Charlottesville,
Virginia
*
Dr Shah has nothing to disclose.
DEAN M. WINGERCHUK, MD, MSc, FRCP(C), FAAN

Associate Professor of Neurology, Consultant, Department of Neurology, Mayo
Clinic, Scottsdale, Arizona
*
Dr Wingerchuk has received personal compensation for activities with
Genentech, Inc. Dr Wingerchuk has received research support to Mayo Clinic
from the National Multiple Sclerosis Society and Genzyme Corporation.
Dr Wingerchuk discusses the unlabeled use of methylprednisolone,

plasmapheresis, and cyclophosphamide for the treatment of myelitis attacks;
carbamazepine for tonic spasms; and prednisone, azathioprine, mycophenolate
mofetil, cyclophosphamide, mitoxantrone, intravenous immune globulin, and
rituximab for prevention of relapse of certain inflammatory myelitides.
MULTIPLE-CHOICE QUESTION WRITERS
RONNIE BERGEN, MD
Assistant Professor of Clinical Neurology, University of Arizona College of
Medicine, Southern Arizona VA Hospital, Tucson, Arizona
*
Dr Bergen has received personal compensation for activities with Biogen Idec.
Dr Bergen has nothing to disclose.
DOUGLAS J. GELB, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
*
Dr Gelb has received personal compensation in an editorial capacity from
Current Opinion in Internal Medicine.
Dr Gelb has nothing to disclose.
Relationship Disclosure
Unlabeled Use of Products/Investigational Use Disclosure
SPINAL CORD, ROOT, AND PLEXUS DISORDERS
EDITORS PREFACE
This issue of Continuum, ably and enthusiastically chaired by Dr Neeraj Kumar,
represents a microcosm of the neurology universe. While less often encountered than disorders of the brain and those involving the peripheral nervous
system (all things considered), disorders of the spinal cord, roots, and plexuses
run the gamut of neurologic disease categories. Dr Kumar has recruited an
outstanding faculty to produce this exciting, highly clinically relevant issue.
The complexity of the spinal cord, so densely packed into an organ hardly
larger than a thumbnail, never ceases to amaze. The first sections eloquent
discussion of the intricate organization of the spinal cord by Drs Gregory
Gruener and Jose Biller helps us exercise that core principle of neurologic
diagnosis, precise anatomic localization. Armed with this information, we are
better prepared to digest the subsequent disease-focused offerings.
Infectious and inflammatory disorders are described by Dr Dean Wingerchuk, who highlights developments in our understanding of transverse myelitis,
as well as emphasizes the excitement surrounding neuromyelitis optica (NMO)
and the implications of the recently discovered NMO-Ig antibody, which is
directed against aquaporin-4, the major water channel in the CNS. Although the
previous issue of Continuum was devoted entirely to neurogenetics, diseases of
the spinal cord exemplify the importance of this field. Dr John Fink, rather than
providing a mind-bending litany of syndromes, focuses on a systematic way to
approach patients with potential genetic disorders of the cord.
Although vascular diseases of the spinal cord are relatively infrequent,
certainly in comparison to cerebral strokes, they nonetheless pose interesting
clinical scenarios. Drs David Geldmacher and Lubdha Shah present a lucid
discussion not only of arterial syndromes but also of venous disorders and
arteriovenous malformations. An incredible variety of toxic-metabolic disorders
can affect the spinal cord. In addition to reviewing many familiar disorders, Dr
Kumar himself discusses some conditions that have more recently gained in
importance, such as copper deficiency myelopathy and other syndromes associated with the rapidly expanding use of bariatric surgery.
Among the most important categories of spinal cord disease are compressive myelopathies and traumatic injuries. It is critically important that neurologists recognize spinal cord compression, as early intervention may mean the
difference in a patients ability to walk. Unfortunately, spinal cord injury too
often reminds us of the vulnerability of the human condition and will remain a
EDITORS PREFACE
major problem in a world dependent on motor vehicles and with those too frequently operated
by intoxicated drivers. Drs Jeremy Fogelson and William Krauss educate us about these
important conditions.
Our attention next switches to the peripheral nervous system as we move outside the spinal
cord to the nerve roots and subsequently the brachial and lumbar plexuses. Dr Kerry Levin
provides an extensive review of the anatomy of the spinal roots and guidance on recognition
of radiculopathies, followed by a discussion of the often-controversial issues of management.
Finally, Dr Devon Rubin analyzes the complex anatomy of the plexuses innervating the upper
and lower limbs, respectively, along with offering a clear discussion of the relatively unusual
afflictions of these anatomic structures.
Complementing these chapters is the ethical discussion by Dr Thomas Cochrane that
analyzes issues concerning surrogate decision making in a patient with severe spinal cord
injury. A patient management problem, neatly crafted by Dr Wingerchuk, reprises the points
emphasized in his chapter. Dont forget to solidify your knowledge by attempting the clinically
oriented multiple-choice questions devised by Drs Ronnie Bergen and Douglas Gelb.
This issue of Continuum also features the bonus of Quintessentials. If you have never tried
Quintessentials, this is a great time to plunge in and test your clinical skills on three important
clinical vignettes. You will receive rapid feedback and the opportunity subsequently to repeat
the exercise and see your progress. This tool has been cited as an outstanding instrument to
help you accomplish what will ultimately be necessary for Maintenance of Certification.
As editor, I am most appreciative of the exceptionally high level of enthusiasm with which
Dr Kumar and his colleagues approached the task of developing this issue of Continuum. I
know you will reap the benefits!
Aaron Miller, MD
10
SPINAL CORD ANATOMY,

LOCALIZATION, AND
OVERVIEW OF SPINAL
CORD SYNDROMES
Gregory Gruener, Jose Biller
ABSTRACT
Spinal cord syndromes are unique clinical presentations that localize lesions to
the spinal cord by their pattern of anatomic dysfunction while implying their underlying
etiology. Recognizing these patterns and their significance is best accomplished by
relearning and appreciating the relevant anatomy and relationships, which are the
major focus of this review. This clinical-anatomic background will provide the framework for the clinical topics that follow in this
issue.
ANATOMY OF THE SPINAL

CORD
Relationship to the Vertebral
Levels and Spine
The typical vertebra consists of a columnar body with a larger transverse
than anterior-posterior diameter and
serving as the primary support for the
spine. The vertebral arch extends from
the body, forming a protective enclosure, and consists of a pedicle on either side that unites posteriorly
through the two laminae. Three processes arise from the vertebral arch,
laterally the transverse and posteriorly
the spinous, serving as the attachment
site for muscles (Figure 1-1). Four
separate articular processes, a superior
pair extending cranially and an inferior pair extending caudally, serve to
direct or limit movement to specific
directions by articulating with the vertebra above and below (Figure 1-2).
A notch in the inferior aspect of the

pedicle will contribute to the boundary
of the intervertebral foramen when adjacent vertebrae are articulated and
through which the spinal nerve and intervertebral vessels will pass.
An intervertebral disc is interposed
between each vertebral body and consists of alternating, crisscrossing bands
of fibrous connective tissue, the annulus fibrosus, which surround a gelatinouslike core, nucleus pulposus. The
vertebral discs will contribute 25% of the
height of the vertebral column. Several
ligaments and fibrous attachments of
muscles help to bind together and enclose the vertebral column. The most
prominent are the anterior longitudinal
(along the anterior aspect of the bodies),
the posterior longitudinal (along their
posterior aspect), the ligamentum flavum (posterior wall of spinal canal), and
the interspinous ligament.
The fused periosteum of the cra-
Relationship Disclosure: Dr Gruener has received personal compensation for speaking engagements with
Medical Education Resources, Inc. Dr Biller has nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Gruener and Biller have nothing to
disclose.
Copyright 2008, American Academy of Neurology. All rights reserved.
KEY POINT:
A notch in the
inferior aspect of
the pedicle will
contribute to the
boundary of the
intervertebral
foramen when
adjacent
vertebrae are
articulated and
through which
the spinal nerve
and
intervertebral
vessels will pass.
11
SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES
FIGURE 1-1
Functions of the constituent parts of a vertebra.

Reprinted with permission from Grant JCB. An atlas of anatomy. 6th ed. Baltimore: Williams &
Wilkins, 1972.
nium and meningeal layer of the dura

matter will separate caudal to the foramen magnum, forming an anatomic
space, epidural space, which extends

the length of the spinal column (Figure 1-3). Within this space reside fatty
12
FIGURE 1-2
Lateral view of a lumbar (second) vertebra.

Sup superior; Inf inferior.
Modified with permission from Grant JCB. An atlas of anatomy. 6th ed. Baltimore: Williams &
Wilkins, 1972.
Continuum: Lifelong Learning Neurol 2008;14(3)
tissue and the vertebral venous plexus.

The separation of these fused layers of
connective tissue allows the vertebral
column to move separately relative to
the dural sac that surrounds the spinal
cord and roots. The dorsal and ventral
roots will enter a dural sleeve at the
level of their intervertebral foramina,
lateral to the dorsal spinal ganglia, fusing to form the spinal nerves. A layer
of pia mater surrounds the surface of
the spinal cord, and between it and the
inner layer of the arachnoid tissue is
the subarachnoid space. Between successive nerve roots, a bandlike extension of the pia mater will arise from
the surface of the spinal cord, denticulate ligament, attaching to the dura
and serving to anchor the spinal cord
(Figure 1-4). The ventral nerve roots
lie anterior and the dorsal nerve roots
posterior to this ligament.
The spinal cord is cylindrical in
shape, but flattened dorsoventrally. It
is widest at the cervical enlargement,
and a second enlargement occurs in
the lumbosacral level of the cord, both
reflecting the innervation levels of the
limbs. At birth the spinal cord typically
extends to the lower border of L3. By
adulthood its tip is usually at the L1-2
vertebral disk level but can end at T12
or descend to the lower border of the
L2 vertebrae.
Each segment of the spinal cord
usually has a set of dorsal (sensory)
and ventral (motor) rootlets that
emerge and join together to form their
corresponding root; dorsal roots have
their corresponding ganglia (dorsal
root ganglia). The dorsal and ventral
roots will fuse to form the spinal nerve
as it exits from the spinal canal. The
spinal nerves then divide into individual branches. There are usually 31
pairs of spinal nerves: eight cervical,
12 thoracic, five lumbar, five sacral,
and usually one coccygeal (Figure
1-5). The first pair of spinal nerves will
exit between the skull and the atlas
(C1), the next six above their respec-
tively numbered vertebrae (C2

through C7), but C8 above the T1 vertebrae. The remaining spinal nerves
will exit below the vertebrae of the
corresponding number. The spinal
nerves will have a dorsal root ganglion
usually located within the intervertebral foramen. C1 lacks a cutaneous
sensory dermatome. Below the L1 vertebra, lumbar and sacral spinal nerve
roots need to descend in order to
reach their point of exit; this collection
of spinal roots is called the cauda
equina. The cord will terminate in a
thin-walled sac covered by pia mater,
the filum terminale, which fuses with
the periosteum of the dorsal surface of
the coccyx.
The gray matter of the spinal cord
can be divided into a posterior column
KEY POINT:
At birth the
spinal cord
typically extends
to the lower
border of L3. By
adulthood its tip
is usually at the
L1-2 vertebral
disk level but
can end at T12
or descend to
the lower border
of the L2
vertebrae.
13
FIGURE 1-3
Spaces associated with the spinal meninges.

Modified with permission from Fitzgerald MJ, Gruener G,
Mtui E. Clinical neuroanatomy and neuroscience. 5th ed.
London: Saunders, 2007:49. Copyright 2007, Elsevier.

KEY POINT:
14
The first pair of

spinal nerve
roots will exit
between the
skull and the
atlas (C1), the
next six above
their respectively
numbered
vertebrae (C2
through C7), but
C8 above the T1
vertebrae. The
remaining spinal
nerves will exit
below the
vertebrae of the
corresponding
number.
FIGURE 1-4
Relationships of the sixth cervical spinal nerve.

Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and
neuroscience. 5th ed. London: Saunders, 2007:171. Copyright 2007, Elsevier.
(or horn), a lateral column, and an

anterior column (or horn) that respectively divide the adjacent white matter into a posterior, lateral, and anterior funiculus. At the junction
between white and gray matter are
short ascending and descending axons
that arise from small neurons within
the spinal cord gray matter and comprise the intrinsic or intersegmental reflex pathways, proprius bundles (or
system) or fasciculi proprii and are
named by their location. While the
posterior funiculi primarily consist of
ascending sensory fibers, they also
contain their descending collateral fibers, which serve to further integrate
intrinsic spinal reflexes and form their
own distinct, but small, fasciculi.
Within the gray matter of the spinal cord cell groups can be identified
(right portion of Figure 1-6), with
those in the posterior horn participating in sensory pathways and those in
the intermediate and anterior horns
serving motor functions. In addition,
layers of synaptic inputs within the
spinal cord have also been identified.
These are called Rexed laminae and
are labeled I to X (left side of Figure
1-6). Those within the posterior horn,
laminae I through V, more clearly

demonstrate a laminated appearance.
Major Ascending Tracts
The diagrammatic representation of
both ascending and descending tracts
within the spinal cord reflects a level
of certainty that, while useful for comprehension, oversimplifies a more
complex anatomic distribution and anatomic variations that likely exist
(Nathan et al, 1990; Nathan et al, 1996;
Nathan et al, 2001). Indeed, the concept of a tract as a homogenous group
of fibers is also an oversimplification.
Despite their shortcomings, however,
such generalizations have proven to
be clinically useful.
The sensory pathways and tracts
we will first review are responsible for
transmitting sensory information that
is perceived (conscious) as well as
nonconscious sensation. The dorsal
root ganglia contribute nerve fibers
that at the dorsal root entry zone will
further segregate into a medial group
of large-diameter fibers, which will enter the posterior funiculi of the spinal
cord, and a lateral group of small-diameter myelinated and unmyelinated
fibers. This segregation is modality
specific and will give rise to the major

ascending tracts within the spinal cord
(Figure 1-7). This lateral group of fibers will divide into short ascending
and descending branches within the
tract of Lissauer and predominantly
synapse on neurons within laminae I
and II of the posterior horn.
The posterior columnmedial lemniscal pathway receives its input from
the largest group of sensory receptors
(neuromuscular spindles and Golgi
tendon organs) entering through the
medial portion of the dorsal root entry
zone. These fibers form a lamination
within the posterior column, and most
medial are those originating from the
lower extremity and trunk, fasciculus
gracilis, carrying sensory information
from the lower extremity; and laterally
is the fasciculus cuneatus, carrying
similar sensory information from the
upper trunk and limb (Figure 1-8). As
these fibers enter the posterior column
they bifurcate and one branch ascends
to the medulla where it will synapse
onto its second-order neuron within
the nucleus gracilis or cuneatus.
Those neurons will then project across
the midline in the sensory decussation,
continuing their ascent to the thalamus
as the medial lemniscus. The thirdorder neurons of this pathway will
then arise from the thalamus and
project to the somatic sensory cortex.
The other branch of that initial bifurcation of entering fibers will synapse
within the posterior gray horn laminae
II, III, and IV at various levels (the
ascending branch also gives off collaterals to the dorsal gray horn). The traditional functions of this system are
believed to be relaying conscious proprioception as well as discriminative
touch. Yet, its role in supporting the
motor cortex as it carries out its intricate and precise digital movements
may better or more accurately characterize its function and importance
(Davidoff, 1989).
The other major conscious sensory
FIGURE 1-5
Vertebral column, spinal cord, and nerve

relationships.
Modified with permission from Moore KL, Dalley AF.
Clinically oriented anatomy. Philadelphia: Lippincott
William & Wilkins, 1999:478.
pathway is the anterolateral spinothalamic tract (Figure 1-9). This tract

arises from neurons in laminae I, II, IV,
and V that receive excitatory as well as
inhibitory input from neurons within
the substantia gelatinosa (lamina II).
The axons that arise from those neurons cross in the anterior commissure
of the spinal cord and arrange themselves in the anterolateral location
within those spinal cord funiculi.
There are two divisions, and the most
anterior is the anterior spinothalamic
tract, which has a somatotopic organization and mediates the sensory moContinuum: Lifelong Learning Neurol 2008;14(3)
15
FIGURE 1-6
Spinal cord laminae and cell groups

(midthoracic level).
Reprinted with permission from Fitzgerald MJ, Gruener
G, Mtui E. Clinical neuroanatomy and neuroscience. 5th
ed. London: Saunders, 2007:182. Copyright 2007,
Elsevier.
dality of touch and pressure. The lateral spinothalamic tract is lateral and
posterior, somatotopically as well as
16
FIGURE 1-7
Primary afferent neuron targets in the

posterior horn.
Elsevier.
modality arranged with cervical representation most medial and sacral most
lateral; pain, tickle, and itch sensory
modalities are more peripheral while
temperature is more medially represented within this tract. These tracts
ascend, merge within the brainstem as
the spinal lemniscus, are joined later
by the trigeminal lemniscus (afferents
from the head), and together terminate
within the thalamus. Their third-order
neurons will also project to the somatic sensory cortex. The spinoreticular tract arises from neurons within
laminae V to VII and accompanies the
spinothalamic pathway, both as a
crossed and uncrossed tract, terminating within the brainstem. It serves as
an arousal system for the cerebral cortex (through the reticular activating
system), and it helps to interpret the
nature of a stimulus (pleasurable or
not).
The spinocerebellar tracts provide
nonconscious proprioception (Figure
1-8). Fasciculus gracilis collaterals provide information from lower limb primary afferents (especially muscle spindle), synapse upon the posterior
thoracic nucleus in lamina VII (extends from T1 through L1 spinal cord
levels, previously called the dorsal nucleus or Clarke column), and give rise
to the posterior spinocerebellar tract.
The tract ascends and reaches the cerebellum through the inferior cerebellar peduncle. A similar group of afferents from the fasciculus cuneatus
provides information from the upper
limb and synapses on the accessory
cuneate nucleus, which gives rise to
the cuneocerebellar tract. It also
reaches the cerebellum through the inferior cerebellar peduncle. The following two spinocerebellar tracts will provide information about the state of
internuncial function in regard to spinal cord reflexes and arise from the
intermediate gray matter of the spinal
cord. (1) The anterior spinocerebellar
tract arises from the lower spinal cord
and will initially cross, ascend to the

superior cerebellar peduncle, cross
again to its side of origin, and terminate within the cerebellum. (2) From
the upper half of the spinal cord the
rostral spinocerebellar tract will ascend and, through the inferior cerebellar peduncle, enter the cerebellum.
The remaining tracts to be considered include the spinotectal tract,
which ends in the superior colliculus,
runs with the spinothalamic tract, and
brings somatic sensory information to
the superior colliculus. The spinoolivary tract projects to the inferior olivary nucleus and through its effects on
the contralateral cerebellar cortex will
modify motor activity.
Major Descending Tracts
The motor cell types within the anterior gray horns are of two types: (1)
Alpha motor neurons (physiologically
defined as tonic or phasic in regard to
the physiologic/functional type of
muscle fibers they innervate) supply
the extrafusal skeletal muscle fibers,
and (2) gamma motor neurons supply
the intrafusal muscle fibers of neuromuscular spindles. The motor unit
comprises an individual alpha motor
neuron, its axon, and all the muscle
fibers (varying from a few to hundreds, dependent on the precision of
the movement) it will subsequently innervate. Recurrent axons of alpha motor neurons excite inhibitory internuncial neurons, Renshaw cells, which
serve to inhibit their own firing (recurrent inhibition). At each segmental
level of the spinal cord, however, alpha motor neurons also receive numerous inhibitory (usually on their
soma) as well as excitatory (through
synapses on their dendritic trees) inputs. These inputs arrive from both
supraspinal pathways as well as
through the propriospinal neurons (local) and their pathways. Most of these
fibers and inputs will exert an inhibitory effect on alpha motor neurons. If
FIGURE 1-8
Ascending pathways (upper cervical level).
GF gracile fasciculus; CF cuneate

fasciculus; PLT posterolateral tract;
PSCT posterior spinocerebellar tract; RSCT rostral
spinocerebellar tract; LSTT lateral spinothalamic tract;
ASCT anterior spinothalamic tract; SOT spinoolivary
tract; ASTT anterior spinothalamic tract; ST
spinotectal tract; SRT spinoreticular tract.
Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical
neuroanatomy and neuroscience. 5th ed. London: Saunders, 2007:187.
Copyright 2007, Elsevier.
those effects are abolished by a cord

lesion, the disproportionately strong
influence of the spinal intrinsic circuits
will lead to the clinical phenomenon
of spasticity.
Figure 1-10 demonstrates the columnar organization of motor neurons
into groups that then innervate muscles with similar function. Those most
medial innervate the axial musculature, and moving traversely through
those groups of neurons, they also
move from the innervation of proximal
to distal limb muscles and finally to the
intrinsic muscles of the hand or foot.
Another result of this neuronal organiContinuum: Lifelong Learning Neurol 2008;14(3)
17

KEY POINTS:
18
The dorsal root

ganglia
contribute nerve
fibers that will
further
segregate at the
dorsal root entry
zone into a
medial group of
large-diameter
fibers that will
enter the
posterior funiculi
of the spinal
cord and a
lateral group of
small-diameter
myelinated and
unmyelinated
fibers.
The traditional
functions of the
posterior
columnmedial
lemniscal system
are believed to
relay conscious
proprioception
and to mediate
discriminative
touch. Yet, its
role in
supporting the
motor cortex as
it carries out its
intricate and
precise digital
movements may
better or more
accurately
characterize its
function and
importance.
FIGURE 1-9
Spinothalamic pathways (sensory modalities, upper cervical level).

Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and
neuroscience. 5th ed. London: Saunders, 2007:187. Copyright 2007, Elsevier.
zation is alpha neurons innervating extensor muscles lying ventral or anterior

to those that innervate flexor muscles.
Dysfunction of these neurons results in
the clinical features of weakness, atrophy, and fasciculations, as well as
areflexia when their loss is marked.
The long descending tracts (corticospinal, reticulospinal, tectospinal,
vestibulospinal, raphespinal) and
aminergic and autonomic pathways
will terminate on interneurons, which
influence alpha and gamma motor
neuron function. The rubrospinal tract
is small and lies anterior to the lateral
corticospinal; in humans its role is unclear. Similar to sensory pathways, the
discrete locations indicated within the
accompanying diagrams are used as
simplifications and conceal a more
complex and variable distribution of
these pathways that explains the discrepancy at times encountered between clinical findings and visualized
anatomic lesions.
The majority of fibers that give rise

to the corticospinal tract have their origin in primary motor cortex (perhaps
50%), but supplementary motor cortex
and premotor cortex, as well as somatic sensory cortex, also contribute.
Some of these projections will end on
brainstem nuclei (corticobulbar or
corticonuclear), while those from sensory cortex project onto sensory nuclei
in the brainstem and spinal cord that
modulate their transmission of sensory
information. Those fibers that reach
the medulla form the pyramids, visible
on its ventral surface. Seventy percent
to 90% of these fibers cross the ventral
midline in the pyramidal decussation,
giving rise to the lateral corticospinal
tract within the spinal cord. A somatotopic organization results with fibers
destined for the sacral area most lateral
and those to the cervical, medial (Figure 1-11). The remaining fibers descend uncrossed either within the lateral corticospinal tract (uncrossed
lateral corticospinal tract) or the majority adjacent to the anterior median

fissure as the anterior corticospinal
tract to innervate paraspinal and axial
muscles. At the appropriate level fibers will cross through the anterior
white commissure to provide their
contralateral innervation.
All corticospinal neurons appear excitatory with glutamate as their neurotransmitter. The corticospinal tract innervates not only alpha and gamma motor
neurons, but also Renshaw cells, excitatory and inhibitory internuncials, and,
through presynaptic inhibition, suppresses some sensory transmission
within the spinothalamic tract in voluntary movement. The proximity of the
lateral corticospinal tract to the motor
neurons that innervate distal limb muscles supports its role in facilitating the
performance of skilled movements and
the belief that an isolated pyramidal lesion only results in flaccid paralysis
and loss of skilled motor function of the
distal limb muscles.
The reticulospinal tracts, through

shared internuncials with the corticospinal tract, act upon motor neurons of
axial as well as proximal limb muscles.
They are considered part of the extrapyramidal system of motor control
(with the lateral vestibulospinal and
tectospinal tracts) and are involved in
locomotion as well as posture. The
medullary reticulospinal tract is believed to act on flexor motor neurons
and the pontine reticulospinal tract on
extensor motor neurons.
The tectospinal tract arises from
brainstem tectum and orients the head
to visual or auditory stimulation. The
lateral vestibulospinal tract originates
in the lateral vestibular nucleus (of
Deiters) and helps in maintaining the
center of gravity for the body. The
raphespinal tract originates from its
nucleus in the medulla and modulates
sensory transmission from its position
within the Lissauer tract. The aminergic pathways arise from their cell
groups within the pons and medulla
KEY POINT:
The lateral
spinothalamic
tract is
somatotopically,
as well as
modality,
arranged with
cervical
representation
most anterior
and sacral most
posterior. Pain,
tickle, and itch
sensory
modalities are
more peripheral
while
temperature is
more medially
represented
within this tract.
19
FIGURE 1-10 Anterior gray horn cell column and somatotopic organization.
Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and neuroscience. 5th ed. London:
Saunders, 2007:192. Copyright 2007, Elsevier.

KEY POINT:
The long
descending
tracts
(corticospinal,
reticulospinal,
tectospinal,
vestibulospinal,
raphespinal),
and aminergic
and autonomic
pathways will
terminate on
interneurons,
which then
influence alpha
and gamma
motor neuron
function.
and have inhibitory effects on sensory

neurons and facilitatory effects on motor neurons through a widespread distribution in the spinal cord gray matter. The central autonomic pathways
arise from the hypothalamus as well as
associated brainstem nuclei, terminating on neurons within the intermediolateral cell columns.
Vascular Supply of the Spinal
Cord
The arterial blood supply to the spinal
cord comprises three longitudinally
oriented vessels as well as contributions from numerous radicular vessels
(Bowen and Pattany, 1999). A rich vascular plexus (arterial or pia vasocorona or plexus) arises from anastomoses between these vessels along the
surface of the spinal cord and from
which medullary vessels penetrate
into both the white and gray matter.
These penetrating vessels are end arteries and do not anastomose further.
20
FIGURE 1-11 Descending pathways (upper cervical level).

Elsevier.
The anterior spinal artery arises

from the union of the anterior spinal
branches of the vertebral artery and
descends within the anterior median
fissure of the spinal cord down to the
conus medullaris. Its largest caliber is
at the lumbosacral area, and smallest
at the thoracic area, which is also considered its watershed area. The two
posterior spinal arteries also originate
from the vertebral arteries but descend
along the line of attachment of the
dorsal nerve roots, posterolateral sulcus, on either side. At the conus medullaris, the anterior and posterior spinal arteries communicate though
anastomotic branches (Figure 1-12).
Thirty-one pairs of small radicular
arteries enter every intervertebral foramen supplying their corresponding
nerve roots. Some of these are larger
and also supply the spinal cord, radiculomedullary branches. There may
be six to 10 such arteries, and through
their anterior radicular branch they
contribute to the anterior spinal artery.
The cervical and first two thoracic segments receive these arteries from
branches of the vertebral and thyrocervical trunk, T3 to T7 spinal cord
usually from an intercostal artery, and
the remainder of the spinal cord receives the largest and most constant
artery of Adamkiewicz (arises from a
left-sided intercostal or lumbar artery,
usually at the T9 through L2 spine
level), which supplies the lumbar enlargement and conus medullaris. The
posterior spinal arteries receive contributions from 12 to 16 posterior radicular
arteries, including a radicular branch
from the artery of Adamkiewicz.
The intrinsic arterial supply of the
spinal cord consists of a centripetal
(posterior spinal arteries and the anterolateral plexuses) and a centrifugal
(anterior sulcal arteries) system (Figure 1-13). The centripetal system is
formed from radial arteries directed inward and supplying the posterior
white columns, and through shorter
KEY POINTS:
FIGURE 1-12 Arterial supply of the spinal cord.

Reprinted with permission from Moore KL, Dalley AF. Clinically oriented anatomy. Philadelphia:
Lippincott William & Wilkins, 1999:487.
radial penetrating vessels the peripheral rim of perhaps one-third to onehalf of the spinal cord. The centrifugal
system arises from sulcal arteries of the
anterior spinal artery that pass back
into the anterior medial sulcus and
then turn right or left to supply the
adjacent gray and white matter. Smaller
branches from the anterior spinal artery
also contribute to the arterial vasocorona that envelops the spinal cord and
through their short penetrating arteries
supply the anterior rim of the spinal
cord. In general, the centrifugal system
(anterior spinal artery) supplies the anterior two-thirds of the spinal cord.
Analogous to the arterial blood
supply, venous drainage of the spinal
The majority of
fibers that give
rise to the
corticospinal tract
have their origin
in primary motor
cortex, but
supplementary
motor cortex and
premotor cortex,
as well as
somatic sensory
cortex, also
contribute.
Within the
pyramidal
decussation,
70% to 90% of
fibers will
decussate and
give rise to the
lateral
corticospinal
tract. A
somatotopic
organization
develops with
fibers to the
sacral area most
lateral and those
to the cervical,
medial.
Thirty-one pairs
of small
radicular arteries
enter every
intervertebral
foramen
supplying their
corresponding
nerve roots.
Some of these
are larger and
also supply the
spinal cord,
(radiculomedullary
branches). There
may be six to 10
such arteries,
and through
their anterior
radicular branch
they contribute
to the anterior
spinal artery.
21
FIGURE 1-13 Arterial supply of a spinal cord segment.

Reprinted with permission from Haerer AF. DeJongs: the neurologic examination. 5th ed. Philadelphia: Lippincott Company,
1992:582.
22
FIGURE 1-14 Venous drainage of a spinal cord segment.

Krauss WE. Vascular anatomy of the spinal
cord. Neurosurg Clin N Am 1999;10(1):915.
Reprinted with permission from Mayo Foundation for Medical Education
and Research. All rights reserved.
cord also involves a longitudinal system of veins, the larger posterior spinal
vein and the anterior. Through a circumferentially arranged venous anastomosis, coronal venous plexus, within
the pia mater on the spinal cords surface, they are connected (Figure
1-14). The anterior spinal vein will
communicate superiorly with the venous system of the brainstem and inferiorly end at the dural sac in the
sacrum. The posterior spinal vein
communicates with radicular veins at
the cervical level and extends down to
the conus medullaris. At each spinal
cord segment small radicular veins
drain the nerve roots, but at some levels larger veins, medullary veins, will
arise from the anterior median spinal
vein. There are approximately 10 to 20

anterior veins and a similar number of
posterior medullary veins, asymmetric
in location and not concomitant with
the medullary arteries. The largest are
in the lumbar region: the great anterior medullary vein (usually accompanying the nerve roots between T11
and L3) and the great posterior medullary vein usually at L1 or 2. The posterior half of the spinal cord will drain
into the posterior and the anterior half
into the anterior medullary veins.
These medullary veins follow and
penetrate the dura with the nerve root
and in the intervertebral foramen will
unite with the radicular veins, internal
and external vertebral plexus to form
the intervertebral vein that drains blood
from the spine and spinal cord. Prior to
their exit from the dura matter, these
veins are valveless (Gillilan, 1970;
Krauss, 1999).
The cervical intervertebral veins
will drain into the deep cervical and
vertebral veins and will empty into the
superior vena cava through the brachiocephalic and subclavian vein. At
the thoracic cord they will connect
FIGURE 1-15 Vertebral venous plexus.

Modified with permission from Moore KL, Dalley AF.
Clinically oriented anatomy. Philadelphia: Lippincott
William & Wilkins, 1999:466.
with the intercostal veins and then via

the azygos and hemiazygous veins will
enter the superior vena cava. The remainder of the venous drainage from
the spinal cord can follow a similar
pathway or, through the azygous and
hemiazygous veins, enter the common
iliac veins and then the inferior vena
cava.
Within the spinal canals epidural
space is also a longitudinally and cir-
23
FIGURE 1-16 Cord transection (modalities involved).

Reprinted with permission from Souayah N, Khella S. Neurology examination & board review.
New York: McGraw Hill, 2005:44.

cumferentially arranged anastomosis
of valveless veins, the internal venous
plexus (anterior and posterior) (Figure
1-15). It communicates with the spinal
cord through the medullary and radicular veins, and vertebral body through a
basivertebral vein, but it also drains to a
separate plexus that surrounds the vertebra, the external vertebral plexus (anterior and posterior divisions). Through
the previously mentioned routes, it will
eventually empty into the superior or
inferior vena cava.
TABLE 1-1
SPINAL CORD SYNDROMES

A syndrome (symptom complex) represents a complex of signs and symptoms that appear in combination and
present as a clinical picture. It may
have a specific cause, disease, or inherited abnormality, but this is not a
requirement and at times has resulted
in some confusion in the use and diagnostic significance of the term. Some
of the reported etiologies for the respective syndromes are listed in Table 1-1.
Spinal Cord Syndromes and Their Etiologies (Representative Examples)
Etiology
Complete Cord
Transection
BrownSequard
Syndrome
Vascular
Anterior Spinal Artery

Syndrome
*Aortic dissection,
*vasculitis, *atherosclerosis
of the aorta
Inflammatory or
infectious
*Postinfectious,
*multiple sclerosis,
*postvaccinal
Traumatic
Traumatic spine
injury, herniated disc
Iatrogenic or
toxin
Epidural hematoma
(anticoagulants)
*Traumatic
spine injury
Postoperative spine, aorta
or thoracic surgery,
postoperative spinal
arteriovenous
malformation surgery,
decompression injury
24
Metabolic
Endocrine
Neoplastic
Tumor, paraneoplastic
Degenerative or
Hereditary
Intramedullary
tumors
Cervical spondylosis
HTLV-I human T-cell leukemia virus I; HAM human T-cell lymphotropic virusassociated myelopathy.
*Classic or most common associated etiologies.
Complete Cord Transection

A complete cord transection disrupts
the sensory tracts ascending from below the level of the lesion and the
descending tracts from above (Figure
1-16). However, as many such lesions
are incomplete, the clinical deficit will
reflect the extent of the injury. On
physical examination a sensory level
will be detected, using pinprick loss,
and is the most valuable finding that
identifies the spinal cord as the site of
the lesion. While sensory loss is expected to involve all modalities below
Posterolateral
Column Syndrome
the level of the lesion, the actual spinal

cord level involved may be higher and
the presence of radicular pain or segmental paresthesias may serve as a
more accurate localizer. Radiation of
pain may also occur, and with cervical
spinal cord lesions pain can radiate into
the arms, thoracic into the chest or abdomen, and lumbar or sacral spinal cord
into the legs. Careful examination for
overlying vertebral spine tenderness
may suggest an underlying destructive
process such as a neoplasm or infection
as the etiology, and pain that lessens
Central Lesion
HIV HTLV-1 (HTLV

associated myelopathy,
HAM, or tropical
spastic paraplegia)
Late sequelae of
spinal cord injury
Nitrous oxide
myeloneuropathy
KEY POINT:
In cord
transection, the
most valuable
finding that
identifies the
spinal cord as the
site of the lesion is
pinprick sensation.
The actual spinal
cord level involved
may be higher;
the presence of
radicular pain or
segmental
paresthesias may
serve as a more
accurate localizer.
Posterior
Column
Syndrome
Anterior Horn
Cell Syndrome
Combined
Anterior
Horn Cell
Pyramidal
Syndrome
*Neurosyphilis
Poliomyelitis,
West Nile virus
HTLV-1
Epidural spinal
cord compression
Postradiation
25
*Vitamin B12 deficiency
*Copper deficiency
myeloneuropathy
Hexosaminidase
deficiency
Intramedullary spinal
cord tumors
Cervical spondylosis
*Syringomyelia
*Spinal muscular
atrophies
(hereditary motor
neuropathies)
*Amyotrophic
lateral sclerosis

as anhidrosis, trophic skin changes,
impaired temperature control, and vasomotor instability below the level of
lesion can also be demonstrated
(Cases 1-1 and 1-2).
FIGURE 1-17 Hemisection of the cord (Brown-Sequard

syndrome).
Reprinted with permission from Souayah N, Khella S.
Neurology examination & board review. New York:
McGraw Hill, 2005:46.
26
with sitting or standing is suggestive of a

malignancy. While further historical details may be helpful, laboratory and radiologic studies are necessary to more
definitively identify an etiology.
Weakness, either paraplegia or tetraplegia, occurs below the level of the
lesion, owing to the interruption of the
descending corticospinal tracts. Initially, the paralysis may be flaccid and
areflexive because of spinal shock, but
eventually, hypertonic, hyperreflexive
paraplegia or tetraplegia occurs with
bilateral extensor toe signs, loss of superficial abdominal and cremasteric
reflexes, and extensor and flexor
spasms (Adams and Hicks, 2005). At
the level of the lesion lower motor
neuron signs (paresis, atrophy, fasciculations, and areflexia) in a segmental distribution and reflecting
damage to the local anterior horn cells
or their ventral roots may be demonstrated. These lower motor neuron
signs may be quite subtle in thoracic
lesions but can localize a lesion to a
specific spinal cord level. Urinary and
rectal sphincter dysfunction with incontinence, sexual dysfunction, and
signs of autonomic dysfunction such
Brown-Sequard Syndrome
A hemisection of the spinal cord results in this characteristic syndrome
(Tattersall and Turner, 2000) (Figure
1-17). Loss of pain and temperature
sensation occurs contralateral to the
side of injury due to interruption of the
crossed spinothalamic tract, but usually a clinical sensory level is one or
two segments below the level of the
lesion, reflecting the ascending nature
of this crossing tract (Nathan et al,
2001). Below the site of the lesion
there is ipsilateral loss of proprioceptive function due to interruption of the
ascending fibers of the posterior columns, but such modalities of sensation
may also arise from within the spinocerebellar tracts as well (Davidoff,
1989). Ipsilateral weakness below the
lesion reflects the interruption of the
descending corticospinal tract. In a
slowly progressing lesion hyperreflexia and an extensor toe sign will be
elicitable, while in an acute lesion
those findings may initially be absent.
Damage to the ventral roots or anterior
horn cells results in segmental lower
motor neuron findings at the level of
the lesion, but these are clinically difficult to identify in thoracic spinal cord
lesions. Finally, if spinal root irritation
occurs, radicular pain, again at the site
and side of the lesion, may be experienced and more clearly define the spinal cord level.
Anterior Spinal Artery
Syndrome
The vascular nature of this syndrome
is manifested in its abrupt onset with
the deficit occurring within minutes or
hours from its initiation (Novy et al,
2006). Clinically the syndrome presents with back or neck pain and at
times in a radicular pattern, usually

followed by a flaccid paraplegia and
less commonly tetraplegia. Urinary
and bowel incontinence are usually
present. A sensory level to temperature and pinprick is found that reflects
the involvement of the spinothalamic
tracts bilaterally, but posterior column
modalities of sensation remain relatively intact (Figure 1-18). Although
the thoracic spinal cord may be an
anatomic watershed zone with respect
to regional blood supply (Figure
1-19), the lumbosacral cord neurons
appear to be more susceptible to ischemia (Duggal and Lach, 2002). The
initial motor presentation progresses
from a flaccid paraplegia to one of
spasticity with hyperreflexia and Babinski signs (Case 1-3).
Central Lesions
In this and in the syndromes discussed
below, the underlying pathologic process is usually an insidious one, and the
features of the disease develop over an
extended period of time. When fully developed, the specific syndrome is more
clearly recognized, but early during the
process features may be incomplete,
leading to difficulty and a delay in recognizing the syndrome.
This syndrome results from a pathologic process in and around the central
canal, initially involving those tracts that
cross through the gray matter (anterior
and lateral spinothalamic tracts) (Figure
1-22). The resulting sensory impairment is
termed a dissociated sensory loss (loss of
pain and temperature sensation with preservation of position, vibration, and touch).
The typical site of involvement in the cervical spinal cord and the particular sensory
modalities initially involved result in a clinical presentation in which sensory loss occurs in a vest- or shawl-like pattern over
the upper extremities and shoulders. As
the size of the lesion increases, other fiber
tracts will be involved, dependent on the
direction and extent of the pathologic process. With extension anteriorly, a flaccid
FIGURE 1-18 Arterial spinal artery syndrome.

27
FIGURE 1-19 Arterial supply of the spinal cord and

watershed areas.
Reprinted with permission from Bradley WG, Daroff RB,
Fenichel GM, Marsden CD, editors. Neurology in clinical
practice. Volume II. 3rd ed. Boston: Butterworth
Heinemann, 1999:1226.

Case 1-1
28
A 64-year-old right-handed man was brought to the emergency department after having fallen
down a flight of steps. He was not able to move his limbs. His medical history included coronary
artery disease, status post coronary artery bypass graft, diabetes mellitus, and schizophrenia,
but no clear motor difficulties prior to this incident. He remembers that during the fall he hit his
shoulders as he slid down the steps, but he experienced no loss of consciousness. Afterward he
was aware of pain all over, but most of his discomfort was in both upper extremities and
electrical in quality. Before being brought to the emergency department he noted that
passive movements of his head
intensified his upper extremity pain, but
no associated worsening of his sensory
symptoms occurred.
On examination his vital signs were
normal and he was in a rigid cervical
collar. He had abrasions over both upper
extremities. He was awake, alert, and
followed all commands. His cranial nerve
examination showed no clear
abnormalities. He was able to shrug his
shoulders but unable to lift his arms
from the bed; proximal strength in the
upper extremities was 2-3/5 and distal
was 0/5. Lower extremity motor
examination demonstrated weakness of
hip flexion at 4-/5, and the other motor
groups were 4/5. His tone appeared to
be normal. Reflexes were depressed, but
there appeared to be a right and
perhaps a left extensor toe sign. Sensory
examination demonstrated a decrease in
pinprick up to the C4 level on the right
and a patchy decrease in pinprick over
the distal part of his left lower
extremity; sacral sensation to pin was
intact. Position sense appeared to be
intact in his extremities. Rectal tone was
normal; a urinary drainage catheter was
in place.
FIGURE 1-20 Cervical spine MRI (sagittal view, T2
Routine cervical spine x-rays
weighted).
demonstrated no clear fractures or
prevertebral soft tissue swelling. Extensive degenerative changes were noted at multiple levels.
An MRI of the cervical spine demonstrated spinal stenosis, worse at C3-4, and neuroforaminal
stenosis from C3 to C5. There was an increase in spinal cord T2 signal intensity from C3 to C5
without enhancement, which was interpreted as edema (Figure 1-20). Over the next 12 hours his
lower extremity strength improved and his sensory deficits appeared to retract, but upper
extremity strength remained significantly impaired. No improvement with steroids was noted.
His persistent deficit and underlying cervical spine stenosis led to the recommendation for
cervical spine surgery.
Comment. Spinal cord trauma presents with different anatomic syndromes that include
transection, cervicomedullary syndromes with high cervical spine lesions, anterior or posterior
cord syndromes, Brown-Sequard syndrome, conus/cauda equina syndrome, or, as in this case, a
central cord syndrome. Recovery and manifestations are related to the site and extent of the
trauma and underlying mechanisms, eg, presence of preexisting spinal stenosis. These influence
eventual outcome and dictate immediate management.
Case 1-2
A 43-year-old woman with no prior medical history began to develop episodic vertigo and
jumpiness in her eyes when she was in her late 30s. Attributed to vertigo, the symptom
persisted but did not result in a disability. It was not until several years later that she began to
notice numbness over both of her hands, unaccompanied by neck or radicular pain. She
attributed this to carpal tunnel syndrome precipitated by her administrative and secretarial
work. It was the gradual involvement of ambulatory difficulties and an acute worsening over
the last several months that led her to seek further evaluation.
Her general physical examination
and vital signs were normal. Cervical
spine examination and hairline were
normal; there was no spinal scoliosis.
Her cranial nerve examination
demonstrated a left Horner syndrome,
and rotary nystagmus was evident on
horizontal as well as downward gaze.
She had weakness predominantly in
the distal lower extremities, more so
on the left side and to a 4/5 degree,
but her tone appeared to be increased
in all extremities. Sensory examination
showed a decrease in pinprick over the
right extremity that extended onto
the upper thorax; similar, but lessmarked, findings were found on the
left, suggesting a shawl-like pattern.
Her reflexes were generally increased,
and she demonstrated bilateral
Babinski signs.
An MRI scan of her brain and
cervical spinal cord demonstrated a
Chiari type-one malformation
associated with syringomyelia. She
underwent foramen magnum
decompressive surgery, upper cervical
spine laminectomy, and fusion and
shunt placement (fourth ventricle to
upper cervical spine). The
FIGURE 1-21 Cervical spine MRI (sagittal view, T1
postoperative cervical spine MRI scan
weighted).
is shown in Figure 1-21. Since surgery
her neurologic deficit has remained
relatively stable, but recently she has begun to experience lower extremity radicular pain
secondary to lumbar degenerative disc and neural foraminal stenosis.
Comment. The insidious nature of this patients deficit initially delayed her seeking further
clinical evaluation. However, the presence and pattern of her nystagmus, bilateral upper
extremity sensory impairment, and cortical spinal tract involvement suggest an intramedullary
spinal cord lesion that may extend into the brainstem. The onset of syringomyelia is often
insidious, and symptom onset occurs between the ages of 25 and 40. A presentation with
isolated findings may delay identification while the combination of brainstem dysfunction (eg,
vertigo, oscillopsia, dysphonia, and facial sensory loss), dissociated sensory loss in the extremities,
and later involvement of upper and lower motor neurons usually suggest the diagnosis.
Radiologic confirmation is necessary for definitive diagnosis. Surgical interventions and extent
are dependent on the assumed etiology and preexisting neurologic deficit. Decompression
surgery or shunting procedures may be required in selected cases.
29

KEY POINTS:
30
The sensory
impairment in
central cord
lesions is termed
a dissociated
sensory loss (loss
of pain and
temperature
sensation with
preservation of
position,
vibration, and
touch).
The lamination
of the lateral
spinothalamic
tract results in
fibers conveying
sensation from
the sacrum to be
more laterally/
superficially
placed within
the spinal cord.
These are often
preserved for an
extended period
of time with
central spinal
cord lesions
(sacral sensory
sparing).
Case 1-3
A 67-year-old right-handed woman was brought to the emergency
department by her husband. Without any clear precipitants, she had
awakened with severe low back pain, accompanied by radicular pain
down both lower extremities, and abdominal discomfort. She had gone to
her toilet but was unable to raise herself. While being transported to the
emergency department she developed urinary incontinence and later
bowel incontinence.
On evaluation, her vital signs and cardiac and vascular examinations
were normal. Her examination was significant for lower extremity
paraplegia and hyporeflexia. Plantar stimulation elicited no response; a
Beevor sign was present. She demonstrated a sensory level to pinprick up
to T10, decreased temperature to L1, and normal position sense. Sacral
sensation to pinprick was absent; rectal tone was absent, and a urinary
drainage catheter was in place (initially 1000 cc of urine had been
drained). There was no tenderness to percussion over the spine, and
straight-leg raise was negative. Her pain resolved over 2 days.
Steroids were initially administered because of the possibility of spinal
cord compression, and an emergent MRI of the entire spine was
performed as well as imaging of the aorta. Both were normal. Over the
ensuing weeks her lower extremity strength improved, and hyperreflexia,
as well as bilateral Babinski signs, appeared. However, her ambulation
remained impaired. Her sensory deficits lessened, and although her bowel
incontinence improved she required periodic urinary catheterization.
Comment. While this initial clinical presentation suggested a spinal cord
infarction and an anterior spinal artery syndrome, a compressive spinal
cord or conus/cauda equina lesion required exclusion. Aortic dissection can
also cause spinal cord ischemia/infarction, and such an evaluation is
required as soon as possible. Usually (67%) of the time MRI demonstrates
a T2-weighted abnormality, but a normal study does not exclude a spinal
cord infarction, which then becomes a diagnosis of exclusion. Back or neck
pain and radicular pain can occur at symptom onset (59%), resolving in
several days, but later neurogenic pain can develop. In the majority of
spontaneous cases (70%) an etiology is not discovered, but the possibility
of mechanical stress-induced vascular compromise has been suggested in
some cases. Prognosis is related to the extent of the injury, but
ambulation usually remains impaired (Novy et al, 2006).
paralysis with fasciculations and atrophy

occurs as the anterior horns and their motor neurons are affected. Lateral extension
involves the corticospinal tracts, resulting
in spastic paralysis of muscles below the
lesion, while posterior extension involves
the posterior columns with disruption of
their sensory modalities. The lamination of
the lateral spinothalamic tract results in fibers conveying sensation from the sacrum
to be more laterally/superficially placed
within the spinal cord and are often preserved for an extended period of time
with central spinal cord lesions, representing a form of sacral sensory sparing.
At times an acute cervical spinal
cord injury, especially after hyperextension injuries of the neck, results in a
unique neurologic presentation that
signifies an injury to the central portion of the spinal cord (distinguished
from the man-in-the-barrel syndrome
reported after ischemic cerebral lesions within the border zone between
anterior and middle cerebral arteries
and cruciate paralysis, a syndrome of
brachial diplegia after medullary lesions).

Such individuals at first may be quadriplegic, but recovery of lower extremity
strength often occurs early, and the
prognosis may be better because of a
predominantly white matter injury (Collignon et al, 2002). However, a unique
pattern of weakness that is more pronounced in the arms, worse distally than
proximally, characterizes the syndrome
and the unique site of injury. Urinary
dysfunction, as well as patchy sensory
loss below the level of the injury or upper and lower levels of sensory loss (suspended sensory level), can be demonstrated (Cases 1-1 and 1-2).
FIGURE 1-22 Syringomyelia (modalities involved).

Posterolateral Column
Syndrome
Involvement of the posterior and lateral
columns of the spinal cord will lead to a
pattern of sensory loss that predominantly
involves the modalities of position and vibratory sense and a motor syndrome of
spastic paralysis that reflects involvement
of the corticospinal tract (Figure 1-23).
This pattern of dysfunction leads to a sensory ataxia with a positive Romberg sign,
while pain and temperature sensation remain intact because of preservation of the
spinothalamic tracts. A spastic-ataxic gait
reflects this constellation of fiber tract dysfunction.
This pattern of involvement usually develops insidiously, reflecting
the underlying pathologic processes.
In the syndrome known as subacute
combined degeneration, related to a
deficiency of vitamin B12 or copper,
the initial neurologic manifestations
may be those of limb paresthesia, predominantly involving the feet, followed later by the development of the
more distinctive posterior column and
corticospinal tract deficits. The complete
features of this syndrome usually develop over an extended period of time.
Posterior Column Syndrome

A process involving the posterior columns
is characterized by loss of position sense,
vibration sense, and two-point discrimination. These deficits occur distal to the lesion. The lack of proprioceptive information and feedback to the motor system
affects those muscle groups required for
discriminative movements, resulting in a
sensory ataxia. While vision can partially
compensate for this loss of proprioceptive
information when the eyes are open,
ataxia worsens when they are closed, resulting in the presence of a Romberg sign.
The gait is described as ataxic (or stomp-
FIGURE 1-23 Posterolateral column syndrome.

31

KEY POINTS:
32
Dysfunction in
the posterior
column
syndrome is
characterized by
a sensory ataxia
with a positive
Romberg sign
while pain and
temperature
sensation remain
intact because
of preservation
of the
spinothalamic
tracts.
With
dysfunction of
the posterior
columns in the
cervical region,
neck flexion may
elicit an electriclike sensation
that radiates
down the back
or into the arms
(Lhermitte sign).
FIGURE 1-24 Combined anterior horn cellpyramidal

syndrome.
ing) in character, and the deficit can be

more prominent in darkness or with eye
closure as visual cues no longer can assist
in maintaining balance. The affected limbs
may become hypotonic but usually are
not weak. At times other spinal cord lesions can produce a truncal ataxia but
without the associated proprioceptive difficulties. In such cases, spinocerebellar
tract dysfunction, as a manifestation of spinal cord compression, appears to be responsible for this clinical syndrome.
With dysfunction of the posterior columns in the cervical region, neck flexion
may elicit an electric-like sensation that
radiates down the back or into the arms
(Lhermitte sign). It is thought to represent
increased mechanosensitivity of the dorsal
columns with neck flexion further activating those sensory pathways. The symptom is most frequently associated with spinal cord involvement in multiple sclerosis.
Anterior Horn Cell Syndrome
Damage to the motor anterior horn cells
leads to an ipsilateral flaccid paralysis accompanied by atrophy and fasciculations.
Because larger muscles are supplied by
motor neurons from more than one segment, damage to a single spinal cord segment may lead only to muscular weakness rather than complete paralysis of the
affected motor group (Figure 1-10).
When the lateral horns are involved, a
decrease in sweating and vasomotor functions may also be demonstrated, as the
cell bodies of the sympathetic neurons are

involved.
Combined Anterior Horn Cell
Pyramidal Syndrome
This syndrome is perhaps best exemplified by ALS. These lesions produce a combination of flaccid and spastic paralysis.
Damage to the anterior horns or lower
motor neurons will result in a flaccid paralysis with atrophy and fasciculations,
while a lesion of the lateral corticospinal
tract or upper motor neurons results in a
spastic paralysis with associated hyperreflexia and Babinski sign (Figure 1-24).
The degree of injury to either site can be
highly variable and reflected in the clinical
presentation. If one site is more or predominantly affected, an additional lesion
in the other at the same level may not
produce noticeable effects.
INTRAMEDULLARY VERSUS
EXTRAMEDULLARY CORD
LESIONS
Neoplasms arising within the spinal
canal tend to produce their symptoms
and signs in a slow and progressive
manner, although an acute presentation can occasionally be encountered.
When arising from lesions within the
spinal cord (intramedullary), symptoms often begin within the vicinity of
the central canal. Sensory symptoms
are initially less localizing and dissociation of sensory loss can occur. Early
KEY POINT:
TABLE 1-2
Clinical Features of Intramedullary Versus

Extramedullary Spinal Cord Lesions
Symptoms and
Signs
Extramedullary
Intramedullary
Spontaneous pain
Radicular in type and

distribution; an early
and important
symptom
Burning in type and

poorly localized
Sensory deficit
Contralateral loss of
pain and temperature;
ipsilateral loss of
proprioception
Dissociation of
sensation; patchy
distribution
Changes in pain and

temperature
sensations over
perineum (saddle area)
More marked than at

level of lesion
Less marked than at

level of lesion
Lower motor neuron

involvement
Segmental
Widespread with
atrophy and
fasciculations
Upper motor neuron

involvement
Prominent, early
Late, minimal
Muscle stretch reflexes
Increased early,
markedly
Late, minimal changes
Corticospinal tract
signs
Early
Late
Trophic changes
Usually not marked
Marked
A more
symmetric
pattern of
sensory loss and
motor
dysfunction is
more consistent
with a conus
than a cauda
equina lesion.
Data from Brazis PW, Masdeu JC, Biller J. Localization in clinical neurology. 5th ed. Philadelphia: Lippincott
Williams & Wilkins, 2007:111.
Data from Haerer AF. DeJongs the neurologic examination. 5th ed. Philadelphia: Lippincott Williams & Wilkins,
1992:588.
evidence of lower motor neuron findings, later accompanied by corticospinal tract findings, characterizes these
lesions, and their clinical presentation
can mimic a syrinx. Extramedullary
lesions can arise from the dura and
adjacent structures (extramedullary
intradural) or can have an extradural
site of origin such as the vertebral bodies or extradural space (extramedullary extradural). Spontaneous pain,
especially in a radicular pattern, can
be a presenting feature and suggests
the level of involvement. Subsequent
motor and sensory changes are usually
slow to develop, and because of the
asymmetric nature of such lesions a
Brown-Sequard pattern may appear.

The features of either type of clinical
syndrome are described and contrasted in Table 1-2.
CONUS MEDULLARIS VERSUS
CAUDA EQUINA LESIONS
The close anatomic localization of the conus medullaris and overlying cauda
equina makes distinction of either syndrome difficult, and at times involvement
of both structures occurs. A symmetric
pattern of sensory loss and motor dysfunction is more consistent with a conus than a
cauda equina lesion. The clinical features
of both conditions are further described
and contrasted in Table 1-3.
33
TABLE 1-3
Clinical Features of Conus Medullaris and Cauda

Equina Lesions
Symptoms and
Signs
Conus Medullaris
Cauda Equina
Spontaneous pain
Not common or
severe; bilateral and
symmetric; over
perineum and thighs
May be most
prominent symptom;
severe and radicular in
type; unilateral or
asymmetric; over
perineum, thighs, legs,
and back
Sensory deficit
Saddle distribution;
bilateral, usually
symmetric; dissociation
of sensation
Saddle distribution;
may be unilateral and
asymmetric; all
modalities affected; no
dissociation of
sensation
Motor loss
Symmetric; not
marked; fasciculations
may be present
Asymmetric; more
marked; atrophy may
occur; usually no
fasciculations
Reflex loss
Only Achilles reflex

absent
Patellar and Achilles

reflexes may be absent
Bladder and rectal

symptoms
Early and marked
Late and less marked
Trophic changes
Decubitus common
Decubitus less marked
Sexual function
Erection and
ejaculation impaired
Less marked
impairment
Onset
Sudden and bilateral
Gradual and unilateral
Data from Brazis PW, Masdeu JC, Biller J. Localization in clinical neurology. 5th ed. Philadelphia: Lippincott
Williams & Wilkins, 2007.
Data from Haerer AF. DeJongs the neurologic examination. 5th ed. Philadelphia: Lippincott Williams & Wilkins,
1992:591.
34
REFERENCES AND SELECT READINGS

Note: There are many general textbooks of neuroscience, neuroanatomy as well
as clinical neurology that you may have found useful. The following recommendations represent our bias and are driven by familiarity with and the
usefulness we have found in the following general resources for teaching and
review.
Adams MM, Hicks AL. Spasticity after spinal cord injury. Spinal Cord 2005;43(10):577586.
Bowen BC, Pattany PM. Vascular anatomy and disorders of the lumbar spine and spinal
cord. Magn Reson Imaging Clin N Am 1999;7(3):555571.
Bradley WG, Daroff RB, Fenichel GM, Marsden CD, editors. Neurology in clinical practice.
Volume II. 3rd ed. Boston: Butterworth Heinemann, 1999:1226.
Brazis PW, Masdeu JC, Biller J. Localization in clinical neurology. 5th ed. Philadelphia:
Lippincott Williams & Wilkins, 2007.
Collignon F, Martin D, Lenelle J, Stevenaert A. Acute traumatic central cord syndrome:
magnetic resonance imaging and clinical observations. J Neurosurg 2002;96(1 suppl):29 33.
Davidoff RA. The dorsal columns. Neurology 1989;39(10):13771385.
Duggal N, Lach B. Selective vulnerability of the lumbosacral spinal cord after cardiac
arrest and hypotension. Stoke 2002;33(1):116 121.
Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and neuroscience. 5th ed.
London: Saunders, 2007.
Gillilan LA. Veins of the spinal cord. Anatomical details; suggested clinical applications.
Neurology 1970;20(9):860 868.
Grant JCB. An atlas of anatomy. 6th ed. Baltimore: Williams & Wilkins, 1972.
Haerer AF. DeJongs the neurologic examination. 5th ed. Philadelphia: Lippincott,
Williams & Wilkins, 1992.
Krauss WE. Vascular anatomy of the spinal cord. Neurosurg Clin N Am 1999;10(1):9 15.
Moore KL, Dalley AF. Clinically oriented anatomy. Philadelphia: Lippincott Williams &
Wilkins, 1999.
Nathan PW, Smith M, Deacon P. Vestibulospinal, reticulospinal and descending
propriospinal nerve fibres in man. Brain 1996;119(pt 6):1809 1833.
Nathan PW, Smith M, Deacon P. The crossing of the spinothalamic tract. Brain
2001;124(pt 4):793 803.
Nathan PW, Smith MC, Deacon P. The corticospinal tracts in man. Course and location of
fibres at different segmental levels. Brain 1990;113(pt 2):303324.
Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and
imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006;63(8):
11131120.
Souayah N, Khella S. Neurology: examination & board review. New York: McGraw Hill, 2005.
Tattersall R, Turner B. Brown-Sequard and his syndrome [erratum published in Lancet
2000;356(9226):344]. Lancet 2000;356(9223):61 63.
35
KEY POINTS:
Acute or rapidly
progressive
myelopathy is a
medical
emergency.
All patients with

myelitis should
be evaluated for
clues to an
infectious cause
for the disorder.
INFECTIOUS AND
INFLAMMATORY
MYELOPATHIES
Dean M. Wingerchuk
ABSTRACT
Inflammatory and infectious myelopathies are common and often treatable. Infectious causes include viral, bacterial, mycobacterial, fungal, and parasitic agents.
Noninfectious inflammatory myelopathies were previously often categorized as idiopathic transverse myelitis, but advances in neuroimaging and the discovery of a serum
autoantibody marker, neuromyelitis optica immunoglobulin G (NMO-IgG), have allowed more specific diagnoses, such as multiple sclerosis and neuromyelitis optica, to
be made more confidently and at an earlier stage than previously possible. This chapter
summarizes an approach to evaluation and management of infectious and inflammatory causes of acute and subacute myelitis and chronic progressive myelopathy.
Note: Text referenced in the Quintessentials Preferred Responses, which appear
later in this issue, is indicated in yellow shading throughout this chapter.
36
INTRODUCTION
Infectious and inflammatory diseases
can produce virtually any temporal
pattern of myelopathy, including
acute, subacute, or chronic presentations. A comprehensive and consistent
approach to evaluating the patient
with an inflammatory myelopathy can
minimize the chance of missing a
treatable condition and allow early initiation of therapy that impacts clinical
recovery and future prognosis.
DIFFERENTIAL DIAGNOSIS OF
ACUTE OR SUBACUTE
INFLAMMATORY MYELOPATHY
The clinical presentation of a myelopathy that developed over hours
to weeks requires urgent spinal cord

MRI (Transverse Myelitis Consortium
Working Group, 2002). When imaging reveals an intramedullary spinal
cord lesion without evidence for extrinsic cord compression, the diagnosis of an inflammatory or infectious
myelitis be comes a primary consideration. Clinical features that suggest
an infectious cause include fever
and meningismus, encephalopathy,
rash, lymphadenopathy, known systemic infection, immunocompromised status, or known exposure to
an infectious agent. Lumbar puncture, to determine the presence of
inflammation, is the immediate next
step if no medical contraindications
Relationship Disclosure: Dr Wingerchuk has received personal compensation for activities with Genentech,
Inc. Dr Wingerchuk has received research support to Mayo Clinic from the National Multiple Sclerosis
Society and Genzyme Corporation.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Wingerchuk discusses the unlabeled use of
methylprednisolone, plasmapheresis, and cyclophosphamide for the treatment of myelitis attacks;
carbamazepine for tonic spasms; and prednisone, azathioprine, mycophenolate mofetil,
cyclophosphamide, mitoxantrone, intravenous immune globulin, and rituximab for prevention of relapse
of certain inflammatory myelitides.
TABLE 2-1
Some Infectious and Inflammatory Considerations in

Chronic or Progressive Myelopathy
Infections
Fungal infections
HIV-associated myelopathy
Human T-cell lymphotrophic virus type 1associated myelopathy
Syphilis
Tuberculosis
Inflammatory Diseases
Granulomatous diseases, including neurosarcoidosis
Paraneoplastic myelopathies/encephalomyelitis
Progressive forms of multiple sclerosis
are present. In most instances of inflammatory myelopathy, CSF sampled during the evolution of clinical
symptoms reveals pleocytosis and
increased total protein level. Although neoplastic diseases (eg,
lymphoma) and paraneoplastic myelopathies may also cause CSF
pleocytosis, these findings usually
lead to investigations to determine
whether the patient has an infectious myelopathy, a demyelinating
disease such as multiple sclerosis
(MS), acute disseminated encephalomyelitis (ADEM), or neuromyelitis optica (NMO), a noninfectious inflammatory disorder (eg, connective-tissue
disease or sarcoidosis), a postinfectious
or postvaccinial syndrome, or idiopathic transverse myelitis. The results
of these tests are usually sufficient to
establish prognostic information and
an initial treatment plan. In some settings, such as the first-ever event of an
inflammatory demyelinating myelitis,
further observation may be required to
clarify the diagnosis, especially conversion to relapsing diseases such as MS
and NMO.
INFECTIOUS AND
INFLAMMATORY
CONSIDERATIONS IN CHRONIC
PROGRESSIVE MYELOPATHY
Inflammatory or infectious diseases
must be also considered in patients
with chronic progressive myelopathy,
in which deterioration in spinal cord
function occurs over months to years,
although the diagnostic considerations
are fewer (Table 2-1). In most instances, however, the diagnostic approach focuses on excluding identifiable and treatable infectious and
non-MS causes of myelopathy and
gathering evidence to support the
most common inflammatory cause,
primary progressive MS. The characteristics of these disorders are discussed in their respective sections of
this chapter.
INFECTIOUS MYELOPATHIES
Acute infectious myelitis may be associated with viral or bacterial infections
(Table 2-2) and rarely fungal or parasitic agents. In many instances, the myelitis accompanies an evolving meningoencephalitis and such patients have
prominent systemic symptoms such as
37
INFECTIOUS AND INFLAMMATORY MYELOPATHIES

KEY POINT:
HIV may cause

myelopathy, but
the physician
should consider
co-infections
and other
concomitant
medical
disorders.
TABLE 2-2
Infections
Associated With
Acute Transverse
Myelitis
Viral Infections
California encephalitis virus
Coxsackie viruses
Cytomegalovirus
Epstein-Barr virus
Hepatitis A and B
Herpes simplex types 1 and 2
HIV
Human herpesvirus 6
Human T-cell lymphotrophic
virus type 1
Influenza A or B
Measles
Mumps
Parainfluenza virus
Poliovirus
Rubella
Vaccinia
Varicella-zoster
West Nile virus
Bacterial and Other Infections

Campylobacter
Cat scratch disease
38
Chlamydia
Legionella
Lyme borreliosis
Mycoplasma pneumoniae
Pertussis
Rocky Mountain spotted fever
Streptococcus pneumoniae
fever, encephalopathy, and meningismus. Other clues pointing to a potential acute infection include recent or
active systemic infection or immunoContinuum: Lifelong Learning Neurol 2008;14(3)
suppressed state, rash, lymphadenopathy, and historical evidence suggesting exposure to an infectious agent
(eg, swimming in waters infected with
parasites; presence of HIV risk factors). Even when these characteristics
are absent, the presence of significant
inflammatory changes in the CSF
(pleocytosis and elevated protein) requires careful evaluation for infection.
The next sections summarize distinct
myelitis syndromes associated with
the various infectious categories.
Viral Infections
HIV. In the setting of HIV infection or
AIDS, myelopathy may be related to
the HIV infection, to other infections
that arise because of HIV/AIDS-related
immunosuppression, or to other medical causes (McArthur et al, 2005). Tuberculosis and a variety of viruses,
such as herpes zoster and human Tcell lymphotropic virus type I (HTLVI), may result in an infectious myelopathy, especially in regions where such
infections are endemic and HIV infection is common. However, primary
HIV-related myelopathy, termed vacuolar myelopathy, is the most common cause.
HIV-associated vacuolar myelopathy is a clinical diagnosis of exclusion,
although it has singular pathologic
characteristics. It is symptomatic in
about 5% to 10% of people with AIDS
but is detectable pathologically in
about 50% at autopsy (Dal Pan et al,
1994; Petito et al, 1985). Neurologic
examination abnormalities include relatively symmetric painless spastic
paraparesis, impaired vibratory and
proprioceptive sensation (to a greater
degree than pain and temperature
sense impairment), and sensory gait
ataxia. Affected patients with concomitant peripheral neuropathy may have
reduced or absent tendon stretch reflexes.
Histologic study of the spinal cord
reveals profound lateral and posterior
column demyelination and spongy degeneration localized mainly in the thoracolumbar region and micro-vacuolar
changes in the cord white matter similar to that of subacute combined degeneration of the cord (Figure 2-1).
Axons are relatively preserved. The
role of HIV in causing vacuolar myelopathy remains uncertain because
only about 6% of patients have productive HIV infection in the spinal
cord (Petito et al, 1994), but macrophage activation and cytokines such
as tumor necrosis factor are present.
Together with dysfunction of vitamin
B12-dependent transmethylation pathways (Di Rocco et al, 2002), these
changes may contribute to the vacuolar pathology that is also seen in some
HIV-negative patients with cancer or
chronic immunosuppression.
All patients with myelopathy of
unknown cause should be tested for
HIV/AIDS. In patients with known
HIV/AIDS, the emergence of myelopathic symptoms and signs warrants
rapid MRI and CSF evaluations. Acute
myelitis syndromes in HIV suggest
other co-infectious causes discussed
below. To date, no effective treatment
is available for HIV-associated vacuolar myelopathy, but it is hoped that
early and consistent HIV treatment
with contemporary antiretroviral therapies may reduce the incidence of the
disorder.
Human T-cell lymphotrophic
virus types I and II. HTLV-I is common in the Caribbean and can be
transmitted through parenteral, sexual,
or maternal routes. In the United
States, risk factors for infection include
IV drug use and prostitution. HTLV-I is
associated with adult T-cell leukemia/
lymphoma and a chronic progressive
myelopathy known as tropical spastic
paraparesis or HTLV-I-associated myelopathy (Gessain et al, 1985; Osame
et al, 1986). HTLV-II can cause a similar disorder. This myelopathy develops in approximately 1 in 250 individ-
uals who are HTLV-I infected and is

associated with spinal cord viral load.
The virus causes pyramidal, spinocerebellar, and spinothalamic tract injury,
especially in the thoracic region, with
demyelination, perivascular inflammation, and gliosis evident on microscopic examination. Inflammatory infiltrates may also be found in the
posterior columns, and vacuolization
can be detected in some lesions.
The diagnosis of HTLV-I-associated myelopathy is based on clinical
evidence of myelopathy and laboratory evidence of antibodies to HTLV-I
in serum and CSF. Demonstration by
PCR of HTLV-I DNA in CSF and the
intrathecal synthesis of antibodies to
HTLV-I also confirms the diagnosis of
HTLV-I-associated myelopathy/tropical spastic paraparesis. No effective
long-term treatment is available, although treatment with plasmapheresis, interferon alpha, other immunomodulating drugs, and antiretroviral
therapies have anecdotal support. Corticosteroids have only temporary
symptomatic benefits.
KEY POINT:
Acute
myelopathy in
the setting of
HIV warrants
urgent
evaluation for
causes other
than HIV itself.
39
FIGURE 2-1
HIV-related myelopathy. Vacuolar changes

are evident in the lateral and posterior
columns of the thoracic spinal cord.
Modified with permission from McArthur JC, Brew BJ, Nath A. Neurological
complications of HIV infection. Lancet Neurol 2005;4(9):543555.
Copyright 2005, Elsevier.

KEY POINTS:
Herpesvirus
infections are
important to
recognize as
they may
respond to
antiviral
medication.
West Nile virus

causes a
poliomyelitis-like
clinical
syndrome.
Herpesviruses. Members of the

herpesvirus family, including herpes
simplex virus type 2, varicella-zoster
virus (VZV), and cytomegalovirus are
associated with infectious or postinfectious myelitis. VZV causes varicella
(chickenpox) and herpes zoster (shingles) in adults (Case 2-1). Upon reactivation, latent VZV residing in the dorsal root ganglia spreads along the
affected nerve to cause a painful, vesicular eruption confined to a dermatomal distribution. Much less commonly, and usually in the setting of
immunosuppression, VZV may spread
toward the spinal cord to cause a
monophasic inflammatory myelitis.
The antiviral drugs used to treat cuta-
neous zoster, such as acyclovir, valacyclovir, or famciclovir, should be

considered in myelitis associated with
a dermatomal rash or when VZV infection is confirmed (eg, detecting VZV in
CSF using PCR). Transverse myelitis
events occurring in conjunction with
other herpesvirus syndromes may also
be treated with an appropriate antiviral drug. For example, genital herpes
infection with herpes simplex virus
type 2 or infectious mononucleosis
(Epstein-Barr virus) may be treated
with acyclovir, whereas cytomegalovirus-associated myelitis should be
treated with ganciclovir or foscarnet.
In 2006, a live attenuated herpes zoster
virus vaccine was approved for use in
Case 2-1
40
An 81-year-old man with a history of chronic lymphocytic leukemia presented with a 4-day
history of bilateral leg weakness, numbness, and lower abdominal pain. Examination revealed
asymmetric paraparesis, extensor
plantar responses, bilaterally impaired
vibratory and proprioceptive sensation
in both lower extremities, a T10 sensory
level, and an erythematous tender area
over the right flank. Blood tests were
remarkable only for an elevated white
blood cell (WBC) count of 15,000,
consistent with his known malignancy.
CSF analysis showed 65 white blood cells
(WBCs) (25% neutrophils and 75%
lymphocytes) and an elevated protein
level of 85 mg/dL. MRI of the spinal cord
showed an intramedullary cord lesion
extending from T7 to T9, more
prominent on the right, with gadolinium
Rash of herpes zoster.
FIGURE 2-2
enhancement. He received empiric
Reprinted with permission from Wareham DW, Breuer J. Herpes zoster.
therapy with IV methylprednisolone 1000
BMJ 2007;334(7605):12111215. With permission from the BMJ
Publishing Group.
mg for presumed transverse myelitis. The
day after admission, the skin eruption
evolved to include vesicular lesions (Figure 2-2); a diagnosis of herpes zoster was suspected, and IV
acyclovir was administered for presumed zoster myelitis. The diagnosis was confirmed by PCR detection
of VZV in the CSF and culture from a vesicular lesion; CSF flow cytometry was negative for malignancy.
He recovered well enough to ambulate without assistance after 6 weeks of rehabilitative therapy.
Comment. Myelitis more commonly complicates VZV reactivation in immunocompromised
patients, including those with underlying malignancy. Detection of anti-VZV IgG antibody in CSF
also supports the diagnosis, especially in later stages when PCR may be negative. It is reasonable to
use a brief course of corticosteroids together with antiviral therapy as early as possible in the
disease course, but it is not clear whether the treatments improve outcome.
immunocompetent adults over age 60;

it is hoped that the incidence of all
zoster-related neurologic complications will decrease with common use.
Enterovirus. Enterovirus is a large
family of viruses responsible for many
pediatric infectious illnesses. There are
more than 70 different strains, including enterovirus strains, coxsackievirus
types A and B, echoviruses, the polioviruses, and hepatitis A virus. Many
enteroviruses have been associated
with transverse myelitis, usually as a
postinfectious phenomenon. Identification of recent infection with one of
these viruses helps identify the cause,
but no effective treatments are available.
Poliovirus stands out among this
family because of its predilection for
infection and inflammation of anterior
horn cells, classically in the setting of
febrile aseptic meningitis, resulting in
areflexic flaccid paralysis with virtual
sparing of sensory, bowel, and bladder function. Although vaccination
programs have almost eradicated poliomyelitis in developed nations, rare
cases still occur in immigrants or unvaccinated children or young adults.
Most poliovirus infections are asymptomatic or cause a minor illness with
mild systemic symptoms, but paralytic
poliomyelitis is an occasional complication (approximately 1% to 2% of
cases). There are no effective treatments for established infection.
Flavivirus. West Nile virus, a member of the Japanese encephalitis antigenic complex of the Flavivirus genus,
is common in Israel and in regions of
Africa and spread throughout North
America earlier this decade (Nash et al,
2001). It is a mosquito-borne infection,
which causes encephalitis or meningitis in about 1 of 150 infected persons,
a small proportion of whom develop a
poliomyelitis-like illness characterized
by flaccid paralysis (Sampathkumar,
2003). The diagnosis should be suspected in patients presenting with
acute flaccid paralysis in summer or

early autumn months and is confirmed
by detection of IgM antibody to West
Nile virus in serum or CSF. Other CSF
findings are nonspecific, including
lymphocytic pleocytosis and protein
elevation. Pathologic examination reveals patchy gliosis and perivascular inflammation in the ventral horn of the
cord (Figure 2-3). Treatment consists of
supportive care. Preventive measures
include reducing regional mosquito
counts and wearing insect repellant.
Bacterial Infections
Syphilis. Syphilis is caused by the spirochete Treponema pallidum, which
has enjoyed a comeback in the AIDS
era (Marra, 2004). Early CNS infection
may cause acute meningitis, and if not
treated, approximately 5% of affected
individuals later develop symptomatic
neurosyphilis. Syphilitic involvement
of the spinal cord may manifest itself
as tabes dorsalis, meningomyelitis,
spinal vascular syphilis, hypertrophic
pachymeningitis, or development of
intra- or extramedullary gummas.
Tabes dorsalis now accounts for
less than 5% of neurosyphilis cases
and is characterized by demyelination,
gliosis, and inflammation of the posterior columns and posterior spinal roots
of the lower cord. It is much more
common in men and develops in three
phases an average of greater than 10
years after primary infection. The first
preataxic phase consists of lightning pains of the legs and sphincter
and sexual dysfunction; signs include
areflexia, sensory loss, abnormal Romberg testing, and Argyll Robertson pupils. The second ataxic stage lasts 2
to 10 years and is notable for prominent leg ataxia, proprioceptive loss
causing a slapping gait, impaired deep
pain sensation putting the person at
risk of arthropathy, and worsening of
the pain. The third stage, termed terminal or paralytic, also lasts 2 to 10
years and consists of cachexia, spastic
KEY POINT:
Neurosyphilis
should be
considered in
any patient with
myelopathy and
especially those
with HIV risk
factors.
41

KEY POINTS:
Tuberculosis
should always
be considered in
the differential
diagnostic
evaluation of
myelopathy.
Myelopathy
related to
bacterial
infection is more
likely to be a
result of epidural
abscess than
direct cord
infection.
paraparesis, and autonomic dysfunction.

Syphilitic meningomyelitis primarily affects middle-aged males with a
wide variation in latency after primary
infection. Lower extremity sensorimotor complaints and autonomic symptoms predominate, and examination
reveals spastic paraparesis (less frequently quadriparesis). Pathologic
changes include granulomatous inflammation, fibrosis, and perivascular
infiltration of small- and medium-sized
vessels, especially affecting regions
such as the fasciculus gracilis, the root
entry zone, and the Lissauer tract.
Neurosyphilis may be confirmed
by detecting a combination of a reactive serum treponemal antibody assay
together with either a lymphocytic CSF
pleocytosis or a reactive CSF Venereal
Disease Research Laboratory test.
Treatment consists of administration of
daily aqueous penicillin, 12 million to
24 million units in divided doses, for
10 to 14 days.
Tuberculosis. Mycobacterium tuberculosis infection remains a leading
cause of neurologic morbidity in developing countries but still occurs in
the United States in certain popula-
42
West Nile virus encephalomyelitis. A, Crosssection of the cervical spinal cord showing
anterior hornpredominant inflammatory
infiltrate (arrows). B, Higher magnification shows
destruction of anterior horn neurons with perivascular
lymphocytic cuffing seen at lower right; arrow indicates a
remaining neuron.
FIGURE 2-3
Modified with permission from Hollander H, Schaefer PW, HedleyWhyte ET. Case records of the Massachusetts General Hospital. Case
22-2005. An 81-year-old man with cough, fever, and altered mental
status. N Engl J Med 2005;353(3):287295. Copyright 2005,
Massachusetts Medical Society. All rights reserved.
tions, such as Native Americans. Tuberculous spondylitis (Pott disease) is

a common cause of myelopathy in
which the bacterium destroys the anterior vertebral body, causing pus to
compress the spinal cord. Other mechanisms of myelopathy include intraspinal granulomas and infectious or parainfectious myelitis. Spine x-ray and
spinal cord MRI serve to differentiate
some of these causes. Successful treatment may require surgical decompression followed by at least 12 months of
antibiotic administration.
Other bacterial myelopathy
mechanisms, including epidural
abscess. Direct bacterial infection of
the cord is uncommon, and systemic
bacterial infections are occasionally
associated with transverse myelitis
(Table 2-2). The most important association of bacterial infection and myelopathy is with spinal epidural abscess. This is a rare disorder usually
caused by Staphylococcus aureus that
originated from an adjacent area of
osteomyelitis or spread hematogenously from a skin or lung infection.
The pathophysiology, clinical features,
and management of spinal epidural
abscess are covered in the chapter
Compressive and Traumatic Myelopathies.
Fungal Infections
Fungal myelopathies are rare, but
granulomatous meningitis, with intraspinal or extradural granulomas,
can occur with Aspergillus, Blastomyces, Coccidioides, or Cryptococcus
species. Extension of a fungal infection from adjacent vertebral osteomyelitis may compress the cord. Meningovascular inflammation can cause
cord infarction. Inflammatory myelitis
in association with fungal infections
has been reported rarely.
Parasitic Infections
Parasite-related myelopathies are rare
in the United States, but travel to re-
gions where infection is common is an

important clue. Toxoplasmosis-related
spinal cord abscess has rarely been
associated with AIDS. Most other parasitic myelopathies occur in regions
where infection is endemic. In South
America, East Asia, and Africa, parasitic infection occurs after water contact with cercariae of Schistosoma
haematobium or Schistosoma mansoni. Hydatid disease from infection
with the larval form of the canine tapeworm Echinococcus granulosa can invade bone and cause secondary cord
compression, or it may cause a cystic
cord infection.
Cysticercosis is caused by infection by the larval form of pork tapeworm Taenia solium and is common
in parts of the world such as Mexico
and Central American countries. A
slowly progressive myelopathy can
occur from direct subarachnoid invasion of the organisms or development
of intramedullary cysts; albendazole
treatment may be effective.
INFLAMMATORY
MYELOPATHIES
The presentation of a noncompressive
myelopathy in a person with no history of neurologic disease most commonly raises concern for an inflammatory demyelinating myelitis. The
evaluation should achieve either a
specific diagnosis (eg, MS or an NMO
spectrum disorder) or categorize the
patient as having a descriptive clinical
syndrome (eg, postinfectious or postvaccinial myelitis, ADEM, or idiopathic
transverse myelitis). Clinical, laboratory, and neuroimaging criteria are often sufficient to categorize individual
patients for purposes of prognosis and
therapy, although in some cases further observation is required to establish a confident diagnosis (Table 2-3).
The most important investigations are
brain and spinal cord MRI, lumbar
puncture, and evaluation of NMO-IgG

serologic status.
Idiopathic Acute Transverse
Myelitis
The Transverse Myelitis Consortium
Working Group proposed diagnostic
criteria for idiopathic acute transverse
myelitis, requiring bilateral (not necessarily symmetric) sensorimotor or autonomic spinal cord dysfunction, a
sensory level, progression to nadir of
clinical deficits between 4 hours and
21 days after onset, demonstration of
spinal cord inflammation (CSF showing pleocytosis or elevated IgG index
or MRI revealing a gadolinium-enhancing cord lesion), and exclusion of
a compressive cause (Krishnan et al,
2006; Transverse Myelitis Consortium
Working Group, 2002). A recent study
incorporating these criteria showed
that although patients had fairly uniform CSF and MRI results, their clinical
outcome and treatment response were
not predictable (de Seze et al, 2005).
The criteria are therefore a helpful
guide for recognition of an inflammatory myelitis, but the patients identified by the criteria are likely a rather
heterogeneous group.
Fewer patients are receiving a diagnosis of idiopathic acute transverse myelitis because of the specificity of two diagnostic elements. First,
the length of the spinal cord lesion
assists with determining whether a
myelitis attack is more likely to represent MS (partial myelitis with an
asymmetric cord lesion spanning one
to two cord segments) or an NMO
spectrum disorder (centrally based,
longitudinally extensive cord lesion
extending over three or more segments). Second, NMO-IgG serology is
positive in about 75% of patients with
NMO and one-third to one-half of patients presenting with longitudinally
extensive myelitis (Lennon et al,
2004). Seropositivity is predictive of
KEY POINTS:
Travel history
can reveal
important clues
to an infectious
myelopathy.
Idiopathic
transverse
myelitis is a
heterogeneous
group of
disorders.
An asymmetric,
peripheral cord
lesion that is one
to two vertebral
segments in
length is most
consistent with
multiple
sclerosis.
A longitudinally
extensive cord
lesion spanning
three or more
vertebral
segments is
suggestive of a
neuromyelitis
optica (NMO)
spectrum
disorder.
43
TABLE 2-3
Comparison of the Clinical, Laboratory, and Imaging Features of Multiple

Sclerosis, Neuromyelitis Optica, and Acute Disseminated
Encephalomyelitis
Neuromyelitis Optica
Acute
Disseminated
Encephalomyelitis
Antecedent
Variable (may trigger
infection/immunization relapse)
Variable
Typical
Age
Uncommon in children
and 50 y; median
29 y
Any; median 39 y
Children adults
Gender (female:
male)
2:1
Up to 9:1
1:1.2
Clinical
presentation
Usually
monosymptomatic
Usually
monosymptomatic;
sometimes simultaneous
myelitis and optic
neuritis
Polysymptomatic
Typical attack
severity
Mild to moderate
Moderate to severe
Moderate to severe
Typical attackrelated impairment
None to mild
Moderate to severe
Mild to moderate
Clinical course
85% Relapsing with

most developing
secondary progression;
15% primary
progressive
85% Relapsing
Monophasic ?Rare
multiphasic or
relapsing acute
disseminated
encephalomyelitis
CSF cell count and

differential
50 106/L WBCs;
lymphocytes
Any; lymphocytes,
sometimes
polymorphonuclear cells
50 106/L WBCs;
lymphocytes
CSF oligoclonal
bands
85%
30%
Usually absent
Brain MRI lesion

size, distribution,
gadolinium
enhancement
Small to medium;
asymmetric,
periventricular;
variable enhancement
None/punctate;
subcortical; number of
brain MRI lesions
increases with time; 10%
meet multiple sclerosis
criteria; less than 10%
hypothalamic/thalamic/
periependymal
Larger, fairly
symmetric and
subcortical
Brain MRI
gadolinium
enhancement
Variable
None
Relatively uniform
Spinal cord MRI
Short lesions (up to

two vertebral
segments)
Longitudinally extensive
( three vertebral
segments)
Variable
Characteristic
44
Multiple Sclerosis
WBC white blood cell.

Reproduced with permission from Wingerchuk DM, Lucchinetti CF. Comparative immunopathogenesis of acute disseminated encephalomyelitis,
neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol 2007;20(3):343350.
relapse in patients presenting with a

first event of longitudinally extensive
transverse myelitis (LETM) (56% risk of
recurrent LETM or optic neuritis (ON)
over the subsequent 12 months)
(Weinshenker et al, 2006). The implications of this finding are that all patients with new-onset transverse myelitis should undergo NMO-IgG testing
and that there is a strong argument for
treating patients with NMO-IgG seropositive LETM with immunosuppressive therapy after the first attack in order
to reduce the risk of recurrence (Case
2-2). Together with brain MRI and CSF
data, these studies can convert a patients diagnosis from an idiopathic
myelitis to one with a recognized prognosis and specific treatment plan.
Multiple Sclerosis
MS is the prototypic inflammatory demyelinating CNS disease (Frohman et
al, 2006; Noseworthy et al, 2000). In
85% of patients, it begins as a relapsing-remitting disorder in which clinical
relapses lasting days to weeks are separated by periods of clinical remission.
Spinal cord demyelination is a common cause of clinical relapse in MS.
The responsible lesions are typically
small (less than one to two vertebral
segments long) and located in the cord
periphery, especially the dorsal columns. As such, these lesions cause
partial myelitis attacks, resulting in
asymmetric sensorimotor clinical symptoms such as an incomplete Brown-Sequard syndrome, Lhermitte sign, or a
useless hand syndrome resulting from
profound proprioceptive loss in an upper extremity (Case 2-3). Fever, meningismus, encephalopathy, and systemic
symptoms are absent.
Spinal cord MRI reveals the responsible short-segment lesion, which may
enhance after gadolinium administration. Partial myelitis attacks may occur
during any phase of MS. When partial
myelitis occurs as a first-ever neurologic event, the likelihood of future
KEY POINTS:
confirmation of MS is increased by
other abnormal findings such as the
presence of white matter lesions with
brain MRI, oligoclonal bands (frequency greater than 85% in confirmed
MS), elevation of the IgG index (frequency greater than 65% in confirmed
MS) in the CSF, or abnormalities of
optic pathway conduction detected
with visual evoked responses. NMOIgG serology is virtually always negative in partial myelitis and typical MS.
The most helpful investigation is brain
MRI; the presence of two or more
white matter lesions portends a 90%
risk of conversion to MS (ie, experiencing another clinical attack) over the
next 10 to 14 years, whereas the risk is
approximately 19% if the initial brain
MRI is normal (Brex et al, 2002).
Postvaccinial or Postinfectious
Myelitis
Postvaccinial or postinfectious acute
transverse myelitis occurs within 3
weeks of vaccine administration or an
acute systemic infection (Table 2-4).
Compared with partial myelitis of MS,
these acute syndromes tend to be
more severe and symmetric and are
more commonly diagnosed in children
and adolescents. The infectious agents
TABLE 2-4
Immunizations
Associated With
Myelitis
Hepatitis B
Influenza
Japanese B encephalitis
Measles
Pertussis
Polio
Rabies
Rubella
Smallpox
The serum
autoantibody
marker NMO-IgG
is highly specific
for neuromyelitis
optica.
Patients with
longitudinally
extensive
myelitis should
be tested for
NMO-IgG and, if
seropositive,
treated with
immunosuppressive
therapy to
prevent relapses.
In patients with
partial myelitis,
the strongest
predictor of
future
development of
multiple sclerosis
is the presence
of white matter
lesions on brain
MRI.
45

Case 2-2
46
A 45-year-old South Korean woman

with a history of hypothyroidism
developed severe radicular left arm
pain followed 2 days later by
ascending numbness, moderate
quadriparesis precluding
independent ambulation, and
urinary incontinence. Brain MRI was
normal, but cervical spine MRI
showed a longitudinally extensive
lesion involving most of the cervical
spinal cord and extending into the
medulla (Figure 2-4). Spinal fluid
examination showed 26 WBCs (39%
neutrophils, 61% lymphocytes) and
no oligoclonal bands; NMO-IgG
serology was positive. She made a
rapid recovery after IV corticosteroid
administration and had no further
attacks over the next 2 years while
taking mycophenolate mofetil 1000
mg twice daily.
Comment. Several features of this
case suggest an NMO-spectrum
disorder: onset of severe myelitis in
a middle-aged nonwhite female
with a probable history of systemic
autoimmune disease (thyroid
Sagittal T2-weighted MRI of the cervical
FIGURE 2-4
disorder), neutrophilic CSF
spinal cord in a patient with inflammatory
pleocytosis without oligoclonal
myelitis demonstrates a longitudinally
extensive lesion with involvement of the medulla and
bands, the presence of a
pons. This lesion phenotype can occur in idiopathic
longitudinally extensive cord lesion
transverse myelitis but is suggestive of an NMO spectrum
with brainstem extension, and
disorder with risk for future relapse.
negative brain MRI. Her NMO-IgG
seropositive status confirms that she
is at high risk for development of recurrent myelitis or ON (greater than 50% over the next 12
months), justifying initiation of immunosuppressive therapy after this first-ever myelitis attack.
associated with myelitis are discussed

in the Infectious Myelopathies section; in many instances, evidence for
recent viral infection is limited to recollection of a nonspecific febrile illness, and a specific virus is neither
isolated nor confirmed with acute and
convalescent serologic tests. The vaccines associated with myelitis include
smallpox, hepatitis B, influenza, rubella, and rabies vaccines, among others. The type and timing of exposure
to an immunologic challenge is
known with greater certainty than with

postinfectious myelitis; however, the
wide spectrum of vaccines and infections that appear to trigger myelitis
suggests that multiple or nonspecific
immune activation may trigger the
event in a susceptible individual.
Pathophysiologic mechanisms might
include molecular mimicry (portions
of the vaccine or virus resemble selfantigens, prompting an autoimmune
response) or stimulation by superantigens. The diagnosis of postinfectious
Case 2-3
A 34-year-old woman noted the onset of left upper extremity numbness and clumsiness
followed 3 days later by left leg numbness, gait imbalance, and Lhermitte sign. She was unaware
that she had burned her wrist while baking. Examination revealed profound loss of vibratory
and proprioceptive sensation and pseudoathetosis of the left hand, minimal distal weakness of
the left upper and lower extremities, mild gait ataxia, and a left wrist burn. MRI of the cervical
spinal cord demonstrated two focal lesions located at C2 and C3-4 vertebral levels (Figure 2-5).
Brain MRI revealed numerous periventricular white matter lesions compatible with
FIGURE 2-5
A, Sagittal T2-weighted MRI of the cervical spinal cord reveals two separate short-segment lesions
characteristic of multiple sclerosis. B, Axial T2-weighted MRI shows the symptomatic C3-4 left
posterior column lesion.
demyelination, and she was deemed to be at high risk for development of MS. She made a slow
but complete recovery from this event over the next 8 months and remained relapse free at
follow-up 16 months later while using interferon beta, which was prescribed with the intent of
delaying a second clinical attack.
Comment. This woman experienced useless hand syndrome caused by the dorsal column
lesion that effectively caused loss of sensory input from her left upper extremity. Although
patients often describe weakness, careful examination while the patient looks at the limb during
voluntary muscle strength testing usually reveals normal power or only minimal weakness, as the
primary problem is sensory loss. Such patients are often unable to adequately judge the amount
of pressure applied by the hand and report crushing soft drinking cups or dropping objects.
Recovery is often remarkably good but may be delayed over several months. This syndrome is
highly suggestive of MS, and the patient did well using an approved immunomodulatory
therapy aimed at attack prevention.
or postvaccinial transverse myelitis

should be made with caution because
such immune-activating events may trigger clinical attacks of myelitis in more
specific disorders such as MS and NMO;

patients should undergo a similar evaluation to that outlined in the section on
idiopathic transverse myelitis.
47

KEY POINTS:
48
Infections and
immunizations
may be associated
with relapse of
any of the
demyelinating
diseases.
Acute
disseminated
encephalomyelitis
is more common
in children and
usually affects
the deep gray
brain structures.
Acute
disseminated
encephalomyelopathy has distinct
pathology with
perivenular
inflammatory
infiltrates and
demyelination.
The
immunopathology
of NMO reveals
many features
consistent with
humoral
autoimmunity.
NMO-IgG
targets the
water channel
aquaporin-4.
NMO makes up
a greater
proportion of
relapsing CNS
demyelinating
disease in
nonwhites
compared with
whites.
New diagnostic
criteria are
highly sensitive
and specific for
differentiating
NMO from
multiple
sclerosis.
Acute Disseminated
Encephalomyelitis
ADEM is characterized by acute to
subacute onset of fever, meningismus,
encephalopathy, and multifocal symptoms and signs of CNS dysfunction. It
is more common in children, and a
recent vaccination or systemic infection (such as a typical childhood exanthem) is noted in about half of
cases. Brain MRI reveals numerous
medium to large size, fairly symmetric
subcortical white matter lesions, often
with involvement of the deep gray
matter. Because the lesions are essentially the same age, most or all of the
lesions enhance with gadolinium. Spinal cord MRI lesions are variable in
length, sometimes exceeding three
segments. The CSF reveals a prominent lymphocytic pleocytosis, but oligoclonal bands are generally not detected. Pathology is distinct in that the
lesions have relatively indistinct margins and consist of perivenular
sleeves of demyelination and macrophage-predominant inflammatory
infiltrates (Wingerchuk and Lucchinetti, 2007).
Although ADEM is considered a
monophasic disorder, the diagnosis
should be applied cautiously, especially because pathologic confirmation
is rarely available. The presence of a
longitudinally extensive spinal cord lesion should prompt evaluation for an
NMO spectrum disorder accompanied
by brain lesions. In addition, improved
recognition and follow-up by specialized pediatric MS clinics are revealing
that many patients diagnosed initially
with ADEM eventually relapse and follow a clinical course consistent with
MS.
Neuromyelitis Optica
NMO was long considered an MS variant but is now recognized as a distinct
inflammatory demyelinating disease
consisting of ON in combination with
a specific myelitis pattern: LETM, in
which the spinal cord lesion extends

over three or more vertebral segments,
but usually without significant brain
involvement (Wingerchuk et al, 2007).
It is pathologically distinct from MS;
although both have inflammatory demyelinating lesions, NMO lesions often contain necrosis, a high proportion
of polymorphonuclear cells and eosinophils, association with hyalinized
blood vessels, and evidence of humoral immune activation, including
very prominent IgG and complementrelated (C9 neoantigen) deposits (Figure 2-6) (Lucchinetti et al, 2002). Recent discovery of the NMO-IgG
autoantibody marker, which targets
the water channel aquaporin-4,
strengthens the case for humoral autoimmunity in NMO (Lennon et al, 2004;
Lennon et al, 2005).
Several epidemiologic, clinical,
and laboratory features serve to distinguish NMO from MS. The female to
male ratio is 9:1 for NMO compared
with 2:1 for MS. The age of disease
onset is about a decade later for NMO
(late 30s) than for MS (late 20s).
Whereas MS most commonly affects
persons of Northern European/white
ancestry, NMO makes up a substantial
proportion of CNS demyelinating disease in nonwhites, including Asians,
Hispanics, African Americans, native
North Americans, and black Africans.
Diagnostic criteria for NMO are
summarized in Table 2-5 (Wingerchuk et al, 2006). The criteria are 99%
sensitive and 90% specific for differentiating NMO from MS with an opticospinal presentation. At disease onset,
most patients have no brain MRI white
matter lesions, or, if they are present,
they typically do not meet MS diagnostic criteria. Although most patients
have no symptoms affecting CNS regions other than the optic nerves and
spinal cord, neither such symptoms
nor the presence of brain MRI lesions
precludes the diagnosis of NMO.
The clinical features of ON (visual
loss pattern, orbital pain) in NMO are

severe but do not otherwise differ
from other forms of inflammatory ON,
including MS. In contrast, NMO-related myelitis attacks differ from the
partial myelitis of MS in that they are
longitudinally extensive, centrally
based within the cord, and usually
cause more severe bilateral impairment. Hallmarks of central demyelination include Lhermitte symptom (spine
or limbs paresthesias elicited by neck
flexion; about equally common in
NMO and MS) and paroxysmal tonic
spasms (painful, stereotypic events of
limb dystonia; more common in NMO
than MS). Symptoms such as respiratory
failure (sometimes fatal) or hiccoughs
are more specific for NMO and may occur when cervical lesions ascend into
the medullary respiratory center and
area postrema (Misu et al, 2005).
Spinal cord MRI detection of LETM
(three or more segment lesions) is very
helpful in suggesting an NMO diagnosis. It is important to note at what point
the spinal cord MRI was performed
relative to the myelitis attack because
the LETM lesion may later contract or

break up into several shorter noncontiguous segments. Therefore, an MRI
performed several weeks after the onset of myelitis may be misleading.
Brain MRI is typically normal at
onset in NMO. Up to 60% of patients
will develop nonspecific white matter
lesions on serial MRI studies over
years of follow-up, but only about 10%
develop lesions that meet MS radiologic criteria (Pittock et al, 2006a).
NMO should therefore be considered
in patients with first-ever or recurrent
ON or myelitis in whom the brain MRI is
normal or reveals only nonspecific
white matter lesions at disease onset. In
less than 10% of patients with NMO,
atypical lesions may involve the diencephalon (thalamus or hypothalamus),
brainstem, or cerebrum (Figure 2-7)
and correspond to regions of high aquaporin-4 expression (Pittock et al, 2006c).
CSF inflammation during active
NMO relapses can be dramatic, revealing marked pleocytosis (50 to 1000
106 WBCs/L, with the differential
showing polymorphonuclear cells)
KEY POINTS:
Brain lesions,
whether
symptomatic or
detected by MRI,
do not exclude a
diagnosis of
NMO.
Paroxysmal tonic
spasms and
neurogenic
respiratory failure
are characteristic
features of cervical
myelitis attacks in
NMO.
The timing of
spinal cord
imaging is
important to
detect the
longitudinally
extensive cord
lesion seen in
NMO.
49
FIGURE 2-6
Pathologic characteristics of neuromyelitis optica. A, Extensive inflammatory demyelination of cord gray

and white matter. Deposition of immunoglobulin (B) and complement (C9 neoantigen [C]) are
prominent.
Modified from Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devics neuromyelitis optica.
Brain 2002;125(pt 7):1450 1461. Reprinted by permission of Oxford University Press.

KEY POINTS:
Brain lesions in
NMO may occur
in regions of
high aquaporin4 expression.
CSF findings in
NMO include
neutrophilic
pleocytosis.
Oligoclonal
bands are rare.
Several serum
autoantibodies
are usually
detectable in
patients with
NMO and may
indicate a general
autoimmune
tendency.
TABLE 2-5
Diagnostic Criteria for Neuromyelitis Optica
Transverse Myelitis and Optic Neuritis

At least two of the following features:
MRI brain nondiagnostic for multiple sclerosis
MRI spinal cord lesion extending over three vertebral segments
Neuromyelitis opticaimmunoglobulin G seropositivity
and high protein level (100 mg/dL to

500 mg/dL). In contrast, typical MS is
associated with a normal cell count or
modest pleocytosis (no more than
50 106 lymphocytes/L), even during
acute attacks. Unique oligoclonal
bands in the CSF, which are detectable
in approximately 85% of people with
MS, are found in only 20% to 30% of
NMO cases.
One or more serum autoantibodies such as antinuclear antibody and
extractable nuclear antigen are detectable in a majority of patients with
NMO, usually in the absence of the
systemic autoimmune disease with
which the autoantibody is typically as-
sociated (eg, systemic lupus erythematosus or Sjogren syndrome). In most

instances, it seems likely that the positive serologic results are related to a
general autoimmune susceptibility
(Pittock et al, 2006b). The presence of
the autoantibodies is characteristic but
diagnostically not very helpful; in fact,
they are usually a source of confusion
by suggesting diagnoses such as lupus myelitis for which no other supportive data are available (see section
on systemic autoimmune disease
related myelopathy). The recent discovery of NMO-IgG (anti-aquaporin-4) is an exception; it is about
75% sensitive and greater than 90%
50
FIGURE 2-7
Brain lesion patterns sometimes associated with neuromyelitis optica. A, Axial fluid-attenuated
inversion recovery (FLAIR) sequences show extensive nonenhancing subcortical white matter lesions. B,
Axial FLAIR images reveal hypothalamic-thalamic region abnormalities (arrow). C, Periaqueductal and
pontine tegmentum lesions (arrows) detected with axial FLAIR imaging of the brainstem.
Modified with permission from Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63(3):390 396.
Copyright 2006, American Medical Association. All rights reserved.
TABLE 2-6
Neuromyelitis Optica Spectrum Disorders
Neuromyelitis optica
Limited forms of neuromyelitis optica
Idiopathic single or recurrent events of longitudinally extensive myelitis
(three or more vertebral segment spinal cord MRI lesions)
Optic neuritis, recurrent or simultaneous bilateral
Asian optico-spinal multiple sclerosis
Optic neuritis or myelitis associated with neuromyelitis opticatypical brain

lesions (hypothalamic, corpus callosal, periventricular, brainstem)
Optic neuritis or longitudinally extensive myelitis associated with systemic

autoimmune disease
Modified with permission from Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum
of neuromyelitis optica. Lancet Neurol 2007;6(9):805 815. Copyright 2007, Elsevier.
specific for distinguishing NMO from

an optico-spinal presentation of MS
and is one of the three supportive criteria for NMO diagnosis. Aquaporin-4
is the most common of the aquaporin
water transport proteins in the CNS
(Amiry-Moghaddam and Ottersen,
2003), where it is found on astrocyte
foot processes and the abluminal surface of blood vessels, the same regions
where NMO pathology (immunoglobulin and complement deposition) is
located. Whereas loss of aquaporin-4
is dependent on the stage of demyelination in MS lesions, NMO lesions are
characterized by severe aquaporin-4
loss regardless of the stage of demyelinating activity or extent of tissue necrosis (Roemer et al, 2007). Furthermore, foci of aquaporin-4 loss in NMO
coincided with sites of vasculocentric
immune complex deposition. These
data suggest that a complement activating aquaporin-4-specific autoantibody is the primary initiator of the
NMO lesion.
NMO-IgG has broadened the
NMO spectrum of disorders (Table
2-6). In addition to the patients with
coexisting autoimmune/connectivetissue diseases and serologic tests,
NMO-IgG is found in patients with
Asian optico-spinal MS (which makes

up more than half of MS cases in Japan) (Kira, 2003) and in patients with
limited forms of NMO, including recurrent LETM and recurrent ON with
normal brain MRI.
Treatment of Myelitis and Its
Associated Diseases
Treatment recommendations are based
largely on anecdotal experience. Acute
myelitis attacks are typically treated with
IV corticosteroids such as methylprednisolone (1000 mg/d for 5 consecutive
days). Some severe attacks of LETM fail
to respond to corticosteroids. In this setting, evidence from a randomized, controlled trial (Weinshenker et al, 1999)
supports use of rescue plasmapheresis
(administered every other day for seven
exchanges). In that crossover trial for
patients with idiopathic CNS demyelinating disease (MS, transverse myelitis,
NMO, ADEM) and severe deficits (eg,
paraplegia or coma), meaningful clinical
improvement occurred in significantly
more plasmapheresis patients (42%)
than sham exchange patients (6%). Observational experience also supports use
of plasmapheresis for treatment-refractory myelitis attacks in NMO and for
severe, corticosteroid-refractory ON
51

KEY POINTS:
52
Corticosteroidrefractory
attacks in NMO
may respond to
plasmapheresis.
Long-term
treatment with
agents that
suppress
humoral
immunity are
needed to
prevent relapses
of NMO
spectrum
disorders.
(Keegan et al, 2002; Ruprecht et al, 2004;

Watanabe et al, 2007). A recent study
showed that very severe attacks (loss of
motor and sensory function) may benefit from the combination of corticosteroids, plasmapheresis, and IV cyclophosphamide (Greenberg et al, 2007).
No definite evidence supports the use of
IV immunoglobulin in inflammatory
myelitis.
Preventive therapy is indicated for
patients who have established relapsing disease or are at high risk of developing relapsing disease (Wingerchuk and Weinshenker, 2005). After a
first-ever partial myelitis event associated with brain MRI lesions suggestive
of MS (clinically isolated syndrome),
use of interferon beta therapy is indicated. In NMO spectrum disorders,
disability is related entirely to the residual effects of attacks; a secondary
progressive course is very uncommon.
Therefore, preventive therapy should
be instituted as early as possible for
relapsing NMO and for NMO-IgG seropositive patients with a first attack of
LETM. Experience and observational
series suggest that standard MS immunomodulatory therapies (eg, interferon beta, glatiramer acetate) are
likely not effective for NMO spectrum
disorders; rather, immunosuppressive
regimens that impact the humoral
mechanisms underlying NMO are required (Papeix et al, 2007; Warabi et
al, 2007). Experience is greatest with
oral azathioprine (2 mg/kg/d to 3 mg/
kg/d) in combination with oral prednisone (1 mg/kg/d) with a goal of
eventually maintaining clinical remission with azathioprine monotherapy
after slowly tapering and discontinuing the daily prednisone dosage over a
few months (Mandler et al, 1998). Mycophenolate mofetil is sometimes
used in place of azathioprine. The chimeric anti-CD20 monoclonal protein
rituximab has received increasing attention because of its selectivity for
B-cell depletion. A preliminary report

described eight patients with active,
relapsing NMO that failed to respond
to other therapies who stabilized and
improved their neurologic function for
at least 12 months following rituximab
therapy (Cree et al, 2005). B-cell
counts recover in 6 to 12 months after
treatment, at which time repeat infusions may be administered, but data
concerning long-term therapy for
NMO are not yet available. Other immunosuppressive approaches include cyclophosphamide, mitoxantrone (Weinstock-Guttman et al, 2006), or IV
immune globulin. Five years of relapsefree immunosuppression is recommended for NMO-IgG seropositive patients with a single LETM attack
(Weinshenker et al, 2006). Long-term
immunosuppression is indicated for patients with established relapsing disease.
NONINFECTIOUS
INFLAMMATORY
MYELOPATHIES
Myelopathies Associated With
Systemic Autoimmune
Diseases
Acute myelitis syndromes may occur
in the setting of an established connective-tissue disease or systemic granulomatous disease. For example, an
acute spinal cord lesion may occur in
the setting of known systemic lupus,
often with prior clinical or MRI evidence of brain involvement. Caution is
needed in making this diagnostic association, however, when the acute
myelitis event is the presenting disorder. In many instances, a diagnosis of
lupus myelitis or another similar descriptive mimicker is reached from the
clinical syndrome and the presence of
a serum autoantibody such as antinuclear antibody. In the absence of systemic symptoms convincing for lupus,
such patients seem much more likely
to be part of the NMO spectrum disorders in which NMO, or its partial
Case 2-4
A 37-year-old previously healthy white man noted the insidious onset and nonstepwise
progression of gait imbalance over 8 months. Over the prior 2 months, he also noted right-hand
numbness,
left footdrop,
and urinary
urgency.
Examination
confirmed
findings
consistent with
an asymmetric
cervical
myelopathy,
and he needed
unilateral
assistance to
walk. MRI of
the brain and
spinal cord
showed
innumerable
nodular
lesions, many
at the pial
Neurosarcoidosis. T1-weighted brain (A, axial plane) and cervical spinal
FIGURE 2-8
surface; most
cord (B, sagittal plane) MRI with gadolinium reveal multifocal nodular
areas of enhancement, many near the pial surface.
enhanced after
gadolinium
administration
(Figure 2-8). CSF examination showed 16 WBCs, all lymphocytes, but no other abnormalities.
Extensive serologic studies, chest x-ray, and body CT were normal. Biopsy of a cerebellar nodule
and nearby leptomeninges revealed noncaseating granulomas, confirming a diagnosis of isolated
neurosarcoidosis. He improved markedly after IV and oral corticosteroid therapy and remained
clinically stable with minimal gait ataxia on a maintenance regimen of hydroxychloroquine.
Comment. The numerous enhancing periependymal and subpial lesions were key to the
provisional diagnosis of sarcoidosis, ultimately confirmed by CNS and meningeal biopsy. Fewer
than 5% of sarcoidosis cases are isolated to the CNS. Confirmation by pathologic diagnosis is
strongly recommended in order to confidently guide short- and long-term immunotherapy.
forms, are associated with clinical or

serologic evidence of systemic autoimmunity (Case 2-4).
The diagnostic evaluation should
include screening for systemic symptoms and signs of lupus (malar or discoid rash, photosensitivity, oral ulceration, arthritis or serositis, nephropathy,
hematologic disorder, and neurologic
disorders [seizures, psychosis]), Sjogren
syndrome (sicca syndrome), Behcet disease (recurrent genital ulcers, uveitis or
retinal vasculitis, rash such as erythema
nodosum), mixed connective-tissue disease (edema, evidence of synovitis or

myositis, Raynaud phenomenon), or
scleroderma (sclerodactyly). Laboratory
studies should include antinuclear antibody, anti double-stranded DNA, extractable nuclear antigen (including antiSSA and anti-SSB antibodies), and antiribonucleoprotein. Spinal cord MRI will
reveal one or more lesions that typically
enhance with gadolinium but do not
otherwise have specific morphology.
Rheumatology, dermatology, and ophContinuum: Lifelong Learning Neurol 2008;14(3)
53

KEY POINTS:
Connective-tissue
disorders may
cause myelopathy
but should be
diagnosed using
standard
rheumatologic
criteria rather than
the mere
presence of
autoantibodies.
Neurosarcoidosis
is a mimicker of
multiple sclerosis
and other
inflammatory
CNS diseases.
thalmology consultations are often useful. Treatment is generally guided by the

underlying rheumatologic diagnosis
(Case 2-5).
Sarcoidosis is a noninfectious granulomatous disease that more commonly causes a subacute to chronic
progressive myelopathy than an acute
myelitis. MRI of the spinal cord usually
provides a clue to the diagnosis, revealing multiple enhancing lesions
with a nodular appearance and subpial location. Serum or CSF laboratory
abnormalities occur, including elevated angiotensin-converting enzyme
level, CSF pleocytosis, increased protein level, and presence of oligoclonal
banding, but they are not sufficient to
confirm neurosarcoidosis. Involvement of other organ systems, especially the lungs, is often key to establishing the diagnosis, because biopsy
confirmation of noncaseating granulomas from a biopsy-accessible site is
strongly recommended.
Neoplastic and Paraneoplastic
Myelopathies
Most primary tumors of the spinal cord
do not usually cause acute myelitis
syndromes or confusion with inflammatory diseases. Lymphoma is an exception; it can cause a subacute myelopathy and be associated with an
enhancing cord lesion, mild CSF pleocytosis and protein elevation, and
transient oligoclonal band positivity.
Furthermore, it is often temporarily,
but dramatically, corticosteroid responsive. Persistent gadolinium enhancement or recurrence after steroid
therapy should raise concerns about
this diagnosis, which may require biopsy for confirmation.
Spinal cord inflammation may occur as a paraneoplastic disorder. An
association has been noted between
an NMO-like syndrome and collapsing
response-mediator protein-5 autoantibody in the setting of small cell lung
cancer. Breast carcinoma may be associated with antiamphiphysin antibodies and a severe spastic myelopathy,
sometimes with an extensive lesion
that selectively involves long tracts.
Other progressive myelopathies have
been associated with ovarian and
nonsmall cell lung cancer as well as
with glutamic acid decarboxylase 65
autoantibodies causing a stiff manlike
Case 2-5
54
A 39-year-old African American man experienced right ON 6 years ago and recovered
completely. Results of his evaluation at the time included a normal brain MRI; abnormal right
visual evoked potential; and positive antinuclear antibody, rheumatoid factor, and IgM
anticardiolipin antibody. He had no systemic complaints, and a rheumatologic evaluation was
unrevealing; he was prescribed aspirin. One year ago, he developed thoracic transverse myelitis
with a longitudinally extensive cord lesion. His antinuclear antibody and rheumatoid factor titers
were again elevated, and he also had positive thyroperoxidase antibodies. He was diagnosed
with systemic lupus erythematosusrelated myelitis and treated initially with IV corticosteroids
and cyclophosphamide for presumed CNS vasculitis. After 18 months of treatment, during which
he was in remission, he had another event of ON. His NMO-IgG serology was positive, and he
was treated with rituximab with no relapses over 12 months of follow-up.
Comment. This patient has NMO with multiple associated serum autoantibodies. Often, such
cases are diagnosed as lupus myelitis or CNS lupus because of the autoantibody status but
despite lack of any other confirmatory features of lupus. Such patients probably have a tendency
to develop multiple autoimmune disorders that coexist with NMO. In this case,
cyclophosphamide may have been beneficial, but establishing an accurate diagnosis clarifies the
need for long-term immunosuppression with agents considered to be effective for attack
prevention in NMO.
syndrome with brainstem features and

ataxia, and often occurs in the setting
of diabetes mellitus. A complete paraneoplastic antibody panel is recommended in patients with these disor-
ders, and body imaging, including

chest, abdomen, and pelvic CT and
possibly PET scanning, are required to
detect and subsequently remove the
underlying malignancy.
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57
KEY POINTS:
58
Hereditary
myelopathic
syndromes can
be recognized as
four clinical
paradigms: (1)
spinocerebellar
ataxia, (2) motor
neuron
disorder, (3)
leukodystrophy,
and (4) distal
motor-sensory
axonopathy.
Neurologic
involvement in
nearly all
hereditary
myelopathies
includes
structures
outside of the
spinal cord.
Spinocerebellar
degenerations
(eg, Friedreich
ataxia, MachadoJoseph disease
[spinocerebellar
ataxia type 3],
BassenKornzweig
syndrome, and
vitamin E
deficiency
[occasionally
familial]) are
recognized by a
combination of
progressive
cerebellar ataxia,
peripheral
neuropathy and
dorsal column
impairment, and
variable
corticospinal tract
involvement.
HEREDITARY
MYELOPATHIES
John K. Fink
ABSTRACT
Hereditary myelopathies are a diverse group of disorders in which major aspects of
the clinical syndrome involve spinal cord structures. Hereditary myelopathic syndromes can be recognized as four clinical paradigms: (1) spinocerebellar ataxia, (2)
motor neuron disorder, (3) leukodystrophy, and (4) distal motor-sensory axonopathy. This review illustrates these hereditary myelopathy paradigms with clinical
examples with an emphasis on clinical recognition and differential diagnosis.
INTRODUCTION AND
SYNDROMIC CLASSIFICATION
Hereditary myelopathies are diverse
inherited disorders in which major
clinical and pathologic features involve spinal cord structures. In contrast to disorders such as inherited
neuropathies, in which clinical and
pathologic abnormalities are often limited to one region of the nervous system, neurologic involvement in nearly
all hereditary myelopathies includes
structures outside of the spinal cord.
Most hereditary myelopathies conform
to the following syndromes: spinocerebellar degeneration, motor neuron
disorder, leukodystrophy, and distal
axonopathy (Table 3-1).
FOUR INHERITED MYELOPATHY
SYNDROMES
Spinocerebellar Degeneration
Spinocerebellar degeneration (eg,
Friedreich ataxia, Machado-Joseph
disease [MJD] [spinocerebellar ataxia
type 3 (SCA3)], Bassen-Kornzweig
syndrome, and vitamin E deficiency
[occasionally familial]) are recognized by a combination of progres-
sive cerebellar ataxia, peripheral

neuropathy and dorsal column impairment, and variable corticospinal
tract involvement. Diagnostic recognition of these disorders is increased
if one bears in mind that these elements may exist in variable proportions, that diagnostic elements may
appear asynchronously as the disorder evolves, and that some of the
diagnostic elements may be absent
entirely (Cases 3-1 and 3-2).
The frataxin trinucleotide repeat is
GAA instead of the more common
polyglutamine expansion (CAG) repeat responsible for Huntington chorea, MJD, and many other spinocerebellar degenerations. Furthermore, the
frataxin GAA trinucleotide repeat occurs in an intron (frataxin intron 1) and
does not alter the frataxin coding sequence. Nonetheless, this intronic mutation leads to reduced frataxin messenger RNA (possibly through locally
increased DNA methylation leading to
reduced transcription) (Greene et al,
2007), iron accumulation in mitochondria, and an apparent increased vulnerability to oxidative stress.
Relationship Disclosure: Dr Fink has received personal compensation from Athena Diagnostics, Inc. Dr
Fink has received royalty payments for atlastin and NIPA1 patents.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Fink has nothing to disclose.
TABLE 3-1
Syndromic Classification of Hereditary Myelopathies
Major
Syndrome
Spinocerebellar
ataxias (SCA)
(Paulson, 2007)
Representative Examples Diagnostic Testing

SCA 1 through 28
Genetic testing for specific SCA

gene mutation; neuroimaging to
demonstrate cerebellar atrophy
Machado-Joseph disease (SCA3) Genetic testing for specific SCA

gene mutation; neuroimaging to
demonstrate cerebellar atrophy
Friedreich ataxia
FRDA gene analysis
Familial vitamin E deficiency
Serum vitamin E
Abetalipoproteinemia (Bassen- Lipoprotein electrophoresis

Kornzweig)
Charlevoix-Saguenay (ARSACS)
Motor neuron
disorders (Pasinelli
and Brown, 2006)
Leukodystrophies
(Lyon et al, 2006)
Spinal muscular atrophy
Survival motor neuron gene

analysis
Familial ALS
SOD1 gene analysis
Primary lateral sclerosis (rarely

familial)
ALSin gene analysis (for juvenile

familial primary lateral sclerosis)
Hereditary spastic paraplegia

(HSP)
HSP gene analysis
Spinobulbar muscular atrophy

(Kennedy syndrome)
Androgen-receptor gene mutation

(CAG repeats)
Partial hexosaminidase
deficiency
Leukocyte hexosaminidase assay
Subacute combined
degeneration (rarely familial)
Serum B12
Multiple sclerosis (occasionally

familial)
MRI of brain and spinal cord; CSF

analysis; clinical course
Adrenoleukodystrophy,
Adrenomyeloneuropathy
(Moser et al, 2007)
Serum very long chain fatty acid

analysis
Krabbe disease
Leukocyte -galactosidase assay
Metachromatic leukodystrophy Leukocyte arylsulfatase assay

Pelizeaus-Merzbacher (Garbern Proteolipid protein gene analysis
et al, 2002)
Cerebrotendinous
xanthomatosis
Serum cholestanol
Hereditary spastic paraplegia

CNS predominant,
distal motor-sensory
axonopathies (Fink,
2007a; Fink, 2007b)
HSP gene analysis
Other
MRI spectroscopy (brain), muscle

biopsy for ragged red fibers and
histochemical evidence of
oxidative phosphorylation deficit;
mitochondrial gene analysis
Mitochondrial myelopathy
(Scheper et al, 2007)
continued on next page
59
HEREDITARY MYELOPATHIES
TABLE 3-1
Major
Syndrome
Continued from page 59
Representative Examples Diagnostic Testing

Myelopathy related to Leber
optic atrophy (Bruyn and Went,
1964)
Variant Alzheimer disease with Presenilin 1 gene analysis
spastic paraplegia due to
presenilin 1 mutation
Hyperzincemia
Serum zinc
Neurofibromatosis type 2
MRI scan
Hereditary exostosis with spinal CT and MRI scans

cord compression
Hereditary hemorrhagic
telangiectasia
MRI scan
Von Hippel Lindau (vHL)

(hereditary hemangiomata)
MRI scan and VHL gene analysis
Tropical spastic paraplegia (due HTLV-1 antibody testing

to human T-lymphotropic virus
type 1 [HTLV-1] infection; may
occur in familial clusters)
60
Arginase deficiency
Increased plasma arginine, reduced

red blood cell arginase
Biotinidase deficiency
Reduced serum biotinidase
Syringomyelia (rarely familial)
MRI scan
Sjogren-Larsson syndrome
Clinical features of congenital

ichthyosis, mental deficiency, and
spastic diplegia or tetraplegia
(typically accompanied by
additional features), and
demonstrating enzyme (fatty
aldehyde dehydrogenase) defect
in cultured fibroblasts.
Bruyn GW, Went LN. A sex-linked heredo-degenerative neurological disorder, associated with Lebers optic
atrophy. I. Clinical studies. J Neurol Sci 1964;54:59 80.
Fink JK. Hereditary spastic paraplegia. In: Rimoin D, Connor JM, Pyeritz RE, Korf BR, editors. Emery and Rimoins
principles and practice of medical genetics. 5th ed. Philadelphia: Churchill Livingstone, 2007a:27712801.
Fink JK. The hereditary spastic paraplegias. In: Rosenberg RN, DiMauro S, Paulson HL, et al, editors. The molecular
and genetic basis of neurologic and psychiatric disease. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2007b.
Garbern JY, Yool DA, Moore GJ, et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop
length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002;125(pt
3):551561.
Lyon G, Fattal-Valevski A, Kolodny EH. Leukodystrophies: clinical and genetic aspects. Top Magn Reson Imaging
2006;17(4):219 242.
Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 2007;3(3):140 151.
Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci
2006;7(9):710 723.
Paulson HL. Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type
3. Semin Neurol 2007;27(2):133142.
Scheper GC, van der Klok T, van Andel RJ, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet
2007;39(4):534 539.
KEY POINTS:
Case 3-1
A 24-year-old woman began to notice insidiously progressive difficulty
with walking and balance beginning at approximately age 12. There was
no previous illness and no family history of similar symptoms. Although
able to walk and run, she noted that she had to concentrate on keeping
her balance. Within the next 2 years she began noticing tingling sensation
in both legs. Classmates began commenting that she walked as if she were
drunk. Gait disturbance continued to worsen slowly. Her neurologic
examination at age 24 revealed normal speech and normal cranial nerves
with the exception of saccadic intrusions into smooth pursuit. Muscle bulk,
tone, and strength were normal in the upper extremities. In the lower
extremities, however, muscle tone was increased (particularly at the
hamstrings and ankles and to a lesser extent at the quadriceps), and she
had marked weakness of tibialis anterior, moderate weakness of iliopsoas,
and mild weakness of hamstring muscles. There was profound impairment
of distal vibratory sensation (she was able to perceive vibratory sensation
applied to her shins but not to her toes) as well as moderately impaired
distal proprioception. There was subjectively decreased pinprick sensation
in the distal aspects of lower extremities. Deep tendon reflexes were 1 to
2 at the biceps, triceps, and brachioradialis; 3 at the knees; and absent
at the ankles. Finger-nose testing was normal. Heel-to-shin testing was
minimally abnormal. Plantar responses were extensor bilaterally. Nerve
conduction studies and EMG were consistent with sensory-motor
polyneuropathy. MRI scan of the brain was normal.
Neuro-localization. Neuro-localization indicated deficits referable to
corticospinal tracts serving bilateral lower extremities (weakness,
increased tone, extensor plantar responses); subtle midline cerebellar
disturbance (saccadic intrusions into smooth pursuit and mild heel-to-shin
abnormality); dorsal columns and/or dorsal roots (marked vibration and
proprioception impairment, which were out of proportion to subtle
diminution in pinprick perception); and peripheral nerve (absent ankle
deep tendon reflexes and stocking distribution of subjectively decreased
pinprick sensation).
Diagnosis. Friedreich ataxia. Friedreich ataxia (frataxin, FRDA) gene
analysis indicated that the patient was a compound heterozygote, having
one FRDA allele with an expanded repeat ([GAA]962) and the other FRDA
allele with a missense mutation resulting in amino acid substitution
(G130V).
Comment. Friedreich ataxia is the most common form of autosomal
recessive SCA. Friedreich ataxia is often associated with hypertrophic
cardiomyopathy (absent in the patient described above). The vast majority
of patients with Friedreich ataxia are homozygous for expanded
trinucleotide repeat in the frataxin gene, which encodes a mitochondrial
protein. The patient described is not homozygous for this trinucleotide
repeat. Rather she is a compound heterozygote, having an expanded GAA
repeat on one frataxin allele and a point mutation on the other. Point
mutations (instead of GAA expansion) are responsible for only 2% of
patients with Friedreich ataxia.
Motor Neuron Disorder

Motor neuron disorders involve degeneration of corticospinal tracts, an-
terior horn cells, or both. Cortical

motor neurons may also be involved,
although generally to a lesser extent.
The vast majority

of patients with
Friedreich ataxia
are homozygous
for expanded
trinucleotide
repeat in the
frataxin gene,
which encodes a
mitochondrial
protein.
Machado-Joseph
disease/
spinocerebellar
ataxia type 3 is
due to
trinucleotide
repeat (CAG)
expansion that,
like other
polyglutamine
expansions, is
thought to be
pathogenic
through protein
misfolding.
61
Case 3-2
62
A 52-year-old man began having insidiously progressive gait disturbance at age 38. Over the
next decade he developed progressive lower extremity weakness, spasticity, fasciculations, and
increasing inversion of his feet. By age 50 his symptoms had extended to include hypophonia,
dysarthria, and generalized bradykinesia. Neurologic examination at age 52 demonstrated
masked facies, saccadic intrusions into smooth pursuit eye movements, and both generalized
spasticity and diffuse fasciculations involving all extremities and the tongue, distal extremity
atrophy, and lower extremity hyporeflexia. After age 55, the patient was unable to ambulate.
Neurologic examination at age 57 showed hypophonia, spastic and hypokinetic dysarthria, lid
retraction, saccadic intrusions into smooth pursuit eye movements, sustained end-gaze
nystagmus, facial myokymia, and masked facies. There was moderate atrophy of distal upper
and lower extremity muscles and diffuse fasciculations, moderate to marked weakness of
intrinsic hand and proximal lower extremity muscles, and severe weakness of distal lower
extremity muscles. Spasticity, which had been a prominent feature previously, was no longer
present. There was a glove-and-stocking distribution of sensory loss to all modalities. Deep
tendon reflexes were hypoactive in the upper extremities and absent in the lower extremities.
Plantar responses were flexor on the right and extensor on the left. Finger-to-nose testing
revealed marked bradykinesia but no dysmetria.
Family history (Figure 3-1) was significant for a similarly affected father, paternal half-brother,
and paternal half-sister. EMG obtained at age 52 and repeated at age 53 revealed severe,
progressive chronic sensorimotor
neuropathy primarily of the axonal
type. Fasciculations were diffuse in
all regions (including paraspinal
muscles). Sural nerve biopsy
obtained at age 55 showed a
moderate to severe axonal
neuropathy.
Neuro-localization. At the onset
of disease, deficits were localized
primarily to corticospinal tracts
Machado-Joseph disease (spinocerebellar
FIGURE 3-1
serving bilateral lower extremities
ataxia type 3).
(causing spastic gait). As the
disorder progressed, these deficits
became associated with signs of extrapyramidal disturbance (generalized bradykinesia) and
subsequently lower motor neuron abnormalities (generalized fasciculations and atrophy) and
motor-sensory neuropathy. As peripheral neuropathy advanced, initially prominent spasticity
resolved and hyperreflexia gave way to areflexia. Midline cerebellar abnormalities were limited
to saccadic intrusions into smooth pursuit eye movements.
Diagnosis. MJD (SCA3). Genetic testing for MJD/SCA3 revealed one expanded allele (69 CAG
repeats) and one normal allele (30 CAG repeats). CSF revealed increased protein (74 mg/dL) but
was otherwise normal.
Comment. MJD/SCA3 is due to trinucleotide repeat (CAG) expansion that, like other
polyglutamine expansions, is thought to be pathogenic through protein misfolding (Paulson,
2007). MJD/SCA3 phenotypes vary from spastic paraparesis (which dominated the first decade of
this patients symptoms) to complex syndromes involving elements of cerebellar ataxia,
extrapyramidal disturbance (eg, nigrostriatal pathway disturbance), and peripheral neuropathy.
Symptoms often evolve as the disorder progresses and other neurologic regions become
involved.
Syndrome diversity depends on the

relative combination of upper and
lower motor neuron involvement. In

primary lateral sclerosis (PLS) for ex-
ample, progressive spastic weakness, initially affecting the legs and

later involving the arms, speech, and
swallowing, reflects corticospinal
and corticobulbar tract involvement,
and to a lesser extent, loss of cortical
motor neurons (Case 3-3). In PLS,
there is either no evidence of lower
motor neuron involvement or, at
most, minimal evidence on EMG of
chronic denervation late in the disease. At the other extreme, spinal

muscular atrophy is characterized by
muscular weakness and atrophy due
to anterior horn cell degeneration
with preservation of corticospinal
tracts. Disorders collectively known
as the amyotrophic lateral scleroses
typically involve degeneration of
both anterior horn cells and cortico-
Case 3-3
Two sisters were each products of uncomplicated full-term gestations,
labors, and deliveries. Each attained early developmental milestones
normally. Beginning in the second year of life, each childs gait became
progressively abnormal with scissoring and a tendency to drag her toes.
Wheelchairs became necessary at ages 10 and 7, respectively. At
approximately these ages, each patient began to experience insidiously
progressive, upper extremity spasticity, weakness, and decreased dexterity
along with dysarthria and dysphagia (which later required supplemental
feedings via gastrostomy tubes). Intelligence was preserved, and they
were able to attend school, manipulate controls on motorized
wheelchairs, and type on communicative keyboards. Ultimately, however,
upper extremity involvement prevented any functional use of the hands
and arms.
Both sisters were examined annually for more than 10 years. Recent
examination of the younger (age 20) and older (age 22) sister showed that
they were alert, attentive, able to follow simple commands, but unable to
speak. Each patient had weakness of facial muscles, limited tongue
movements, brisk jaw jerk, and drooling. Slowing of downward saccadic
eye movements was noted. They had marked spasticity of upper and
lower extremities, generalized hyperreflexia, and extensor plantar
responses. There was no muscle atrophy or fasciculation. Light touch,
pinprick, and vibratory sensations were normal. MRI scans of the brain
and spinal cord, EMG, and nerve conduction studies were normal.
Neuro-localization. Deficits on examination were referable to
corticospinal tracts serving all extremities; corticobulbar tracts serving the
face, speech, and swallowing; and to a limited extent, supranuclear
control of downward eye movements.
Diagnosis. Juvenile, familial PLS (also referred to as infantile
ascending spastic paraplegia).
Comment. For most individuals, PLS occurs as an apparently sporadic,
adult-onset disorder (Yang et al, 2001). Rarely, PLS begins in early
childhood and occurs in families, where it appears to be an autosomal
recessive disorder. Yang and colleagues (2001) identified mutations in the
ALSin gene in subjects with autosomal recessive, juvenile PLS. Depending
on the precise location of the ALSin gene mutation, subjects exhibit either
a phenotype of pure upper motor neuron impairment (PLS phenotype) or
also manifest lower motor neuron disturbance (consistent with juvenileonset, autosomal recessive ALS phenotype). Like the patients described
above, the family described by Yang and colleagues (2001) also had
supranuclear gaze disturbance.
KEY POINT:
In primary lateral
sclerosis, there is
either no
evidence of lower
motor neuron
involvement or at
most, minimal
evidence on EMG
of chronic
denervation late
in the disease. At
the other
extreme, spinal
muscular atrophy
is characterized
by muscular
weakness and
atrophy due to
anterior horn cell
degeneration
with preservation
of corticospinal
tracts.
63
KEY POINTS:
64
Childhood-onset
adrenoleukodystrophy (ALD)
and adolescentand adult-onset
adrenomyeloneuropathy
(AMN) are Xlinked disorders
in which ABCD1
gene mutation
leads to impaired
peroxisomal oxidation and
accumulation of
very long chain
fatty acids
systemically.
ALD/AMN
phenotypes
include rapidly
progressive
childhood,
adolescent, and
adult cerebral
forms; slowly
progressive
myelopathic
forms
(characterized by
slowly
progressive
spastic
paraparesis and
peripheral
neuropathy,
often with
complete
sparing of the
brain); and
isolated adrenal
insufficiency.
spinal tracts, and to a lesser degree,

loss of cortical motor neurons.
The syndromic classification motor neuron disorder and the pathologic classification distal axonopathy
overlap. The primary differences are the
degree to which anterior horn cells are
lost (eg, a major aspect of spinal muscular atrophy) and the degree of sensory
(eg, dorsal column) involvement (a finding common in hereditary spastic paraplegia but absent in PLS and ALS).
Leukodystrophy
Leukodystrophies have variable presentations, including cognitive disturbance, signs of progressive corticospinal tract deficits (spasticity, slowness
of movements, loss of dexterity, hyperreflexia, extensor plantar responses, Hoffman and Tromner signs).
The complete constellation of insidiously progressive cognitive impairment, spasticity, optic neuropathy,
and demyelinating peripheral neuropathy is very suggestive of leukodystrophy (Case 3-4). Often, however, all
elements of this constellation may not
be present. In particular, demyelinating peripheral neuropathy, which typically accompanies childhood-onset
leukodystrophies (eg, Krabbe disease
and metachromatic leukodystrophy)
may be absent in the rare adolescentand adult-onset forms of these disorders.
Distal Axonopathy
Distal axonopathies involving the spinal cord may be entirely motor (eg,
PLS) or involve both long motor (corticospinal) and sensory (dorsal column) fibers (eg, uncomplicated hereditary spastic paraplegia) (Case 3-5).
Distinguishing between leukodystrophies and axonopathies at the bedside is important to arrive at a differential diagnosis. Signs of corticospinal
tract impairment (spastic weakness,
hyperreflexia, extensor plantar responses, Hoffman and Tromner signs)
are typical of both leukodystrophies
and axonopathies. Clinical distinction

of leukodystrophies from axonopathies is based on the presence of additional neurologic findings, particularly
sensory
disturbance.
For
example, patients with generalized
leukodystrophies (those affecting myelin of both the central and peripheral
nervous systems) classically (although
not always) also have peripheral neuropathy, which may manifest as stocking distribution of hypesthesia, and, in
the context of corticospinal tract deficits, a gradient of deep tendon reflexes, with grade 3 patellar and 1
ankle reflexes. On the other hand, sensory impairment in motor-sensory axonopathies (eg, hereditary spastic paraplegia) is limited typically to mild dorsal
column impairment affecting longer fibers (fasciculus gracilis) predominantly
and manifests as impaired vibration perception in the toes with preservation of
other sensory modalities.
The hereditary spastic paraplegias
(HSPs) are a group of more than 35
disorders in which the primary clinical
feature is progressive lower extremity
spastic weakness (Table 3-2) (Fink,
2007a; Fink, 2007b). This is often accompanied by subtle decrease in vibration perception in the toes. Generalizing
from the limited postmortem material
available, at least several genetic forms
of HSP involve axon degeneration that
is maximal in the distal aspects of the
longest motor (corticospinal tracts) and
sensory (fasciculus gracilis) fibers in the
CNS. Degeneration is maximal at the
ends of these fibers: corticospinal tract
degeneration is maximal in the thoracic
region, and fasciculus gracilis fiber degeneration is maximal in the cervicalmedullary region. In addition to degeneration of long axons in the CNS, axonal
degeneration in peripheral motor and
sensory fibers is recognized in an increasing number of types of HSP. Such
complicated HSP syndromes include
distal wasting in addition to spasticity,
hyperreflexia, and upper motor neuron
pattern of weakness. Distal motor-sensory axonopathy of the CNS (eg, uncomplicated HSP) can be considered
analogous to Charcot-Marie-Tooth type
KEY POINT:
Case 3-4
A 35-year-old man, now severely disabled by progressive neurologic

disease, was the product of full-term, uncomplicated labor, gestation, and
delivery. Developmental milestones were normal, although he did not
walk independently until 16 months of age. He excelled in academic and
athletic activities throughout high school and college. A testicular mass
noted at age 23 was diagnosed as malignant with spread to local lymph
node and required orchiectomy and chemotherapy. He became seriously
ill following chemotherapy and was discovered to have adrenal
insufficiency (age 23), which required replacement therapy. At
approximately this time he began noting numbness in his feet and ankles
while playing tennis. These symptoms increased and within a year became
associated with stumbling and tripping. At approximately age 24 he
began to experience slowly progressive memory disturbance as well as
behavioral symptoms that became increasingly severe, including extreme
anxiety, depression, self-injurious behavior, and drug use. He also began
experiencing both progressive hearing impairment (beginning at
approximately age 29) and progressive visual impairment (progressive
optic atrophy, first noted at age 30). Gait disturbance increased slowly,
and he required a wheelchair by age 30. Intermittent generalized tonicclonic seizures began at age 33 and included an episode of status
epilepticus. Neurologic examination at age 32 showed him to be alert,
slightly disoriented, with normal speech, and able to follow two-step
commands. He had short-term memory impairment, slightly decreased
visual acuity, significantly impaired hearing, markedly increased muscle
tone, and moderate to marked weakness in the lower extremities.
Symmetric, generalized hyperreflexia was present. Sensation was impaired
in the lower extremities, with decreased vibration perception below the
knees. He was able to stand briefly. By age 35 he was aphonic and
required jejunostomy feeding. Although awake, he was only minimally
responsive to social interaction. He had generalized severe spasticity and
very few and very slow spontaneous movements. There was no family
history of similar disorder.
Neuro-localization. Neurologic deficits involved corticospinal tracts
(symmetric, four-limb spastic weakness with hyperreflexia); peripheral
nerve (reduced pinprick and vibratory sensation in the lower extremities);
optic and acoustic nerves (optic neuropathy and deafness); and frontal
lobes (dementia and behavioral disturbance).
Diagnosis. Adrenomyeloneuropathy (AMN) was diagnosed by elevated
serum very long chain fatty acids.
Comment. This patients clinical course illustrates aspects common to
many leukodystrophies: spasticity, peripheral neuropathy, optic atrophy,
behavioral and cognitive disturbance, and late-onset seizures.
Childhood-onset adrenoleukodystrophy (ALD) and adolescent- and
adult-onset AMN are X-linked disorders in which ABCD1 gene mutation
leads to impaired peroxisomal -oxidation and accumulation of very long
chain fatty acids systemically (Moser et al, 2007). ALD/AMN phenotypes
include rapidly progressive childhood, adolescent, and adult cerebral
forms; slowly progressive myelopathic forms (characterized by slowly
progressive spastic paraparesis and peripheral neuropathy, often with
complete sparing of the brain); and isolated adrenal insufficiency. The
patient described above has confluent leukodystrophy in brain MRI and
conforms to the adult-onset cerebral form of ALD/AMN.
Demyelinating
peripheral
neuropathy,
which typically
accompanies
childhood-onset
leukodystrophies
(eg, Krabbe
disease and
metachromatic
leukodystrophy)
may be absent
in the rare,
adolescent- and
adult-onset
forms of these
disorders.
65
KEY POINTS:
66
SPG3A/atlastin
gene mutation is
the most
common cause
of childhoodonset, autosomal
dominant
hereditary spastic
paraplegia.
Clinical
distinction of
leukodystrophies
from
axonopathies is
based on the
presence of
additional
neurologic
findings,
particularly
sensory
disturbance.
Patients with
generalized
leukodystrophies
classically
(although not
always) also have
demyelinating
peripheral
neuropathy.
Sensory
impairment in
motor-sensory
axonopathies (eg,
hereditary spastic
paraplegia) is
limited typically
to mild dorsal
column
impairment
affecting longer
fibers (fasciculus
gracilis)
predominantly,
and manifest as
impaired
vibration
perception in the
toes with
preservation of
other sensory
modalities.
Case 3-5
A 34-year-old woman had infantile-onset, nonprogressive spastic gait, the
appearance of which was consistent with spastic diplegic cerebral palsy. At
age 26 she had a son who also had infantile-onset, nonprogressive spastic
gait. They were diagnosed as having familial cerebral palsy. Each
subject was the product of full-term, uncomplicated gestation, labor, and
delivery. Examination revealed brisk lower limb tendon reflexes, clonus,
waddling gait, normal bulbar and upper limb function, bowel and urinary
control, and normal intelligence. Diagnostic evaluations, including CT scan
of the brain and routine laboratory studies, were normal for both the
mother and child.
Localization. Neurologic deficits were referable to corticospinal tracts
serving bilateral lower extremities.
Diagnosis: A diagnosis of autosomal dominant, uncomplicated, earlyonset HSP was made on the basis of neurologic findings and family
history, and confirmed by identification of SPG3A/atlastin gene mutation
in both affected subjects (Rainier et al, 2006).
Comment. SPG3A/atlastin gene mutation is the most common cause of
childhood-onset, autosomal dominant hereditary spastic paraplegia. As in
this example, when HSP symptoms begin in infancy, they may not worsen
significantly even over the course of several decades. With the exclusion
of mistaken paternity (data not shown) (Rainier et al, 2006), the absence
of this mutation in the probands parents indicates that the mutation
arose de novo in the proband. This is an example of a subject with the
syndrome of spastic diplegic cerebral palsy actually representing de novo
mutation in a gene for autosomal dominant hereditary spastic paraplegia.
TABLE 3-2
Summary of Hereditary Spastic Paraplegia
Genetics
More than 35 different genetic types: dominant, recessive, and X-linked forms. SPG4
HSP (due to spastin gene mutation) is the most common type of autosomal dominant
HSP. SPG3A HSP (due to atlastin gene mutation) is the most common type of
childhood-onset, autosomal dominant HSP. Genetic penetrance for autosomal
dominant HSP is age-dependent and high (85% for SPG4) but often incomplete.
Clinical Variability
Variability between and within different genetic types. Individuals with severe and
mild forms may coexist in the same family.
Uncomplicated and Complicated Hereditary Spastic Paraplegia

Uncomplicated HSP: gait disturbance due to lower extremity spastic weakness;
subtle vibration impairment in the toes; urinary urgency. Complicated HSP:
symptoms and signs of uncomplicated HSP plus additional systemic or neurologic
involvement (such as muscle wasting, peripheral neuropathy, cataracts, ataxia,
mental retardation).
Increasingly, additional neurologic involvement is shown for types of HSP long
considered to be uncomplicated (eg, SPG3A and SPG4 due to atlastin and spastin
gene mutation, respectively). These include lower motor neuron involvement in
SPG3A (atlastin mutation) subjects, and cognitive disturbance and dementia in SPG4
(spastin mutation subjects).
KEY POINTS:
TABLE 3-2
Distal motorsensory
axonopathy of
the CNS (eg,
uncomplicated
hereditary spastic
paraplegia) can
be considered
analogous to
Charcot-MarieTooth type 2
disease, in which
distal motorsensory
axonopathy is
limited to the
peripheral
nervous system.
Clinically
available genetic
testing can
diagnose
approximately
65% of
dominantly
inherited
hereditary spastic
paraplegia and
two forms of
X-linked
hereditary spastic
paraplegia (due
to mutations in
proteolipid
protein and L1
cell adhesion
molecule genes).
SPG4/spastin
mutations are
the most
common cause
of dominantly
inherited
hereditary
spastic
paraplegia.
Neuropathology
Axon degeneration maximally affecting the distal ends of the longest CNS motor
(corticospinal tracts) and sensory (fasciculus gracilis) fibers. Complicated HSP types
have additional, syndrome-specific neuropathology.
Molecular Basis
Several different molecular processes underlie various forms of HSP. These include
disturbance in microtubule dynamics (eg, SPG4/spastin), axonal transport (eg, SPG10/
KIF5A), mitochondria (eg, SPG7/paraplegin, SPG13/chaperonin 60, and SPG31/REEP1,
which are mitochondrial proteins), corticospinal tract development (SPG1/L1CAM),
and myelination (SPG2/proteolipid protein).
Treatment
Exercise, gait and balance training, spasticity-reducing medications (eg, oral or
intrathecal baclofen), ankle-foot orthotic devices, medication to reduce urinary
urgency (eg, oxybutynin).
Exercise recommendations (to improve balance, strength, aerobic capacity, and
endurance, and reduce spasticity) are based largely on anecdotal reports by subjects
with HSP who have reported benefit.
Prognosis
Infantile-onset HSP often shows little worsening for the first 2 decades. Childhood- and
later-onset HSP typically worsen insidiously over years and decades. Assistive devices
(including wheelchairs) may be needed. Uncomplicated HSP does not involve upper
extremity, speech, bulbar, or respiratory muscles or shorten life expectancy. In view of
the clinical variability noted above, a cautious wait-and-see prognosis is advised, rather
than assuming that the disorder will be uniformly severe within a given family.
Diagnosis and Genetic Testing

Diagnostic criteria include signs and symptoms of HSP; exclusion of other disorders;
family history is important but may be absent (eg, recessive HSP, new mutation,
nonpaternity). Genetic testing of four genes for dominantly inherited HSP is available
(through Athena Diagnostics Laboratory, Boston) that together can diagnose 65%
of dominantly inherited HSP.
Differential Diagnosis
Structural disorders affecting brain or spinal cord; spinal cord arteriovenous
malformation; leukodystrophies (including vitamin B12, adrenomyeloneuropathy,
Krabbe disease, metachromatic leukodystrophy, multiple sclerosis), dopa-responsive
dystonia, ALS, primary lateral sclerosis, and human T-cell lymphotropic virus type 1.
HSP hereditary spastic paraplegia.

Modified with permission from Fink JK. The hereditary spastic paraplegias. In: Rosenberg, DiMauro S, Paulson HL,
et al, editors. Molecular and genetic basis of neurologic and psychiatric disease. 4th ed. Philadelphia: Lippincott
William & Wilkins, 2007. Copyright 2007, Lippincott Williams & Wilkins.
2 disease, in which distal motor-sensory

axonopathy is limited to the peripheral
nervous system.
It is not uncommon for HSP gene
testing to reveal a mutation of unknown significance (Cases 3-6 and
3-7). This happens frequently because
many HSP gene mutations are private, being uniquely present in the
family in which they are discovered.
This is particularly common for SPG4/
spastin mutations, which are the most
common cause of dominantly inherited HSP.

CONCLUSION
The clinical and genetic diversity of
hereditary myelopathies limits useful
generalizations. Nonetheless, it is notable that in the patients described
above (with MJD/SCA3, X-linked HSP
due to SPG1/PLP mutation, dominantly inherited HSP due to SPG3A/
67
KEY POINT:
Proteolipid protein
gene mutations
cause both the
X-linked
dysmyelinating
disorder PelizaeusMerzbacher
disease, and Xlinked hereditary
spastic paraplegia
(SPG2 HSP).
atlastin and SPG6/NIPA1, AMN, Friedreich ataxia, and juvenile PLS), spastic
gait disturbance was an early and
prominent symptom. (It was the first
symptom in each patient except the
subject with AMN, for whom lower
extremity paresthesiae preceded gait
disturbance.) Identifying associated
features (eg, subtle dorsal column
signs in HSP, marked dorsal column
impairment in Friedreich ataxia, peripheral neuropathy in AMN) is essential to clinical recognition of these disorders.
ACKNOWLEDGMENTS
Additional Contributions: The patient in Case 3-1 was evaluated with
James Burke, MD, and Talia Siman-Tov,
MD, Department of Neurology, University of Michigan; the patient in Case 3-2
was evaluated and synopsis prepared
with Simon Fishman, MD, Alexandria,
VA. Genetic analysis of the patient in
Case 3-7 was performed by Grace M.
Hobson, PhD, Molecular Diagnostics
Laboratory, AI duPont Hospital for Children, DE; genetic analysis of the patients
Case 3-6
A 25-year-old man has been followed because of a family history of gait disturbance. He was the
product of uncomplicated gestation, labor, and delivery to nonconsanguineous parents. Family
history (Figure 3-2) was consistent with transmission of a highly penetrant, autosomal dominant
FIGURE 3-2
Autosomal dominant hereditary spastic paraplegia due to NIPA1 gene mutation.
Reprinted with permission from Rainier S, Chai JH, Tokarz D, et al. NIPA1 gene mutations cause autosomal dominant hereditary
spastic paraplegia (SPG6). Am J Hum Genet 2003;73(4):967971. Copyright 2003, Elsevier.
68
disorder characterized by insidiously progressive gait disturbance. When first examined at age
17, he was asymptomatic, and even though his gait was normal, he had mildly hyperactive lower
extremity deep tendon reflexes. Beginning at age 20, he began to experience insidiously
progressive gait disturbance. Reexamination at age 25 revealed marked gait abnormality with
anteriorly shifted heel strike, difficulty lifting the legs, and circumduction; lower extremity
spasticity, weakness, hyperreflexia, extensor plantar responses, and mild decrease in vibration
perception in the toes.
Deficits on examination were referable to corticospinal tracts serving bilateral lower
extremities and, to a lesser extent, dorsal column (fasciculus gracilis) fibers.
Diagnosis. Autosomal dominant HSP. Genetic analysis revealed mutation in the SPG6/NIPA1
gene (Rainier et al, 2003).
Comment. HSP gene testing is most useful to confirm a clinical diagnosis of HSP and should be
interpreted in the context of clinical findings. When an HSP gene mutation is identified in a
subject with typical features of HSP, this information can be used for predictive genetic
counseling. Genetic testing is available clinically that can diagnose approximately 65% of
dominantly inherited HSP and two forms of X-linked HSP (due to mutations in proteolipid
protein and L1 cell adhesion molecule genes).
Case 3-7
A 35-year-old man was evaluated because of difficulty walking. He was the product of full-term
uncomplicated gestation, labor, and delivery. Walking was slightly delayed (15 months) and
associated with mild turning in of the right foot, for which he wore corrective leg braces at
night. Despite a slightly awkward gait during childhood, he was active and played sports until
age 14. At approximately that time he began to notice very slowly progressive gait disturbance.
Examination at age 14 showed pes cavus with hammer toe deformity, lower extremity spastic
weakness, lower extremity hyperreflexia, extensor plantar responses, and spastic gait. Nerve
conduction testing and EMG were normal. Gait disturbance worsened slowly, necessitating a
cane by age 34. His symptoms were confined to lower extremity spastic weakness and gait
disturbance and occasional difficulty initiating urination. There was no involvement in the upper
extremities and no reported sensory disturbance.
Family history was significant for five similarly affected male relatives (Figure 3-3): three
brothers of the patients maternal
grandmother and two sons of
unaffected sisters of the patients
maternal grandmother.
Deficits on examination are referable
to corticospinal tracts serving bilateral
lower extremities.
Diagnosis. X-linked hereditary spastic
paraplegia due to mutation in the
proteolipid protein gene (SPG2 mutation
T673C).
Comment. Proteolipid protein (PLP) is
an intrinsic myelin protein involved in
myelin compaction. PLP gene mutations
cause both X-linked dysmyelinating
disorder Pelizaeus-Merzbacher disease
and X-linked HSP (SPG2 HSP). Some
X-linked spastic paraplegia due to PLP
FIGURE 3-3
mouse models of PLP missense mutation
gene mutation.
exhibit progressive axonal degeneration
rather than dysmyelination (Garbern et
al, 2002). This illustrates the important concept that axonal degeneration may arise not only
because of primary abnormalities within axons, but also as the consequence of primary glial
abnormality (oligodendroglia in this case). It is also noteworthy that the particular mutation
identified in this subject (PLP T673C) has also been reported in subjects with the severe, earlyonset leukodystrophy phenotype. The presumed genetic modifying factors that influence
marked phenotype variability that may be associated with PLP gene mutations have not been
identified.
in Cases 3-5 and 3-6 was performed by

Shirley Rainier, PhD, Department of
Neurology, University of Michigan.
I am grateful for the assistance of
patients and their families without
whom this work would not be possi-
ble. This research is supported by

grants from the National Institutes of
Health (R01NS053917), the Department of Veterans Affairs (Merit Review
Awards), and the Spastic Paraplegia
Foundation.
69
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VASCULAR
MYELOPATHIES
David S. Geldmacher, Lubdha Shah
ABSTRACT
Spinal cord vascular disease is rare but can be devastating to patients. Hypotension,
especially in association with vascular procedures, and embolism are common
causes of cord ischemia. Ischemia generally presents with acute painful myelopathy.
The enclosed space of the spinal canal also renders the cord vulnerable to compressive effects of space-occupying vascular lesions, such as the dilated veins associated
with vascular malformations. These are more likely to present with progressive
myelopathy. MRI is the imaging modality of choice in identifying the cause and
extent of vascular myelopathy. Interventional endovascular approaches to spinal
vascular malformations are becoming more common.
INTRODUCTION
Spinal vascular diseases can be grouped
into three main categories: (1) ischemic,
(2) hemorrhagic, and (3) developmental.
Developmental lesions are typically malformations and can lead to neurologic
signs and symptoms through either of the
other two mechanisms or via mass effect.
Each of these categories will be addressed
separately in this chapter. Many other
causes of spinal cord dysfunction, such as
tumor or traumatic compression, also operate through the vascular mechanism of
microcirculatory compromise (Tator and
Koyanagi, 1997). Those illnesses will be
addressed elsewhere in this issue.
VASCULAR ANATOMY OF THE
SPINAL CORD
An understanding of the peculiarities
of spinal vascular anatomy is necessary for approaching patients with potential cord dysfunction of vascular origin. Elements of the vascular anatomy
particularly pertinent for clinical or imaging decision making will therefore

be reviewed (Figure 4-1). The seminal paper by Gillilan (1958) can provide additional detail.
Extramedullary Arteries
In the human embryo, arterial supply
to the spinal cord is provided by radicular vessels that enter at each spinal
level and divide to follow the dorsal
and ventral roots. A single midline anterior spinal artery arises from the anastomoses of these ventral branches. During
development, five to eight anterior radicular arteries become dominant and
provide most of the flow to the anterior two-thirds of spinal cord through a
midline anterior spinal artery. These
feeding vessels are variably known as
radicular, medullary, or radiculomedullary arteries, terms that may be used
interchangeably in the literature. In
most individuals, one of these anterior
Relationship Disclosure: Dr Geldmacher has received personal compensation for activities with Eisai Inc./
Pfizer Inc, Forest Pharmaceuticals, Inc., Medical Care Corporation, Novartis Pharmaceuticals, Inc., and
Takeda Pharmaceuticals, Inc. Dr Geldmacher has received grant or research support from Eisai Inc., Elan
Pharmaceuticals, Inc., Myriad Pharmaceuticals, Inc., and GlaxoSmithKline. Dr Shah has nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Geldmacher and Shah have nothing to
disclose.
71
VASCULAR MYELOPATHIES
smaller radicular branches feed longitudinal anastomoses along the posterolateral aspect of the cord, mesial to
the dorsal nerve roots. These confluences form paired posterior spinal arteries. Much smaller vessels (arteria
vasocorona) provide circumferential
connections between the anterior and
posterior arterial systems, forming a
limited collateral network.
In contrast to the few arteries supplying the lower thoracic and upper
lumbar cord, the cervical and upper
thoracic spinal cord is richly vascularized by a plexus arising from branches
of the ascending cervical and vertebral
arteries. The sacral cord, conus medullaris, and cauda equina are also
highly collateralized, being supplied
by multiple small lower segmental radicular arteries.
Key aspects of segmental spinal vascular
anatomy. The midline anterior spinal artery
is formed from anastomoses between
segmental radicular arteries. The posterior spinal arteries
are paired and smaller. They are also supplied by
segmental arteries.
FIGURE 4-1
A artery; As arteries.
Modified from Lamin S, Bhattacharya JJ. Vascular anatomy of the spinal
cord and cord ischaemia. Pract Neurol 2003;3:9295. With permission
from BMJ Publishing Group.
72
vessels becomes notably larger and

provides a major portion of the blood
flow to anterior portions of the lower
thoracic cord and the lumbar enlargement. This vessel is properly referred
to as the arteria radicularis magna. It
is more commonly known as the great
artery of Adamkiewicz, although as
many as 25% of individuals will demonstrate more than one enlarged feeding artery on angiography (Takase et
al, 2002). In about 90% of individuals,
the arteria radicularis magna arises
from a segmental artery from between
the T8 and L3 levels, more commonly
(60% to 70%) arising from the left side
(Nojiria et al, 2007; Takase et al, 2002).
In general, a larger number of
Intramedullary Arteries
The main blood supply to spinal gray
matter, the anterior columns, and most
of the lateral funiculi is provided by
anterior sulcal arteries. These arise
perpendicularly from the anterior spinal artery and pass posteriorly into the
cord along the ventral median fissure.
Each anterior sulcal artery typically
supplies only one-half (left or right) of
the spinal cord. Sulcal arteries are
closer together in the cervical and lumbar regions than in the thoracic segments, maintaining an arterial supply
proportional to the numbers of neuronal cell bodies at that level. The dorsal
columns and extreme dorsal horns are
supplied by penetrating branches
from the posterior spinal arteries. The
superficial white matter, particularly of
the lateral funiculi, receives blood
flow via the circumflex anastomotic
vessels. As a result of this distribution
pattern, there is a clinically relevant perfusion border zone between the territories of the sulcal and circumferential arterial distributions. As a result, not all
spinal cord infarctions follow the traditionally taught boundaries between an-
terior and posterior arterial distributions

(Ishizawa et al, 2005).
cord disease processes such as embolism and metastasis.
Venous Drainage
The intradural venous drainage of the
spinal cord generally parallels the arterial supply but is more variable in
expression. In contrast to the lateralized arterial supply, deep parenchymal segmental veins drain both right
and left sides of the cord, emptying
into central sulcal veins in the median
fissure. Small radial veins flow outward to the surface of the cord, ending
in a coronal plexus. Intersegmental
anastomoses are more frequently seen
between sulcal veins than arteries. The
anterior median spinal vein lies external to its corresponding artery and fills
from these segmental sulcal veins. The
median spinal vein is often more irregular than the corresponding artery and
is often more plexiform at some levels.
Posteriorly, there is usually a dominant
midline posterior spinal vein without a
corresponding artery. Posterolateral
veins may parallel segments of the
posterior spinal arteries. Eight to 12
larger anterior radiculomedullary
veins arise from the anterior median
spinal vein. They are joined by anterolateral anastomoses from the coronal
venous plexus at the nerve roots before passing through the dura. Typically a large vein drains the levels of
the lumbar enlargement (vena radicularis magna). Posterior radicular veins
are most prominent in the cervical region but are often present at other
levels. After passing through the dura
in the radicular veins, blood from the
entire cord runs into the epidural and
paravertebral venous plexuses, forming a large, valveless system from sacrum to occiput known as the craniospinal venous system or Batson plexus
(Pearce, 2006). The absence of valves
to resist retrograde flow in this continuous venous network, during Valsalva
maneuver for instance, may be a factor
in the pathogenesis of some spinal
SPINAL CORD ISCHEMIA

The absolute prevalence of spinal cord
infarction is unknown. Estimates from
autopsy series suggest that about 1%
to 2% of all central neurovascular events
affect the cord and 5% to 8% of all acute
myelopathies are associated with ischemia (Sandson and Friedman, 1989).
Presentation and Initial Course
The course of spinal ischemic syndromes is variable. In most cases, sensory featuresparticularly pain
emerge first, followed by weakness
within minutes or hours. The pain often follows a radicular pattern, although it may have a more visceral
character that can be mistaken for angina. Intervals of many hours from the
onset of pain to evolution of weakness
can occur and complicate diagnosis.
Maximum weakness is observed
within 12 hours of onset in a majority
of patients, with a trend toward longer
intervals in cases with less severe peak
deficits. Urinary retention is typical in
the acute phase, but involuntary voiding
or defecation may be associated with
the onset of the ischemic insult. The
lower thoracic and lumbar spinal levels
are most commonly affected, rather than
the midthoracic levels predicted by the
vascular anatomy. Lower cervical lesions are less common, and upper thoracic spinal infarcts are rare. Therefore,
quadriparesis is present in only 20% to
25% of most series of spinal infarction.
In one prospective series, weakness (100%), sensory loss (89%), back
pain at onset (82%), and urinary complaints requiring catheterization (75%)
were the most common symptoms of
cord ischemia at the time of presentation (Masson et al, 2004). Retrospective series demonstrate the same major
symptoms but with some differences
in the frequency of the specific complaints (Cheshire et al, 1996;
KEY POINT:
Pain is a
common
presentation of
spinal cord
ischemia.
73
Nedeltchev et al, 2004). Spinal cord
syndromes associated with ischemia
are shown in Table 4-1.
Examination Findings
Flaccid paresis affecting both legs,
along with diminished superficial and
tendon reflexes below the level of the
lesion, is the most common examination finding at the time of presentation. Preservation of strength and reflexes is rare and suggests posterior
spinal artery territory ischemia when
present. Lateralized findings are unusual in the acute phase but may
evolve. Sensory changes nearly always
affect spinothalamic modalities when
present, and proprioception loss often
accompanies them acutely. Isolated
proprioceptive loss is rare. Acute bladder distension is typical but may not
be noticed by the patient because of
sensory failure. Rectal tone is usually
diminished in the acute setting.
Investigations
MRI is the imaging procedure of
choice for detecting spinal cord isch-
TABLE 4-1
74
emia (Figure 4-2). The time course of

evolution and sequence-specific patterns of signal change are similar to
those for cerebral infarction (Rovira et
al, 1998; Weidauer et al, 2002). Sagittal
T2-weighted images appear most sensitive for detecting acute ischemic
change, which has a pencillike
shape and hyperintense appearance
visible as soon as 2 hours after onset of
symptoms (Weidauer et al, 2002). Axial images can have sufficient resolution to distinguish infarctions in the territory of a single sulcal artery. Diffusionweighted imaging has the potential to
be a useful and feasible technique for
the detection of spinal infarction (Thurnher and Bammer, 2006).
Other laboratory and radiographic
studies are usually not diagnostic in
spontaneous spinal cord ischemia.
CSF protein is elevated in up to half of
patients, but pleocytosis is rare (Novy
et al, 2006). The exact cause of spinal
ischemia often remains occult. Specific
causes could not be discerned in more
than half of prospectively observed
Clinical Features Associated With the Stroke

Syndromes
Stroke Syndrome
Feature
Anterior spinal artery infarct
Bilateral motor deficit with spinothalamic

sensory deficit
Anterior unilateral infarct
Hemiparesis with contralateral

spinothalamic sensory deficit
Posterior unilateral infarct
Hemiparesis with homolateral lemniscal

sensory deficit
Central infarct
Bilateral spinothalamic sensory deficit

without motor deficit
Posterior spinal artery

infarct
Bilateral motor deficit with lemniscal

sensory deficit
Transverse infarct
Bilateral motor deficit with complete

sensory deficit
Modified with permission from Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical
and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006;63(8):11131120.
Copyright 2006, American Medical Association. All rights reserved.
cases (Masson et al, 2004) and nearly

three-fourths of a carefully assessed retrospective sample (Novy et al, 2006).
Prognosis
In one prospectively collected series,
approximately half of patients regained the ability to walk with no
more than one assistive device and did
not require urinary catheterization
(Masson et al, 2004). Likelihood of recovery is higher when the maximum
deficits are less severe. In another
study, more than 90% of patients
whose acute deficits were classified at
the mildest level were able to walk
independently or with an assistive device within 4 years; among those with
more severe acute dysfunction, nearly
one-third required a wheelchair
(Nedeltchev et al, 2004). Poor outcome is predicted when proprioceptive loss, gait impairment, or urinary
dysfunction is present at the time of
presentation. The duration of motor
dysfunction is useful in determining
prognosis. Unless significant motor recovery occurs in the first 24 hours, the
likelihood of major improvement is low.
Pain is a major contributor to longterm disability in spinal cord vascular
syndromes but tends to occur only in
individuals with spinothalamic sensory impairment early in the course
(Pelser and van Gijn, 1993).
Causes
Physical activity was the most common acute precipitant of acute spinal
cord infarction in one recent series
(Novy et al, 2006). This link was especially strong in the context of mechanical spinal disease at the same level,
which may increase the risk for occlusion or traumatic injury of the local
radicular artery.
Another common precipitant of
spinal ischemia is local vascular manipulation through open surgical or
less invasive methods. In older series,
open manipulation was among the
most common causes of cord ischemia

(Cheshire et al, 1996), but more modern endovascular approaches also
carry significant risk. Prolonged
clamping of the aorta above the renal
arteries (eg, for more than 20 to 30
minutes) places the cord at risk for
ischemia and infarction. Open thoracoabdominal aortic aneurysm repairs
are therefore associated with a 5% to
20% risk of significant neurologic deficits. Operative ligation of lower thoracic
or lumbar segmental vessels further increases risk. Although endovascular aneurysmal repair techniques appear
safer than open surgery, they do not
eliminate risks for spinal cord ischemia. Other evidence suggests that intraoperative interventions, such as distal aortic perfusion and CSF drainage,
may lower complication rates for aortic surgery (Estrera et al, 2001). Intraoperative monitoring of somatosensory
evoked potentials also may reduce risk
for permanent injury (Cheung et al,
2005). See Case 4-1.
KEY POINTS:
More severe
neurologic
deficits at
presentation are
associated with
worse outcome.
Exercise is the
most common
precipitant of
spontaneous
acute cord
ischemia.
Vascular
manipulation,
endovascular or
open, is a
frequent cause
of cord
ischemia.
75
MRI in acute spinal cord infarction. A,

Sagittal T2-weighted sequence of the lower
thoracic spine demonstrates patchy T2
hyperintensity in the distal cord substance. No evidence of
cord expansion is present, and no abnormal flow voids are
seen. B, Axial T2-weighted sequence of the lower thoracic
spine demonstrates patchy T2 hyperintensity and mild cord
expansion. C, Sagittal T1-weighted sequence with
gadolinium enhancement shows patchy areas of
enhancement in a patient with acute spinal cord ischemia.
Arrows indicate areas of signal abnormality.
FIGURE 4-2
KEY POINT:
76
Risks for
procedurerelated cord
ischemia may be
ameliorated by
intraoperative
somatosensory
evoked potential
monitoring,
maintenance of
adequate blood
pressure (mean
arterial pressure
of 90 or
greater), and
lumbar CSF
drainage.
Case 4-1
A 75-year-old man reported bilateral leg weakness on postoperative day 1
after endovascular repair of an aneurysm involving the thoracic aorta with
grafting and stent placement. He denied numbness, paresthesiae, and
pain. Urinary function could not be assessed as he had an indwelling
urinary catheter. He had experienced no bowel movements or stool
incontinence since the procedure. No hypotension or other operative
complications were noted.
Medical history was significant for cerebral infarction 12 years earlier
with residual right-hand numbness, hyperlipidemia, hypertension,
borderline diabetes, and bilateral femoral artery stenoses. He
acknowledged having two to three alcoholic drinks daily and had a 90pack-year history of cigarette smoking.
Neurologic examination revealed normal power in the upper
extremities and 4/5 weakness in the hip flexors, knee flexors/extensors,
and ankle flexors/extensors. Sensation to touch and pinprick was normal
throughout. He had diminished vibratory sense to a level above the ankle
in both legs. Muscle stretch reflexes were 2 at the left biceps and both
triceps, 3 at the right biceps, and 3 at both knees. Ankle jerks could
not be elicited. Extensor plantar reflexes were present bilaterally.
On examination 24 hours later, Beevor sign was present (ie, the
umbilicus moved cephalad on neck flexion). Lower extremity power
except hip flexors had improved, and plantar responses remained
extensor. MRI of the spine revealed patchy areas of increased T2 signal in
the anterior spinal cord between the T9 and T12 vertebrae.
Comment. Open surgery and modern endovascular approaches both
carry significant risk of spinal cord ischemia. Prolonged clamping of the
aorta above the renal arteries places the cord at risk for ischemia and
infarction. Some evidence suggests that intraoperative interventions, such
as distal aortic perfusion and CSF drainage may lower complication rates
for aortic surgery. Intraoperative monitoring of somatosensory evoked
potentials also may reduce risk for permanent injury. There is no specific
treatment for spinal cord infarctions, and care is generally supportive in
nature. Prognosis often depends on severity of initial deficits.
Systemic hypotension is another

major contributor to cord ischemia.
However, because encephalopathy is
common in these patients, the myelopathy may be missed. In one autopsy study of 145 cases of known
CNS hypoxic ischemic damage, 45% of
cases also had spinal cord damage
(Duggal and Lach, 2002). In contradiction of the traditional teaching about
the spinal thoracic watershed, damage was most prevalent in the lumbosacral levels of the cord. Furthermore,
no evident differences were present in
this pattern between patients who
have sustained cardiopulmonary arrest
and those with primary hypotension,

suggesting that lower levels of the
cord are most prone to the effects of
hypotension. Prolonged hypoxemia
also leads pathologic lesions to be distributed diffusely throughout the spinal gray matter.
Local atherosclerotic or arteriosclerotic disease may result in intermittent claudication of the spinal cord
manifested by activity-induced, transient symptoms of myelopathy (Kauppila et al, 1994). As with cerebral vascular disease, these TIAs may precede
spinal cord infarction. In general, spinal TIAs are rare. Intermittent spinal
claudication may respond positively to

aortobifemoral bypass.
Radiation therapy may produce
myelopathy in part from occlusive
changes in parenchymal spinal cord
arterioles. The degree of myelopathy
depends on the total radiation dose,
dose per fraction, and the length of the
irradiated segment of the cord.
Thromboembolism is associated
with both acute and stepwise spinal
cord dysfunction. Embolism from cardiac valves affected by rheumatic heart
disease and acute bacterial endocarditis has caused acute paraplegia. Similarly, thromboembolism from an atrial
myxoma has resulted in multiple spinal cord infarcts. Myelopathy associated with decompression sickness results from circulating nitrogen bubbles
that block small spinal arteries. Therapeutic embolizations of renal, bronchial, and abnormal dural arteries all
have been complicated by inadvertent
occlusion of spinal arteries.
Fibrocartilaginous emboli generated by traumatic rupture of intervertebral disks have caused an ischemic
syndrome in the spinal cord of a type
unrecognized in the brain. The anterior portion of the cervical cord is the
site of multiple arterial and venous microemboli from a ruptured intervertebral disk in up to 70% of such cases.
Women are affected twice as often as
men. Fragments of disk material are
traumatically forced into bone marrow
sinusoids by local fracture, and increased tissue pressure may introduce
the emboli into the spinal vertebral
plexus and arterial channels, leading
to cord infarction. Approximately onehalf of these events are purely arterial;
the rest have mixed arterial and venous involvement (Toro et al, 1994).
Primary thrombotic and vascular
events also can cause spinal cord ischemia. Meningovascular syphilis was
once a common cause of anterior spinal artery ischemic syndromes, and
paraplegia of vascular origin still occa-
sionally complicates bacterial meningitis. Systemic inflammatory conditions such as Crohn disease,
polyarteritis nodosa, and giant cell arteritis also may lead to ischemic myelopathy. Sickle cell disease, intrathecal chemical irritants, vasospastic
agents such as cocaine, angiographic
contrast material, the postpartum state,
and intravascular neoplastic invasion all
predispose to thrombosis and spinal
cord infarction. Table 4-2 summarizes
common causes of spinal ischemia.
Venous Infarction
Venous infarction without hemorrhage is clinically indistinguishable
from the arterial ischemic syndromes.
An associated systemic thrombophlebitis, which propagates into the spinal
canal via the venous plexus, may be
present. A subacute necrotizing myelitis (Foix-Alajouanine syndrome), caus-
TABLE 4-2
Causes of Spinal
Ischemic Events
Vascular Compression
Local spinal column disease
Aortic manipulation
Endovascular procedures
Hypoperfusion
Systemic hypotension
Local atherosclerotic/
arteriosclerotic lesions
Radiation therapy
Embolism
Thromboembolic disorders
Iatrogenic embolism
Fibrocartilaginous emboli
Prothrombotic disorders
Meningitis
Vasculitis
Neoplasm
77
ing stepwise spinal cord dysfunction,
may occur with extensive spinal cord
thrombophlebitis and no systemic foci
of venous inflammation, or in association with chronic obstructive pulmonary disease or a neoplasm (usually of
the lung). This condition also may be
the end-stage result of chronic venous
hypertension and congestion secondary
to dural venous fistula (Figure 4-3).
Polycythemia rubra vera may be associated with noninflammatory spinal venous thrombosis that results in cord
ischemia. More recently, surgical procedures that increase thoracic venous
pressure, such as ligation of esophageal
varices, have been recognized as causes
of spinal venous infarction.
Treatment
No specific treatment is available for
spinal cord infarctions, and care is
generally supportive in nature. Management also should focus on reducing risk for recurrence. This includes
maintenance of adequate blood pres-
sure, early bed rest, and reversal of

proximate causes, such as hypovolemia
or arrhythmias. Steroids often are used
in the acute phase, but no definitive clinical trial evidence supports this. Lumbar
drainage to maintain CSF pressure at 10
mm Hg or less and blood pressure augmentation to sustain mean arterial pressure at 90 mm Hg or greater also appear
to improve the likelihood of favorable
outcome (Cheung et al, 2005). Acute
thrombolytic and antithrombotic therapies (eg, heparin) have not been systematically studied. Antiplatelet therapies are commonly employed for
spontaneous cord ischemia, but no controlled trials have been reported. At later
stages, rehabilitative care often is directed toward minimizing the excess
disability associated with autonomic
dysfunction and immobility. Although
physical and occupational therapy are
used to promote functional recovery, no
controlled trials of their efficacy in cord
ischemia have been reported.
SPINAL HEMORRHAGE
Spinal cord dysfunction may arise from
hemorrhage into the subarachnoid, subdural, or epidural spaces (Kreppel et al,
2003). In these conditions, the onset is
usually sudden and painful. Trauma,
bleeding diatheses, and vascular malformations are common triggering factors.
Bleeding into the cord itself (hematomyelia) also is recognized.
78
Venous infarction secondary to cervical dural

arteriovenous fistula. A, Sagittal T2-weighted
sequence demonstrates abnormal T2
hyperintensity in the cervical and upper thoracic cord
parenchyma (solid arrows). The cord is mildly enlarged.
Abnormal curvilinear flow voids are seen along the anterior
aspect of the cord (dotted arrows). B, Enhanced sagittal T1weighted sequence demonstrates abnormal patchy
intramedullary enhancement in the cervical and upper
thoracic cord.
FIGURE 4-3
Subarachnoid Hemorrhage
Presentation. Spinal subarachnoid
hemorrhage (SAH) is characterized by
the sudden onset of severe back pain,
which may initially localize near the
level of the hemorrhage. Frequently,
both multiple-level radiculopathic and
myelopathic findings are present. As
blood spreads in the CSF, pain typically becomes more diffuse and signs
of meningeal irritation become
prominent. Headache, cranial neuropathies, and a decreased level of
consciousness may evolve rapidly
with diffusion of blood above the

foramen magnum. Papilledema may
be present.
Clinical investigations. Diagnosis of spinal SAH usually requires a
strong clinical suspicion. Because impaired consciousness is not unusual,
evaluation for spinal SAH frequently follows negative radiologic studies of the
intracranial structures. The CSF is often
grossly bloody, and lumbar opening
pressure is frequently elevated.
Epidemiology. Spinal SAH accounts for less than 1% of all SAHs.
The cause of spinal SAH is often unknown. The most common single
cause is spinal angioma, but these account for only approximately 10% of
the total. Coarctation of the aorta,
rupture of a spinal artery, mycotic
and other aneurysms of the spinal
artery, polyarteritis nodosa, spinal
tumors, lumbar puncture, blood dyscrasias, and therapeutic thrombolytics and anticoagulant use all have
been reported to be associated with
spinal SAH.
Treatment. Initial treatment is directed toward alleviating the local cause
of the hemorrhage, such as embolizing a
vascular malformation, and preventing
recurrence. Subsequently, supportive
and rehabilitative approaches are similar
to those employed for patients with spinal ischemic lesions.
Spinal Epidural Hemorrhage
and Subdural Hemorrhage
Presentation. Spinal epidural hemorrhage (SEH) occurs more frequently
than spinal subdural hemorrhage
(SSH), but the clinical presentation of
these syndromes is indistinguishable.
Severe back pain at the level of the
bleeding is the most common initial
symptom. Sensorimotor findings consistent with myelopathy or cauda
equina syndrome and corresponding
to the level of the lesion develop over
hours to days. SEH tends to evolve
more quickly than SSH.
Investigations. The diagnosis

should be suspected in patients undergoing therapeutic anticoagulation or
with disorders of coagulation who
have experienced recent spinal trauma
or manipulations and develop signs of
spinal cord or root dysfunction or a
change in the character of their back
pain. Patients with a rapidly decreasing platelet count or fewer than 20,000
platelets/L are at particular risk of
developing SEH or SSH with lumbar
puncture and should receive a platelet
transfusion before undergoing the
procedure. Abnormal clotting studies
or platelet count can raise the index
of suspicion for extramedullary spinal hemorrhage in a patient with
acutely evolving myelopathic signs.
In SEH and SSH, the CSF may be
normal, xanthochromic, or contain
increased protein.
MRI is the imaging modality of
choice and can delineate the relationship between the hematoma and the
dura (Figure 4-4). In patients unable
to tolerate MRI or where it is unavailable in the acute phase of the illness,
CT scanning provides an alternative
(Figure 4-5). When positive, myelography will reveal a filling defect or
complete block at the level of the lesion, but differentiation between SEH
and SSH may not be possible.
Epidemiology. SEH occurs more
commonly in males. There is a bimodal age distribution, with peaks
during childhood and the fifth and
sixth decades of life. Cervical lesions
are more common in children; thoracolumbar lesions are more frequent in
adults. Hemorrhages can be spontaneous but often occur after exertion or
trauma. Both lumbar puncture and
epidural anesthesia can be complicated by SEH. Impaired clotting due to
therapeutic anticoagulation, blood
dyscrasia, and thrombocytopenia is
the predominant risk factor for SEH.
Neoplasm, vascular malformations,
and pregnancy also increase risk.
KEY POINTS:
Lumbar
puncture is
associated with
an increased risk
for spinal
epidural or
subdural
hemorrhages in
patients with
platelet counts
lower than
20,000.
MRI and
magnetic
resonance
angiography are
the imaging
modalities of
choice for spinal
vascular disease.
79
MRI in spinal epidural hematoma. A, Sagittal

T1-weighted images demonstrate isointense
material in the epidural space,
circumferentially narrowing (arrows) the cervical and upper
thoracic thecal sac. B, Sagittal T2-weighted images
demonstrate hyperintense material in the epidural space
with similar circumferentially narrowing of the cervical and
upper thoracic thecal sac.
FIGURE 4-4
80
CT scan in spontaneous epidural hematoma.

A, Sagittal reformation of unenhanced CT
of the cervical spine demonstrates
circumferential epidural hyper-density (arrows). B, Axial
unenhanced CT of the cervical spine demonstrates
circumferential epidural hyper-density.
FIGURE 4-5
SSH occurs more commonly in

women. It may occur at any age, but risk
appears to peak in the sixth decade.
Most episodes of SSH affect the thoracic
or lumbar regions. As with SEH, hemorrhagic diatheses, including treatment
with anticoagulants, blood dyscrasias,
and thrombocytopenia, are the most
common precipitating factors seen in
patients with SSH. Other factors include
trauma, lumbar puncture, vascular malformation, and spinal surgery.
Treatment. SEH and SSH are surgical emergencies. Relief of local pressure
and repair of any underlying vascular
abnormality should be the goals of the
initial operative approach, which usually consists of laminectomy and clot
evacuation. The prognosis for recovery
is determined more by the severity of
preoperative neurologic deficits than by
timing of surgery; as might be expected,
milder initial deficits predict better overall recovery (Borm et al, 2004).
Hematomyelia
Presentation. Hemorrhage into the
cord parenchyma most commonly presents with the sudden onset of severe
back pain, which often has a radicular
character. A spinal shock picture with
total loss of cord function distal to the
lesion develops rapidly. After a highly
variable period of time, spasticity and
hyperreflexia evolve below the level of
the lesion. In more limited lesions, fasciculations, atrophy, and areflexia may
occur in the myotomes associated with
areas of gray matter loss.
Investigations. MRI is best for
characterizing the extent of hematomyelia (Figures 4-6, 4-7, and 4-8). The
hemorrhage tends to disrupt spinal gray
matter more than white matter. If the
lesion extends to the margins of the
cord, lumbar puncture will show SAH,
but confinement of the clot within the
cord boundaries is more common.
Epidemiology. Trauma is the
most common cause of intramedullary
spinal hemorrhage. It may follow pen-
etrating trauma to the spinal column or

be induced by mechanical events such
as hyperextension injuries in the cervical spine. Spontaneous hematomyelia is much less common. Rupture of
a spinal vascular malformation, hemorrhage into a spinal tumor or syrinx,
a bleeding diathesis, anticoagulant
drugs, or venous infarction are all possible causes. Unlike their roles in cerebral hemorrhage, neither hypertension nor amyloid angiopathy appears
to be a common cause of hematomyelia.
Treatment. Laminectomy and
drainage of the hematoma, followed
by resection of the tumor or vascular
malformation, can be performed if
neurologic deficits are incomplete or
progressive. For more devastating lesions, supportive care followed by rehabilitative approaches is typical.
SPINAL VASCULAR
MALFORMATIONS
Spinal vascular malformations consist
of normal or enlarged arteries feeding
into venous channels without passing
through capillary channels. While arterial enlargement is variable, the
draining veins are typically enlarged
and tortuous. It is unusual for an unruptured spinal arteriovenous malformation (AVM) to cause sufficient direct mass effect to cause spinal cord
dysfunction, but ruptured AVMs are
among the more common causes of
the spinal hemorrhages described
above. Epidural, subdural, or intramedullary hemorrhages are all possible, depending on the type of malformation. Dural arteriovenous fistulae
(AVFs) rarely produce hemorrhage.
Vascular malformations (AVMs and
dural AVFs) may cause increased local venous pressure, decreased perfusion pressure, decreased tissue perfusion, and finally tissue ischemia
resulting in a slowly progressive myelopathy. Eventually, elevated intra-
Sagittal magnetic resonance image of

cavernous malformation with
hematomyelia. A, Sagittal short tau
inversion recovery image shows an intramedullary
heterogeneous focus T2 hyperintensity and T2
hypointensity. Patchy T2 hyperintensity (dotted arrow)
extends cephalad and caudad in the cord parenchyma and
is consistent with edema. B, Sagittal T1-weighted image
shows an intramedullary heterogeneous focus of T1
hyperintensity with peripheral T1 hypointensity. The
edema is seen as hypointensity (dotted arrow) in the cord
parenchyma.
FIGURE 4-6
81
Axial MRI in hematomyelia. Axial T2weighted image shows an intramedullary

heterogeneous focus of T2 hyperintensity
with peripheral T2 hypointensity. The imaging features are
in keeping with a cavernous malformation with acute
hemorrhage.
FIGURE 4-7
KEY POINTS:
vascular pressure can progress to be

sufficient to cause venous infarction
of the cord.
Spinal epidural
and subdural
hemorrhages are
surgical
emergencies,
with treatment
aimed at
decompression.
Many spinal
hemorrhages are
associated with
endogenous or
iatrogenic
bleeding
diatheses.
Vascular
malformations
may present
with either an
abrupt, painful
ictus or
gradually
progressive
myelopathy.
Sagittal gradient
hemosiderin sequence
shows hematomyelia in
the thoracic cord related to a type II
spinal cord arteriovenous malformation.
FIGURE 4-8
82
FIGURE 4-9
Classification of spinal cord vascular lesions.

AVF arteriovenous fistula; AVM
arteriovenous malformation.
Reprinted with permission from Spetzler RF, Detwiler PW, Riina HA, Porter,
RW. Modified classification of spinal cord vascular lesions. J Neurosurg
2002;96(2 suppl):145156.
Classification
One commonly accepted classification
system incorporates both radiographic
and pathologic features and categorizes spinal vascular malformations
into four types (Anson and Spetzler,
1993). This scheme is depicted in Table 4-3 (Figure 4-9). Spinal vascular
malformations not included in this radiologicpathologic classification system include cavernous angiomas (or
cavernous malformations, sometimes
called cavernomas), venous angiomas (developmental venous anomalies), and epidural/paraspinal AVMs.
Kim and Spetzler (2006) have since
proposed a modified and more inclusive classification scheme that eliminates the numerical identifiers and
subclasses and relies solely on the
anatomic localization of the lesion;
these are shown in Table 4-4.
Presentation and Course
Symptoms. Spinal vascular malformations, especially dural AVFs, vary
markedly in presentation. The onset of
symptoms may be insidious, acute, or
relapsing/remitting. The most common complaints at onset are pain,
weakness, and sensory symptoms.
Pain may be local, radicular, diffuse, or
any combination of these. Vascular
malformations preferentially affect the
lower thoracic and lumbar regions, so
complaints are most commonly referable to those levels. Bowel and bladder complaints typically emerge with
increasing severity of the primary
symptoms. Trauma, exercise, pregnancy, and menstruation are all potential triggers for the symptoms. Leg
weakness or gait difficulties tend to
progress rapidly once they become
evident. Disabling gait abnormalities
develop in about 20% of affected
persons by 6 months after symptom
TABLE 4-3
Commonly Used Classification Scheme for Spinal

Vascular Malformations
Class
Location
Features
Type I
Dural
Arteriovenous fistula subtypes:

IA: Single feeding artery
IB: Multiple feeding arteries
Type II
Intramedullary
Glomus-type AVM
Type III
Intramedullary
Juvenile-type AVM
More extensive than a glomus-type AVM
Frequently possesses extramedullary
component
Sometimes an extradural component.
Type IV
Intradural,
extramedullary
(perimedullary)
Arteriovenous fistula subtypes

IVA, Low shunting, eg:
X Single feeding vessel
X Moderate venous dilatation
IVB, Intermediate
X Often several feeding vessels
X Significant venous dilatation
IVC, High shunting, eg:
X Giant, multi-pediculated fistulas
X Large, tortuous draining veins
AVM arteriovenous malformation.

Data from Anson JA, Spetzler RF. Spinal dural arteriovenous malformations. In: Awad IA, Barrow DL, eds. Dural
arteriovenous malformations. Park Ridge, IL: American Association of Neurological Surgeons, 1993:175191.
onset and increase to affect 50% by 3

years. In less aggressive cases, the interval between symptom onset and
accurate diagnosis may be years. See
Case 4-2.
Examination. Upper motor neuron weakness, lower motor neuron
weakness, or both may be present. A
spinal bruit is a highly specific, although uncommon, finding that is diagnostic of a spinal AVM. Vascular
malformations may coexist in the skin
or paraspinal muscles. In cutaneomeningospinal angiomatosis (Cobb syndrome), dural angioma may coexist
with a cutaneous angioma in the corresponding dermatome.
Venous congestion and mass effect
complicate clinical diagnosis because
they contribute to deficits in multiple
arterial territories. The sometimes confusing and widely varied presentation
of spinal vascular malformations results in a large differential diagnosis,
which includes neoplasm, herniated
discs, multiple sclerosis, intracranial
SAH, subacute combined degeneraContinuum: Lifelong Learning Neurol 2008;14(3)
83
TABLE 4-4
Proposed Revision of Spinal Arteriovenous Lesions
New
Classification
Prior Term
Location
Features
Extradural
AVF
Epidural
fistula
Extradural
Venous engorgement
Local mass effect
Intradural
dorsal AVF
Type I dural
AVF
Intradural
Venous hypertension
Arterialization of coronal
venous plexus
Congestive myelopathy
Intradural
ventral AVF
Type I dural
AVF
Intradural
Fistulous connection from

anterior spinal artery
Subtypes:
Type A: Small
X Single feeder
Type B: Intermediate
X Often one large
and several small
feeders
Type C: Giant
X Multi-pediculated
fistulae
X Massive engorged
veins
Extraduralintradural
AVM
Juvenile or
metameric
AVM
Mixed
Follows somite level

Multiple tissues
affected, (eg, bone,
muscle, skin, spinal
cord, nerve roots)
84
Known as Cobb
syndrome when
severe
Intramedullary
AVM
Intramedullary
Analogous to intracranial
AVM
Conus
medullaris
AVM
Intramedullary
Multiple feeders
Multiple dilated veins
Both upper and lower
motor neuron signs can
result
AVF arteriovenous fistula; AVM arteriovenous malformation.

Reprinted with permission from Kim LJ, Spetzler RF. Classification and surgical management of spinal arteriovenous
lesions: arteriovenous fistulae and arteriovenous malformations. Neurosurgery 2006;59(5 suppl 3):195201.
KEY POINT:
Case 4-2
A 44-year-old man was referred for inpatient neurologic consultation for
inability to walk. He reported progressive weakness of both legs, left
more than right. The symptoms were gradually progressive in nature, and
he first attributed them to overuse injuries related to a new exercise
program he began approximately 2 months before admission. The
weakness persisted despite cessation of the exercise program. He denied
muscular pain, and serum creatine kinase levels were normal, but his
family doctor advised him to discontinue his atorvastatin for 30 days.
There was continued gradually worsening weakness, and he was referred
for outpatient neurologic consultation. On the day of hospital admission
he became acutely unable to walk. He reported increased urinary
frequency for 3 to 4 days before admission but no change in bowel habits.
He denied numbness or tingling sensation. He reported chronic low back
pain, which he related to a remote injury. The pain did not change with
the worsening weakness.
Neurologic examination revealed normal mental state and cranial
nerves. Motor evaluation showed 3/5 power on hip flexion bilaterally, 4/5
knee extension and ankle dorsiflexion. Plantar flexion was 4/5 on the right
and 3/5 on the left. Spasticity was evident in both lower limbs, left slightly
more than right. He had 4 reflexes at both knees and the right ankle.
Crossing of the adductor reflex was noted bilaterally. The left ankle jerk
was 1. Biceps and triceps reflexes were 2 and symmetric. There was
mildly decreased sensation in the left L1 dermatome level and moderate
hypesthesia to all modalities in the right S1 dermatome.
MRI of the thoracolumbar spine was ordered to evaluate for
demyelinating or degenerative joint lesions as the source of his symptoms.
The conus medullaris was found to be hyperintense on T2-weighted
imaging, with multiple curvilinear flow voids in the cauda equina
extending from L1 to L3. A large dilated perimedullary vein was noted
extending to the anterior part of the dural sac. Contrast-enhanced studies
showed enhancement of the flow voids as well as conus. Incidental mild
lateral disc bulge at L5-S1 also was noted.
Comment. MRI suggested the diagnosis of an intraspinal vascular
malformation. A lumbar radicular feeding vessel was identified by
angiography with subselective catheterization and embolized.
Postprocedure angiography revealed obliteration of the fistulous channel.
The patient underwent physical therapy with gradual improvement of
lower extremity power, except for mildly persistent left footdrop. He
returned to independent ambulation. Urinary function was normal. He
deferred surgical repair of the L5-S1 disk.
tion, meningovascular syphilis, and

transverse myelitis.
Epidemiology
Before modern imaging techniques,
patients with vascular malformations
often were included as a subgroup of
patients with manifestations of spinal
tumors. The reported frequency of
vascular malformations as a subset of
spinal tumors ranged from 3% to 11%.

This is an underestimate of the total,
however, because patients with
asymptomatic or misdiagnosed lesions
would not be included.
The most common type of spinal
vascular malformation is spinal dural
AVF. It is typically found in elderly
men, with a 9:1 ratio of affected men
compared with women. Children are
Spinal dural
arteriovenous
fistula is the
most common
type of spinal
vascular
malformation; it
occurs much
more frequently
in men.
85
FIGURE 4-10 Magnetic resonance

image of a type II spinal
cord arteriovenous
malformation. Sagittal T2-weighted
image of the lower thoracic and lumbar
spine shows similarly abnormal
serpentine vessels with prominent flow
voids in the thecal sac.
86
more likely to be diagnosed with AVM

(Type II or III vascular malformation)
(Table 4-3).
Investigations
MRI is the diagnostic procedure of
choice in the initial evaluation of suspected spinal vascular malformations
(Figure 4-10). It can discriminate extramedullary from intramedullary lesions and demonstrate spinal cord
pathology (edema, hemorrhage) attributable to the effects of the vascular malformation. Newer magnetic resonance
(MR) techniques include three-dimensional gadolinium-enhanced MR angiography (Figure 4-11). The spatial
and temporal resolution available with
FIGURE 4-11 Magnetic resonance

angiography in spinal
arteriovenous
malformation. Three-dimensional
reformation of arterial phase of timeresolved contrast-enhanced magnetic
resonance angiography of a type II
spinal cord arteriovenous malformation.
this technique can demonstrate not only

the extent of feeding and draining vasculature but also help guide neurointerventional treatment as to the location of
the feeding artery or fistula. These MR
approaches also can track the success of
therapeutic interventions by confirming
effective thrombosis of the malformation after ligation or embolization of the
feeding vessels or residual nidus.
Routine MRI is sensitive in detecting intramedullary AVMs. Typical findings include intramedullary low signal
on the T2-weighted sequences because of hemorrhagic products surrounded by patchy T2 hyperintensity
due to edema, focal cord enlargement
at the nidus of the malformation, and
serpentine vessels (which appear as
signal voids) within the cord and the
subarachnoid space in the region of
the nidus. MR angiography is optimal
for visualizing the veins draining the
AVM into coronal venous plexus.
The most consistently observed
abnormality for dural AVF is central
cord hyperintensity on T2-weighted
images, which may extend over several levels. Other MR abnormalities are
variable and include cord enlargement, hypointensity on T1-weighted
images, a scalloped appearance of the
cord boundaries on sagittal images,
and enhancement of the cord on postcontrast T1-weighted images. In general, these findings are nonspecific
and can mimic those of other elements
of the clinical differential diagnosis,
such as cord neoplasm, infection, or
ischemia. A finding of blood flow-related signal abnormalities in the subarachnoid space therefore becomes
the key diagnostic feature for identifying dural AVF. Contrast-enhanced
three-dimensional spinal MR angiography allows direct visualization of the
abnormal intradural veins and can
augment standard MRI in detection of
dural fistula. MR angiography is particularly useful in reducing the time
and complexity of digital subtraction
angiography studies, sparing the patient both iodinated contrast load
and radiation exposure from fluoroscopy.
There is little remaining role for
plain radiography or myelography for
diagnosis of AVM, except in patients for
whom MRI is technically impossible.
Contrast-enhanced CT scans with sagittal or coronal reformatting may be use-
FIGURE 4-12 Type II spinal cord arteriovenous

malformation on enhanced CT. A, Coronal
CT reformations of the lower thoracic and
lumbar spine (arrow). B, Sagittal CT reformations of the
same region. Both show abnormal serpentine enhancing
vascular structures in the thecal sac.
87
FIGURE 4-13 Arteriovenous

malformation appearance
on myelography.
Serpentine filling defect on lumbar
myelogram is due to a spinal cord
arteriovenous malformation.
FIGURE 4-14 Angiography. Selective catheterization

angiogram of type IVA spinal cord
arteriovenous malformation. The catheter
angiogram demonstrates an intradural extramedullary
arteriovenous fistula on the surface of the cord that results
from a direct communication between the anterior spinal
artery and a spinal vein without an interposed vascular network.
KEY POINT:
Interventional
radiologic
approaches now
can be used to
treat many
spinal vascular
malformations.
ful in patients who cannot undergo MRI

(Figure 4-12). If myelography must be
done, it is possible to detect serpentine
filling defects caused by abnormal intradural vessels, but this is procedurally
challenging (Figure 4-13).
Selective spinal angiography using
digital subtraction protocols is the definitive approach to evaluating spinal vascular malformations (Figures 4-14 and
4-15). This often requires the patient to
be endotracheally intubated for general anesthesia. Selective spinal angiography typically requires that
each segmental artery in the region
being examined be injected. This is
obviously costly, time-consuming,
andwhen overly prolongedplaces
the patient at considerable risk for anesthesia-related complications. Despite the risk, selective spinal angiography remains the criterion
standard for identifying the characteristics of vascular malformations
that allow for planning appropriate
therapeutic intervention. These features include location, size, configuration, blood flow, feeding arteries,
and draining veins.
Treatment
The definitive treatment of spinal vascular malformations is surgical resection
and/or angiographically directed embolization of the malformation. Therapeutic embolization is used to promote
thrombosis and decrease blood flow.
For malformations that cannot be effectively resolved by embolism alone, a sequential approach of embolization followed by open surgery is common.
88
FIGURE 4-15 Selective catheter

angiogram of a spinal
cord arteriovenous
malformation. This technique delineates
the feeding vessels for both diagnostic
and therapeutic measures.
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90
METABOLIC AND TOXIC

MYELOPATHIES
Neeraj Kumar
ABSTRACT
The myelopathies discussed in this chapter have an underlying metabolic or toxic
etiology. They have many clinical, electrophysiologic, and neuropathologic similarities. Preferential involvement of the dorsal columns and/or corticospinal tracts is
commonly seen. Dorsal column involvement results in impaired position and/or
vibration perception and sensory ataxia. Corticospinal tract involvement may lead to
weakness, spasticity, hyperreflexia, extensor plantars, or sphincteric dysfunction.
Variable degrees of peripheral nerve and/or optic nerve involvement may be
present. In the presence of peripheral nerve involvement, the term myeloneuropathy is commonly used. A subacute symptom onset may be seen. Although therapyrelated improvement may occur, a common outcome of therapeutic intervention is
cessation of progression. Electrophysiologic studies may show evidence of central
conduction delay, at times with variable peripheral nerve involvement. Pathologic
studies may show involvement of the posterior columns, corticospinal tracts, and
peripheral nerves in varying combinations.
INTRODUCTION
A term that has been used to describe
the neuropathologic characteristics of
some of the myelopathies discussed in
this chapter is central-peripheral distal
axonopathy (Spencer and Schaumburg,
1976). Use of this term emphasizes the
fact that in dying-back disorders, both
the central and peripheral nervous systems display a distal axonal degeneration. Loss of dorsal root ganglion cells
results in axon loss in the peripheral
nerves and spinal cord. The distal part of
the dorsal column in the cervical cord,
the distal part of the corticospinal tract in
the lumbar cord, and distal peripheral
nerves are preferentially involved.
Metabolic and toxic myelopathies
can be divided into four categories
(Table 5-1): (1) disorders due to an
identified nutrient deficiency, such as

the subacute combined degeneration
of vitamin B12 deficiency; (2) disorders
that have a geographic predilection
and are due to a suspected toxin, such
as lathyrism; (3) disorders due to a
possible toxin but without a geographic predilection, such as hepatic
myelopathy; and (4) conditions that
may present as a metabolic myelopathy but often have forms that have
additional evidence of CNS involvement, such as spinal xanthomatosis
and adrenomyeloneuropathy (Kumar,
2006b). Some metabolic myelopathies
with a defined mode of inheritance,
such as adrenomyeloneuropathy, are
discussed in the chapter Hereditary
Myelopathies. Although Table 5-1
Relationship Disclosure: Dr Kumar has nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Kumar has nothing to disclose.
91
METABOLIC AND TOXIC MYELOPATHIES

KEY POINTS:
92
Neurologic signs
and symptoms
may be the
earliest
manifestation of
cobalamin
deficiency and
may be
unaccompanied
by hematologic
manifestations.
Neurologic
manifestations
commonly
include a
myelopathy with
or without an
associated
peripheral
neuropathy,
cognitive
impairment, and
optic neuropathy.
Although a
widely used
screening test,
serum
cobalamin
measurement
has technical
and interpretive
problems and
lacks sensitivity
and specificity
for the diagnosis
of cobalamin
deficiency.
Serum
cobalamin can
be normal in
some patients
with cobalamin
deficiency, and
elevated serum
MMA and total
Hcy levels are
useful in
diagnosing
patients with
cobalamin
deficiency.
TABLE 5-1
Causes of Metabolic Myelopathies
Metabolic Myelopathies Due to a Nutrient Deficiency

B12 deficiency
Nitrous oxide toxicity (nitrous oxide renders cobalamin inactive)
AIDS-associated myelopathy (AIDS associated with impaired B12 metabolism)
Folate deficiency
Copper deficiency
Vitamin E deficiency
Metabolic Myelopathies With a Geographic Predilection and Due to

Possible Toxins
Cassava toxicity
Lathyrism
Fluorosis
Subacute myelo-optico-neuropathy (clioquinol toxicity)
Recurrent optic neuromyelitis with endocrinopathies (Martinique and
Guadeloupe, possible neurotoxicity from quinolones in herbal tea)
Tropical myeloneuropathies: nutritional and/or toxic (includes conditions
such as tropical ataxic neuropathy, Cuban myeloneuropathy)
Metabolic Myelopathies Due to Possible Toxins but Without a Geographic

Predilection
Chemotherapy-related myelopathy (methotrexate, doxorubicin, vincristine,
vinorelbine, cytarabine, carmustine, cisplatin)
Hepatic myelopathy
Heroin myelopathy
Superficial siderosis-related myelopathy
Organophosphate toxicity
Others toxins or drugs that have been reported to cause a myelopathy (nhexane, acrylamide, 2,5-hexanedione, 1-bromopropane, podophyllin,
amiodarone, intrathecal amphotericin)
May Present as a Metabolic Myelopathy

Adult polyglucosan body disease
Adrenomyeloneuropathy and other leukodystrophies (X-linked)
Spinal xanthomatosis (autosomal recessive)
Biotinidase deficiency (autosomal recessive)
Arginase deficiency (autosomal recessive)
Mitochondrial disorders (maternal inheritance)
Hexosaminidase A deficiency (autosomal recessive)
Data from Kumar N. Metabolic myelopathy and myeloneuropathy. In: Noseworthy JN, editor.
Neurological therapeutics: principles and practice. 2nd ed. Abingdon, UK: Informa Healthcare,
2006:1766 1781.
provides an exhaustive differential,

the text excludes a discussion of some
rare disorders. Tables 5-2 and 5-3
summarize the salient features of the
conditions discussed in this chapter.
METABOLIC MYELOPATHIES DUE
TO A NUTRIENT DEFICIENCY
Vitamin B12 (Cobalamin)
Deficiency
The physiology and biochemistry of
cobalamin (Cbl) metabolism are summarized in Figures 5-1 and 5-2 (Perkin and Murray-Lyon, 1998; Tefferi
and Pruthi, 1994). Neurologic signs
and symptoms may be the earliest
manifestation of Cbl deficiency (Healton et al, 1991). They may be unaccompanied by hematologic manifestations such as anemia, macrocytosis,
neutrophil hypersegmentation, or
megaloblastic marrow changes. Neurologic manifestations may include a
myelopathy (subacute combined degeneration) with or without an associated peripheral neuropathy, cognitive
impairment, optic neuropathy, autonomic dysfunction, and paresthesias
without abnormal signs (Healton et al,
1991). MRI abnormalities include increased T2-weighted signal in the subcortical white matter and posterior and
lateral columns (Figure 5-3A and
5-3B) (Ravina et al, 2000). Other neuroimaging findings include contrast
enhancement involving the dorsal and
lateral columns, decreased dorsal column signal on T1-weighted images,
and cord swelling (Ravina et al, 2000).
The older microbiologic and radioisotopic assays for serum Cbl
determination have been replaced by
immunologically based chemiluminescence assays. Although a widely used
screening test, serum Cbl measurement has technical and interpretive
problems and lacks sensitivity and
specificity for the diagnosis of Cbl deficiency (Table 5-4) (Carmel, 2000;
Carmel et al, 2003; Green and Kinsella,
Physiology of cobalamin metabolism. In the

stomach, Cbl bound to food is dissociated
from proteins in the presence of acid and
pepsin. The released Cbl binds to R proteins secreted by
salivary glands and gastric mucosa. In the small intestine,
pancreatic proteases partially degrade the R proteins-Cbl
complex at neutral pH and release Cbl, which then binds
with IF. IF is a Cbl-binding protein secreted by gastric
parietal cells. The IF-Cbl complex binds to specific
receptors in the ileal mucosa and is internalized. In
addition to the IF-mediated absorption of ingested Cbl, a
nonspecific absorption of Cbl occurs by passive diffusion
at all mucosal sites. This is a relatively inefficient process by
which 1% to 2% of the ingested amount is absorbed. TCII
is the form that delivers Cbl to tissues. In atrophic gastritis
and achlorhydria, a decrease occurs in acid and pepsin,
and the resultant inability to split Cbl from its binders in
food results in Cbl deficiency.
FIGURE 5-1
Cbl cobalamin; H acidic; IF intrinsic factor; OH

alkaline; TCII transcobalamin II.
Reprinted with permission from Tefferi A, Pruthi RK. The biochemical basis
of cobalamin deficiency. Mayo Clin Proc 1994;69(2):181186.
1995; Snow, 1999). Patients with mild

transcobalamin I (TCI) deficiency may
be responsible for 15% of all unexplained low Cbl levels (Carmel, 2003).
This does not cause cellular Cbl deficiency because TC1, unlike TCII, is not
required for cellular uptake of Cbl
(Carmel, 2003). Serum Cbl can be normal in some patients with Cbl deficiency, and serum methylmalonic acid
(MMA) and total homocysteine (Hcy)
levels are useful in diagnosing patients
with Cbl deficiency. A third of individuals with low-normal Cbl levels may
have elevated MMA and/or Hcy levels.
MMA is at least as sensitive as Hcy for
the diagnosis of Cbl deficiency but has
superior specificity. Elevated MMA
93

and Hcy levels may be seen in other
conditions (Table 5-4).
The sensitivity of the available
metabolic tests has facilitated the development of the concept of subclinical Cbl deficiency (Carmel, 2000; Carmel et al, 2003). This refers to
TABLE 5-2
metabolic evidence of Cbl deficiency

in the absence of clinical manifestations. It is common, particularly in elderly persons, but its clinical significance is poorly understood. A small
proportion of cases with subclinical
Cbl deficiency may progress to overt
Summary of Sources, Causes of Deficiency, Neurologic Significance,

Laboratory Tests, and Treatment for Metabolic Myelopathies Related to
Nutrient Deficiencies (Cobalamin, Folate, Copper, and Vitamin E)
Nutrient
Sources
Major Causes of Deficiency
Neurologic Sequelae
Cobalamin
Meats, egg, milk,

fortified cereals
Pernicious anemia, aging (due

to atrophic gastritis and
achlorhydria-induced food-Cbl
malabsorption), gastric surgery,
acid reduction therapy,
gastrointestinal disease,
parasitic infestation by fish
tapeworm, hereditary
enzymatic defects, N2O toxicity,
rarely strict vegetarianism,
often unknown cause
Myelopathy or
myeloneuropathy,
peripheral neuropathy,
neuropsychiatric
manifestations, optic
neuropathy, autonomic
dysfunction
Folate
In virtually all foods

(grains and cereals
are fortified with
folic acid)
Alcoholism, gastrointestinal
disease, folate antagonists (eg,
methotrexate, trimethoprim),
errors of folate metabolism
(folate deficiency generally
coexists with other nutrient
deficiencies)
Neurologic
manifestations are rare
and indistinguishable
from those due to Cbl
deficiency
Copper
Organ meats,
seafood, nuts,
cocoa, whole grain
products
Gastric surgery, zinc toxicity,

gastrointestinal disease, total
parenteral nutrition and
enteral feeding, rarely acquired
dietary deficiency, often
unknown
Myelopathy or
myeloneuropathy
Vitamin E
Vegetable oils,
leafy vegetables,
fruits, meats, nuts,
unprocessed cereal
grains
Chronic cholestasis (particularly

in children), pancreatic
insufficiency, gastrointestinal
disease, ataxia with vitamin E
deficiency, homozygous
hypobetalipoproteinemia,
abetalipoproteinemia,
chylomicron retention disease
Spinocerebellar syndrome
with peripheral
neuropathy,
ophthalmoplegia,
pigmentary retinopathy
94
N2O nitrous oxide; Cbl cobalamin; MMA methylmalonic acid; Hcy homocysteine.
Adapted with permission from Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209 255.
Data from Kumar N. Metabolic myelopathy and myeloneuropathy. In: Noseworthy JN, editor. Neurological therapeutics: principles and practice. 2nd ed.
Abingdon, UK: Informa Healthcare, 2006:1766 1781.
clinical manifestations. Subclinical Cbl

deficiency increases with age. Further,
the presence of a low Cbl level does
not necessarily imply metabolically
significant deficiency. It is important to
recognize that the presence of a low
Cbl level in association with neuro-
Laboratory Tests
logic manifestations does not imply

cause and effect. The incidence of
cryptogenic polyneuropathy, cognitive decline, Cbl deficiency, and low
Cbl levels increases with age.
To determine the cause of Cbl deficiency, tests to determine the cause
Treatment (Commonly
Used Regimens)
Additional Comments
Serum Cbl, serum MMA,

plasma total Hcy,
hematologic tests (anemia,
macrocytosis, neutrophil
hypersegmentation),
Schilling test, serum gastrin,
intrinsic factor, and parietal
cell antibodies
IM B12 1000 g daily for 5

days and monthly thereafter
Even in the presence of severe

malabsorption, 2 to 5 years may
pass before Cbl deficiency
develops; disturbance in Cbl
metabolism in AIDS-associated
myelopathy
Serum folate, red blood cell

folate (more reliable
indicator of tissue stores
than serum folate), plasma
total Hcy
Oral folate 1 mg 3 times a

day followed by a
maintenance dose of 1 mg a
day (initial parenteral is an
option)
Clinically significant depletion of

body folate stores may be seen in
weeks to months; higher
requirements in pregnancy,
lactation, methotrexate toxicity
Serum and urinary copper,

serum ceruloplasmin, serum
and urinary zinc, hematologic
parameters (anemia,
neutropenia, vacuolated
myeloid precursors, ringed
sideroblasts, iron-containing
plasma cells)
Oral elemental copper: 8 mg

a day for a week, 6 mg a
day for the second week, 4
mg a day for the third week,
and 2 mg a day thereafter
Hyper-zincemia of indeterminate
cause may be present even in the
absence of excess zinc ingestion
(speculative if copper deficiency
may have been responsible for
clioquinol-induced subacute
myelo-optic-neuropathy)
Serum vitamin E, ratio of

serum vitamin E to sum of
serum cholesterol and
triglycerides
Vitamin E ranging from 200

mg/d to 200 mg/kg/d (oral,
IM)
Vitamin E deficiency is virtually

never the consequence of a
dietary inadequacy; neurologic
findings are rare in vitamin
Edeficient adults with chronic
cholestasis
95
TABLE 5-3
Salient Clinical Features of Some Additional Metabolic Myelopathies and

Myeloneuropathies
Disease
Clinical Clues
Laboratory Features
Treatment
Nitrous oxide
toxicity
Among dentists, medical or

nursing staff
Evidence of vitamin B12

deficiency
Cessation of chronic
exposure
Consider when neurologic

symptoms develop after
surgical procedures
Increased signal on T2weighted MRI involving

dorsal column
Prophylactic vitamin B12

prior to surgery in
individuals with a
borderline vitamin B12 who
are expected to receive
nitrous oxide anesthesia
Cassava
toxicity
Symptoms may be delayed

after exposure
IM vitamin B12 with acute

nitrous oxide poisoning
Resembles subacute
combined degeneration
seen with vitamin B12
deficiency
Possible role of methionine

supplementation
Consumption of
insufficiently processed
cassava in parts of Africa
leads to abrupt onset of
spastic paraparesis
Serum thiocyanate is a
biomarker for dietary
cyanide exposure
Improvement in food
processing
Chronic cassava
consumption associated
with slowly progressive
ataxia and peripheral
neuropathy
Lathyrism
Consumption of lathyrus
sativus as a staple
Preventable by mixing
grass pea with cereals, or
detoxification through
aqueous leaching
Subacute- or insidiousonset spastic paraparesis
96
Fluorosis
Hepatic
myelopathy
Consumption of large
amounts of fluoride that is
naturally present in water
in some parts of the world
Osteosclerosis and
ligamentous calcification
on x-ray
Prevention
Back pain, limited spine

mobility, cord compression,
radiculopathy
Calcification of the
interosseous membrane of
the forearm
Surgery may be required

for cord compression
Complication of chronic
liver disease
Elevated serum manganese
Possible benefit of early

liver transplantation
Progressive spastic
paraparesis
Increased pallidal signal on

T1-weighted cranial MRI
Increased cervical cord
signal on T2-weighted MRI
(rare)
TABLE 5-3
Heroin
myelopathy

Acute or progressive
myelopathy
Acute: MRI resembles

transverse myelitis
Chronic: MRI shows

selective involvement of
lateral and posterior
columns
Superficial
siderosis
myelopathy
Generally associated with

cerebellar and eighth
cranial nerve dysfunction
Organophosphate Delayed onset after

toxicity
exposure
Progressive leg weakness
that may be associated
with mild sensory
symptoms and upper limb
involvement
Adult
polyglucosan
body disease
Myelopathy may be
associated with peripheral
neuropathy, sphincteric
disturbance, and dementia
Hemosiderin deposition
around cord and along
cerebellar folia and cord
and cerebellar atrophy
Treatment of the bleeding

source (if found)
Red blood cell

cholinesterase activity is a
measure of chronic
exposure to
organophosphates
Prevented by use of gloves

and protective clothing
Polyglucosan bodies on
axillary skin or sural biopsy
None
Pralidoxime and atropine

for acute toxicity
MRI shows cerebral,

cerebellar, and cord
atrophy with increased
periventricular T2 signal
Data from Kumar N. Metabolic myelopathy and myeloneuropathy. In: Noseworthy JN, editor. Neurological therapeutics:
principles and practice. 2nd ed. Abingdon, UK: Informa Healthcare, 2006:1766 1781.
of malabsorption are undertaken.

Concerns regarding cost, accuracy,
and radiation exposure have led to a
significant decrease in the availability
of the Schilling test. An elevated serum
gastrin level and decreased pepsinogen I are seen in 80% to 90% of patients with pernicious anemia, but the
specificity of these tests is limited. Elevated gastrin levels are a marker for
hypochlorhydria or achlorhydria,
which are invariably seen with pernicious anemia. Elevated gastrin levels
may be seen in up to 30% of elderly
persons. Anti-intrinsic factor antibodies are specific but lack sensitivity and
are found in approximately 50% to
70% of patients with pernicious anemia (Green and Kinsella, 1995). Antiparietal cell antibodies may not be
seen as commonly as was earlier believed and therefore have limited utility. Gastric parietal cell antibodies may
be seen in 10% of individuals over age
70 and also are present in other autoimmune endocrinopathies.
The goals of treatment are to reverse the signs and symptoms of deficiency, replenish body stores, ascertain the cause of deficiency, and
monitor response to therapy. With
normal Cbl absorption, oral administration of 3 g to 5 g may suffice. In
patients with food-bound Cbl malabsorption, 50-g to 100-g cyanocobalamin given orally may be adequate.
The more common situation is one of
impaired absorption, where parenteral
therapy is required (Table 5-2). If the
oral dose is large enough, even paContinuum: Lifelong Learning Neurol 2008;14(3)
97
Biochemistry of Cbl and folate metabolism.

The two active forms of Cbl are methyl-Cbl
and adenosyl-Cbl. Methyl-Cbl is a cofactor
for a cytosolic enzyme, methionine synthase, in a methyltransfer reaction that converts homocysteine to
methionine. Methionine is adenosylated to SAM, a methyl
group donor required for biologic methylation reactions
involving proteins, neurotransmitters, and phospholipids.
Decreased SAM production leads to reduced myelin basic
protein methylation and white matter vacuolization in Cbl
deficiency. Methionine also facilitates the formation of
formyl-THF, which is involved in purine synthesis. During
the process of methionine formation, methyl-THF donates
the methyl group and is converted into THF, a precursor
for purine and pyrimidine synthesis. Impaired DNA
synthesis could interfere with oligodendrocyte growth and
myelin production. Adenosyl-Cbl is a cofactor for Lmethylmalonyl-CoA mutase, which catalyzes the
conversion of L-methylmalonyl-CoA to succinyl-CoA in an
isomerization reaction. Methylmalonyl accumulates in Cbl
deficiency. Accumulation of methylmalonate and
propionate may provide abnormal substrates for fatty acid
synthesis. The branched-chain and abnormal odd-number
carbon fatty acids may be incorporated into the myelin
sheath. The biologically active folates are in the THF form.
Methyl-THF is the predominant folate and is required for
the Cbl-dependent remethylation of Hcy to methionine.
Methylation of deoxyuridylate to thymidylate is mediated
by methylene THF. Impairment of this reaction results in
accumulation of uracil, which replaces the decreased
thymine in nucleoprotein synthesis and initiates the
process that leads to megaloblastic anemia.
FIGURE 5-2
98
Cbl cobalamin; CH3 methyl group; CoA coenzyme

A; SAM S-adenosylmethionine; THF tetrahydrofolate;
THF1 and THFn monoglutamated and polyglutamated
forms of tetrahydrofolate.
Reprinted with permission from Tefferi A, Pruthi RK. The biochemical basis
of cobalamin deficiency. Mayo Clin Proc 1994;69(2):181186.
tients with an absorption defect may

respond to oral Cbl (Carmel, 2000).
Long-term administration of 1000 g
per day of oral vitamin B12 may be
reasonable once Cbl stores are replenContinuum: Lifelong Learning Neurol 2008;14(3)
ished. Most of the symptomatic improvement occurs during the first 6

months. Response of the hematologic
derangements is prompt and complete. Response of the neurologic
manifestations is more variable, may
be incomplete, and is related to extent
of involvement and delay in starting
therapy. Cbl levels rise after injection
regardless of the benefit. Hence, MMA
and Hcy levels are more reliable ways
of monitoring response to therapy
(Carmel et al, 2003). Falsely low red
blood cell folate levels can be seen
with Cbl deficiency (Snow, 1999). Folate therapy may delay recognition of
the Cbl deficiency and cause neurologic deterioration. Anemia due to Cbl
deficiency often responds to folate
therapy, but the response is incomplete and transient.
Nitrous-Oxide Toxicity
Nitrous oxide (N2O) (laughing gas) is
a commonly used inhalational anesthetic agent that has been abused because of its euphoriant properties. It is a
potent oxidizing agent that produces irreversible oxidation of the cobalt core of
Cbl and renders methyl-Cbl inactive.
Earlier reports of N2O toxicity were
among dentists and medical or nursing
staff working in poorly ventilated surgeries. More recently, the practice has
been seen among university students
(Ng and Frith, 2002). Nanging is a term
invented by users to describe the repetitive sound distortions heard when using N2O. Anesthesia paresthetica is a
term proposed to describe the neurologic manifestations seen after N2O anesthesia (Kinsella and Green, 1995).
Neurologic manifestations may result
from chronic exposure or after a single
exposure in individuals with unsuspected Cbl deficiency. They may be
seen despite a normal Cbl level. Signs
and symptoms appear relatively rapidly
with N2O toxicity. Less commonly,
symptoms may be delayed up to 2
months after acute exposure. Neuro-
logic manifestations may include myelopathy, neuropathy, myeloneuropathy, and impaired cognition and mental
status changes (Flippo and Holder,
1993). MRI findings include hyperintense T2 signal in the dorsal and lateral
columns, which may improve with treatment (Figure 5-3C) (Marie et al, 2000).
A myeloneuropathy due to N2O
should be considered when dealing
with patients who develop neurologic
symptoms after surgical or dental procedures. Patients with vitamin B12 deficiency are prone to developing neurologic deterioration after N2O anesthesia
(Kinsella and Green, 1995). It is preventable by prophylactic vitamin B12 given
weeks before surgery in individuals with
a borderline vitamin B12 level who are
expected to receive N2O anesthesia. IM
vitamin B12 should be given to patients
with acute N2O poisoning.
are HIV-infected, but the precise significance of this is unclear (Kieburtz et

al, 1991). The histopathology of AIDSassociated myelopathy resembles that
of subacute combined degeneration
seen in vitamin B12 deficiency. The
pathogenesis of many cases of AIDSassociated myelopathy is possibly unrelated to direct HIV infection of the
spinal cord (Di Rocco et al, 2004). In
AIDS-associated myelopathy, the Cbland folate-dependent transmethylation pathway is depressed and CSF
and serum levels of S-adenosylmethionine (SAM) are reduced. Possible
benefit of administration of the SAM
precursor L-methionine in AIDS-associated myelopathy was suggested by a
pilot study but not confirmed in a subsequent double-blind study (Di Rocco
et al, 2004).
AIDS-Associated Myelopathy
and Cobalamin Deficiency
Increased prevalence of vitamin B12
deficiency has been recognized in patients with neurologic symptoms who
Folate Deficiency
Methionine synthase requires folate as
a cosubstrate. Despite this, for unclear
reasons, neurologic complications due
to folate deficiency are rare and con-
KEY POINT:
N2O produces
irreversible
oxidation of the
cobalt core of
cobalamin and
renders
methylcobalamin
inactive.
Subacute
combined
degeneration
due to N2O
toxicity may
result from
chronic exposure
or after a single
exposure in
individuals with
unsuspected
cobalamin
deficiency.
99
MRI in a patient with vitamin B12-deficiencyrelated myelopathy. Sagittal (A) and axial (B) T2-weighted
cervical MRI from a patient with a myelopathy due to vitamin B12 deficiency showing abnormally
increased signal (arrows) along the posterior columns of the spinal cord extending from C1 through
C6. Axial (C) T2-weighted cervical spine MRI in a patient with nitrous oxide anesthesia-associated myelopathy
showing increased signal involving the posterior (arrows) and lateral columns (dotted arrow).
FIGURE 5-3
A and B modified with permission from Ravina B, Loevner LA, Bank W. MR findings in subacute combined degeneration of the spinal cord: a case of
reversible cervical myelopathy. AJR Am J Roentgenol 2000;174(3):863 865.
C modified with permission from Marie RM, Le Biez E, Busson P, et al. Nitrous oxide anesthesia-associated myelopathy. Arch Neurol 2000;57(3):380
382. Copyright 2000, American Medical Association. All rights reserved.

KEY POINTS:
100
A
myeloneuropathy
due to N2O
should be
considered
when dealing
with patients
who develop
neurologic
symptoms after
surgical or
dental
procedures.
Patients with
vitamin B12
deficiency are
prone to
developing
neurologic
deterioration
after N2O
anesthesia.
The
pathogenesis of
AIDS-associated
myelopathy is
possibly
unrelated to
direct HIV
infection of the
spinal cord. In
AIDS-associated
myelopathy, the
cobalamin- and
folatedependent
transmethylation
pathway is
depressed.
TABLE 5-4
Common Causes, Other Than Cobalamin Deficiency, for

Abnormal Cobalamin, Methylmalonic Acid, and
Homocysteine Levels
Cobalamin
Methylmalonic Acid
Homocysteine
Decrease (Falsely
Low)
Increase
Increase
Pregnancy
Renal insufficiency
Renal insufficiency
Transcobalamin I
deficiency
Volume contraction
(possible)
Volume contraction
Folate deficiency
Bacterial contamination
of gut (possible)
Folate deficiency
Other diseases:
HIV infection,
myeloma
Methyl malonyl
coenzyme A mutase
deficiency
Vitamin B6 deficiency
Drugs:
anticonvulsants,
oral
contraceptives
Methylmalonic acid
related enzyme defects
Other diseases:
hypothyroidism, renal
transplant, leukemia,
psoriasis, alcohol abuse
Idiopathic
Age, pregnancy
Inappropriate sample
collection and processing
Increase (Falsely
Normal)
Decrease
Drugs: isoniazid, colestipol,

niacin, levodopa
Renal failure
Antibiotic-related
reductions in bowel
flora
Enzyme defects:
cystathionine -synthase
deficiency,
methylenetetrahydrofolate
deficiency
Intestinal bacterial
overgrowth
Age, males, increased muscle

mass
Transcobalamin II
deficiency
Liver disease
Myeloproliferative
disorders
(polycythemia
vera, chronic
myelogenous
leukemia)
Data from Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med 2000;51:357
375.
Data from Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 2003;62 81.
Data from Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the
primary care physician. [see comment]. Arch Intern Med 1999;159(12):1289 1298.
troversial. Folate deficiency often coexists with other nutrient deficiencies.

Reported neurologic manifestations of
folate deficiency include a myelopathy

that resembles the syndrome of subacute combined degeneration of the
cord (Parry, 1994; Reynolds et al,

1973). Peripheral neuropathy in isolation or associated with a myelopathy
may be present. Also described are
optic neuropathy and a spectrum of
cognitive and behavioral manifestations (Reynolds et al, 1973). The megaloblastic anemia due to folate deficiency is indistinguishable from that
seen in Cbl deficiency.
Microbiologic assays for folate
measurement largely have been replaced by radioisotopic assays and automated immunologic methods employing chemiluminescence. Plasma
Hcy levels are commonly elevated in
patients with clinically significant folate deficiency.
In women of childbearing age
with epilepsy, a daily oral folate supplement of 0.4 mg is recommended for
prophylaxis against neural tube defects. With documented folate deficiency, initial replacement doses (oral
or parenteral) are followed by an oral
maintenance dose (Table 5-2). Despite malabsorption, patients respond
to oral folic acid because it is readily
absorbed by nonspecific mechanisms.
Coexisting Cbl deficiency should be
ruled out before instituting folate therapy. Reduced folates, such as folinic
acid (N5-formyl-tetrahydrofolate), are
required only when folate metabolism
is impaired by drugs, such as methotrexate, or by an inborn error of metabolism. Plasma Hcy is likely the best
biochemical tool for monitoring response to therapy; it decreases within
a few days of instituting folate therapy
but does not respond to inappropriate
Cbl therapy.
Copper Deficiency
The physiology of copper metabolism
is summarized in Figure 5-4. Copper
functions as a prosthetic group in a
number of metalloenzymes that have a
critical role in maintaining the structure and function of the nervous sys-
tem (eg, copper-zinc superoxide dismutase for antioxidant defense,

cytochrome c oxidase for oxidative
phosphorylation, dopamine--monooxygenase for catecholamine biosynthesis). Copper deficiency-associated
myelopathy has been described in various animal species. Often seen in ruminants, it has been referred to as
swayback or enzootic ataxia. The
most common manifestation in humans is that of a myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen
with Cbl deficiency (Kumar et al,
2004a; Kumar et al, 2004b; Kumar,
2006a; Kumar, 2007a). Also described
is asymmetric motor weakness and atrophy with sensory signs or symptoms
and electrodiagnostic evidence of diffuse denervation (Weihl and Lopate,
2006). Copper and Cbl deficiency can
coexist (Case 5-1). Hematologic manifestations of acquired copper deficiency (anemia, neutropenia, and a
left shift in granulocytic and erythroid
maturation) are not always present
(Figure 5-5C, 5-5D, and 5-5E) (Kumar, 2007a). Spinal cord MRI in patients with copper deficiency myelopathy may show increased signal on
T2-weighted images in the paramedian cord, most commonly cervical
(Figure 5-5A and 5-5B) (Kumar et al,
2006) (Kumar, 2007a).
Because of coppers ubiquitous
distribution and low daily requirement, acquired dietary copper deficiency is rare. Copper deficiency may
result from malabsorption and excess
zinc ingestion. Not infrequently, the
cause for copper deficiency is unknown. Of the known causes of acquired copper deficiency, the most
common is a prior history of gastric
surgery (Kumar et al, 2004a). In a recent series of post-bariatric surgery
related neurologic complications, myelopathy due to copper and/or Cbl
KEY POINTS:
For unclear
reasons,
neurologic
complications
due to folate
deficiency are
rare. Folate
deficiency often
coexists with
other nutrient
deficiencies.
A myelopathy or
myeloneuropathy
that resembles
the subacute
combined
degeneration
seen with
cobalamin
deficiency is the
most common
manifestation of
acquired copper
deficiency.
Copper and
cobalamin
deficiency can
coexist.
Hematologic
manifestations
of acquired
copper
deficiency are
not always
present with the
neurologic
manifestations.
101

KEY POINT:
Of the known
causes of
acquired copper
deficiency, the
most common is
a prior history of
gastric surgery.
deficiency was noted to be the most

common (Juhasz-Pocsine et al, 2007).
Laboratory indicators of copper
deficiency include low serum copper
or ceruloplasmin and low urinary copper excretion, but these parameters
may not be sensitive to marginal copper status. Ceruloplasmin is an acutephase reactant, and the rise in ceruloplasmin is probably responsible for
the increase in serum copper seen in a
variety of conditions such as pregnancy, oral contraceptive use, liver or
kidney disease, malignancy, smoking,

diabetes, myocardial infarction, and
various inflammatory and infections
diseases. Copper deficiency could
therefore be masked under these conditions. Wilson disease, a disease of
copper toxicity, also is associated with
a low serum copper. In Wilson disease, urinary copper excretion and
copper content in the liver and brain
are elevated. A low serum copper
level also can be seen in some carriers
of the Wilson disease gene. Acerulo-
A, Physiology of copper metabolism. Copper absorption occurs primarily in the small intestine. The
Menkes P-type ATPase is responsible for copper trafficking to the secretory pathway for efflux from
enterocytes and other cells. Absorbed copper is bound to albumin and transported via the portal vein
to the liver for uptake by liver parenchymal cells. Copper is then released into the plasma. Ninety-five percent of the
copper is bound to ceruloplasmin. The Wilson P-type ATPase is responsible for copper trafficking to the secretory
pathway for ceruloplasmin biosynthesis and for endosome formation prior to biliary secretion. Biliary copper is
adjusted to maintain balance. Urinary excretion is normally very low, less than 0.1 mg/d. Excretion of copper into the
gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity.
Excessive zinc ingestion is a well-recognized cause of copper deficiency. The zinc-induced inhibition of copper
absorption could be the result of competition for a common transporter or a consequence of induction of
metallothionein in enterocytes. Metallothionein has a higher binding affinity for copper than for zinc. Copper is
retained within the enterocytes and lost as the intestinal cells are sloughed off. Failure to mobilize absorbed copper
from intestinal cells forms the basis of Menkes disease (1). In Wilson disease there is decreased incorporation of
copper into ceruloplasmin (2a) and impaired biliary excretion of copper (2b). B, Copper (Cu) trafficking in yeast is
shown in the figure. Copper is reduced by a plasma membrane reductase and is then transported across the
membrane by a copper transporter (Ctr1). Three copper transporters or chaperones (Cox17, Lys7, and Atx1) deliver
copper to specific proteins (cytochrome c oxidase, CuZn superoxide dismutase, and Fet3 respectively) in different
cellular compartments. Human counterparts for Ctr1 and the three copper chaperones are indicated in the figure.
The human Wilson disease protein is homologous to yeast Ccc2, a P-type ATPase transmembrane Cu transporter. The
multi-copper oxidase Fet3 is homologous to human ceruloplasmin.
FIGURE 5-4
102
Alb albumin; apoCp apoceruloplasmin ; Cp ceruloplasmin; Cu copper; cyt c ox cytochrome c oxidase;

M metallothionein; SOD superoxide dismutase; Zn zinc.
A reprinted with permission by Mayo Foundation for Medical Education and Research. All rights reserved.
B reprinted with permission from Kumar N, Ahlskog JE, Gross JB Jr. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol
2004;2(12):1074 1079. Copyright 2004, Elsevier.
Case 5-1
A 32-year-old woman was evaluated for an 8-month history of progressive
gait difficulty characterized by imbalance and leg stiffness. Her walking
became significantly worse in the dark or on uneven surfaces. She would
often scrape the ground with her toes while walking. Over the past month
she had been having frequent falls. For the preceding 6 months she had
noticed painful tingling and burning involving her hands and, subsequently,
her feet. Additional symptoms included generalized fatigue, exertional
shortness of breath, increased urinary frequency, low back pain, and
constipation. Her past history was remarkable for obesity and hypertension.
She had weight reduction surgery 7 years earlier and since then had been on
periodic vitamin B12 injections. After the surgery, she lost approximately 50
kg over a year and was able to gradually discontinue her antihypertensives.
Five months before presentation she was noted to have a borderline serum
vitamin B12 level and mild elevation in serum MMA level. The frequency of
her IM vitamin B12 injection was increased from 1000 g monthly to 1000 g
weekly. Despite a prompt normalization of her vitamin B12 and MMA levels,
her neurologic symptoms progressed. On examination she had a spastic
ataxic gait with a positive Romberg. Her lower limb tone was increased, and
mild weakness of ankle dorsiflexion and toe extension was present.
Perception of vibration was reduced up to the anterior superior iliac spine,
and perception of position was reduced at the toes. A graded decreased
perception of pinprick and touch was noted distal to the midshin level. The
ankle jerk was depressed, and other deep tendon reflexes were brisk. The
plantar response was extensor.
Workup of her fatigue included a hemoglobin level, which was reduced
to 8.1 g/dL. Her white cell count was reduced to 2300 cells/mm3, and
platelet count was normal. Her mean corpuscular volume and iron studies
were normal. A bone marrow study showed vacuolated myeloid
precursors, ringed sideroblasts, and iron-containing plasma cells. A
somatosensory evoked potential study showed central conduction slowing
that localized to the cervical cord. Nerve conduction studies showed
evidence of a mild distal axonal sensorimotor neuropathy involving the
upper and lower limbs. Her serum copper level was undetectable.
Oral copper supplementation normalized her serum copper over 4
months. Within 6 weeks her hemoglobin and white cell count had
normalized. At 4-month follow-up she reported resolution of her fatigue,
painful paresthesias, and slight improvement in her gait. No definite
change was noted on her examination. She reported no worsening.
Comment. Copper and vitamin B12 deficiency can coexist. A prior
history of gastric surgery is a risk factor for both. Both can cause a
myeloneuropathy (subacute combined degeneration of the cord), and
both can cause neurologic manifestations in the absence of hematologic
derangements. Although either condition may be associated with a T2
lesion involving the dorsal columns, not uncommonly the MRI is normal.
Continued neurologic deterioration despite adequate vitamin B12
supplementation in a patient with a prior history of vitamin B12 deficiency
should prompt a search for possible copper deficiency as the underlying
cause. Copper deficiency can cause a hematologic picture that resembles a
myelodysplastic syndrome. Response of the hematologic parameters is
prompt and complete. Neurologic deterioration is halted, although
objective improvement is rare.
103
Cord MRI and hematology findings in copper deficiency. Sagittal (A) and axial (B) T2-weighted MRIs in
a patient with copper deficiency showing increased signal in the paramedian aspect of the dorsal
cervical cord. Bone marrow study (C, D, and E) in a patient with copper deficiency myelopathy showing
vacuolated myeloid precursors (C). Iron staining (D and E) showing iron-containing plasma cells (D) and ringed
sideroblasts (E).
FIGURE 5-5
Reprinted with permission from Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc 2006;81(10):13711384.
Reprinted with permission from Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209 255. Copyright 2007, Elsevier.
104
plasminemia is a disorder of iron metabolism that is associated with a low

serum copper level despite the absence of a disturbance in copper metabolism.
In patients with zinc-induced copper deficiency, discontinuing the zinc
may suffice and no additional copper
supplementation may be required. Despite a suspected absorption defect,
oral copper supplementation is generally the preferred route for supplementation. In most cases, oral administration of 2 mg of elemental copper a
day is sufficient (Table 5-2). A comparable dose of elemental copper may
be given intravenously. At times, prolonged oral therapy may not result in
improvement, and parenteral therapy
may be required. In some patients, initial parenteral administration followed
by oral therapy is employed. Response
of the hematologic parameters is
prompt and complete. Recovery of
neurologic signs and symptoms is variable; progression is typically halted.
Early recognition and prompt treatContinuum: Lifelong Learning Neurol 2008;14(3)
ment may prevent significant neurologic morbidity.

Vitamin E Deficiency
The physiology of vitamin E metabolism is summarized in Figure 5-6.
Neurologic manifestations of vitamin E
deficiency include a progressive
spinocerebellar syndrome and peripheral neuropathy with resulting gait difficulty, hypo- or areflexia, pyramidal
signs, impaired position and vibration
perception, dysarthria, and gaze palsies (Sokol, 1988). The clinical presentation in some may be similar to that of
subacute combined degeneration
(Vorgerd et al, 1996). The phenotype
may be similar to that of Friedreich
ataxia. MRI may show high-signal lesions on T2-weighted images in the
posterior columns (Figure 5-7) (Vorgerd et al, 1996). Vitamin E deficiency
in adults may be due to gastrointestinal, pancreatic, or hepatic disease. In
addition to these causes, particularly
in children, vitamin E deficiency may
result from genetic defects in -to-
copherol transfer protein, apolipoprotein B, microsomal triglyceride transfer

protein, or a defect in chylomicron
synthesis and secretion (Table 5-5).
Pathologic studies of vitamin E deficiency-related neurologic manifestations have shown degeneration of axons in the posterior column, loss of
large myelinated fibers in the spinal
cord and, to a lesser extent, peripheral
nerves, lipofuscin accumulation in
dorsal sensory neurons and peripheral
Schwann cell cytoplasm, and spheroids (swollen dystrophic axons) and
neuronal dropout in the gracile and
cuneate nuclei (Rosenblum et al,
1981).
Serum vitamin E levels are dependent on the concentrations of serum
lipids. Hyperlipidemia or hypolipidemia can independently increase or
decrease serum vitamin E without reflecting similar alterations in tissue levels of the vitamin. Effective serum vitamin E levels are calculated by
dividing the serum vitamin E by the
sum of serum cholesterol and triglycerides (Sokol et al, 1984). Serum vitamin E concentrations may be in the
normal range in patients with vitamin
E deficiency due to cholestatic liver
disease, a condition in which lipid levels often are elevated. In patients with
neurologic manifestations due to vitamin E deficiency, the serum vitamin E
levels are frequently undetectable.
Children with chronic cholestasis
may require large oral doses or IM
administration of dL--tocopherol.
The doses used in patients with homozygous hypobetalipoproteinemia,
abetalipoproteinemia, and chylomicron retention disease are much
higher than doses used in ataxia with
vitamin E deficiency (Tables 5-2 and
5-5). Supplementation of other fat-soluble vitamins may be required, and
excess fat, particularly in the form of
long-chain fatty acids, should be
avoided. An empiric approach is to
start with a lower dose, increase it

gradually, and, based on the clinical
and laboratory response, consider a
higher dose or parenteral formulation.
Supplements of bile salts may be of
value in some patients.
METABOLIC MYELOPATHIES
WITH A GEOGRAPHIC
PREDILECTION AND DUE TO A
POSSIBLE TOXIN
Cassava Toxicity
Weeks of high dietary cyanide exposure due to consumption of insufficiently processed cassava in parts of
Africa results in Konzo, a distinct tropical myelopathy characterized by the
KEY POINT:
Neurologic
manifestations of
vitamin E
deficiency
include a
progressive
spinocerebellar
syndrome and
peripheral
neuropathy with
resulting gait
difficulty, hypoor areflexia,
pyramidal signs,
impaired position
and vibration
perception,
dysarthria, and
gaze palsies. The
phenotype is
similar to that of
Friedreich ataxia.
Physiology of vitamin E metabolism. Vitamin E

absorption from the gastrointestinal tract
requires bile acids, fatty acids, and
monoglycerides for micelle formation. After uptake by
enterocytes, all forms of dietary vitamin E are incorporated
into chylomicrons. The chylomicrons are secreted into the
circulation, where lipolysis by lipoprotein lipase takes place.
During lipolysis, various forms of vitamin E are transferred to
high-density or other circulating lipoproteins and
subsequently to tissues. The chylomicron remnants are taken
up by the liver. In the liver, the -tocopherol transfer protein
(TTP) incorporates -tocopherol into very low-density
lipoproteins (VLDLs), which are secreted into plasma. Lipolysis
of VLDL results in enrichment of circulating lipoproteins with
RRR--tocopherol, which is delivered to peripheral tissue.
Most ingested vitamin E is eliminated by the fecal route. The
majority of vitamin E in the human body is localized in the
adipose tissue. Analysis of adipose tissue -tocopherol
content provides a useful estimate of long-term vitamin E
intake. More than 2 years is required for adipose tissue -/tocopherol ratios to reach new steady-state levels in response
to changes in dietary intake.
FIGURE 5-6
HDL high-density lipoprotein.
105

KEY POINT:
Serum vitamin E
levels are
dependent on
the
concentrations
of serum lipids.
Hyperlipidemia
or hypolipidemia
can
independently
increase or
decrease serum
vitamin E
without
reflecting similar
alterations in
tissue levels of
the vitamin. In
patients with
neurologic
manifestations
due to vitamin E
deficiency, the
serum vitamin E
levels are
frequently
undetectable.
abrupt onset of spastic nonprogressive

paraparesis (Howlett et al, 1990). The
upper limbs and visual pathways may
be involved. Sensory or autonomic
disturbance is absent. Years of cassava
consumption also has been implicated
in a syndrome of slowly progressive
ataxia, peripheral neuropathy, and optic atrophy seen in parts of Africa (Osuntokun, 1968). Drought increases the
natural occurrence of cyanogenic glucosides in the cassava roots. Further,
due to food shortage, the processing
procedure normally used to remove
cyanide before consumption is shortened.
pyramidal signs also may be present in

the upper limbs. Lower limb sensory
symptoms may occur; sensory signs are
rare. In the early stages, diffuse CNS excitation of somatic motor and autonomic
function may occur, including the presence of bladder symptoms. An early improvement in limb strength is seen and
may be substantial. Some patients stabilize in a subclinical, asymptomatic stage
with minimal deficits. Neurolathyrism
may be prevented by mixing grass pea
preparations with cereals or by detoxification of grass peas through aqueous
leaching.
Lathyrism
Lathyrism is a self-limiting neurotoxic
disorder that is endemic in parts of
Bangladesh, India, and Ethiopia. It
presents as a subacute- or insidiousonset spastic paraparesis and afflicts
individuals who consume the environmentally tolerant legume Lathyrus sativus (grass pea or chickling pea) as a
dietary staple (Ludolph et al, 1987).
-N-Oxalyl-amino-L-alanine, an excitotoxic amino acid in L. sativus, is the
likely toxin. The typical gait is a lurching, scissoring gait characterized by
patients walking on the balls of their
feet. In severely affected individuals,
Fluorosis
Fluorosis occurs when large amounts
of fluoride, naturally present in the
earth and water in certain parts of the
world, are deposited in bones. The
vertebral column is commonly involved. This results in back pain and
stiffness with limited spine mobility.
Neurologic manifestations are delayed
and are seen in 10% of patients with
skeletal fluorosis. These include cord
compression and, less commonly, radiculopathy (Misra et al, 1988). The
spastic paraparesis may be accompanied by sensory manifestations and
lower motor neuron involvement, but
a sensory level is not seen. Sphincter
disturbance may be present. Some patients may have decreased hearing due
to compression of the auditory nerves
in the sclerosed auditory canal. Entrapment neuropathies may result
from bony deformities. The typical radiologic findings are osteosclerosis
and ligamentous calcification. A
characteristic finding is calcification
of the interosseous membrane of the
forearm. Laboratory studies show elevation of alkaline phosphatase and
parathormone levels with normal
calcium and phosphorus. Estimations of urinary fluoride levels are
not reliable.
106
Axial (A) and sagittal (B) T2-weighted MRI in

a patient with progressive myeloneuropathy
associated with malabsorption-related
vitamin E deficiency showing increased signal (arrows) in
the posterior column of the cervical cord.
FIGURE 5-7
Vorgerd M, Tegenthoff M, Kuhne D, Malin JP. Spinal MRI in progressive

myeloneuropathy associated with vitamin E deficiency. Neuroradiology
1996;38(suppl 1):111113. Reprinted with kind permission of Springer
Science and Business Media.
TABLE 5-5
Summary of Disorders of Vitamin E Metabolism

Abetalipoproteinemia
(BassenKornzweig
Disease)
Ataxia With
Vitamin E
Deficiency
Homozygous
Hypobetalipoproteinemia
Source of
defect
Mutations in tocopherol transfer

protein gene on
chromosome 8q13
(AR)
Defect in
apolipoprotein
B gene (AD)
Genetic defect in
microsomal
triglyceride
transfer protein
(AR)
Chylomicron synthesis
and secretion
Consequence
of defect
Impaired
incorporation of
vitamin E into hepatic
lipoproteins for tissue
delivery
ApoBcontaining
lipoproteins
secreted into
the circulation
turn over
rapidly
Normal lipidation
of apoB is
prevented and
secretion of
apoB-containing
lipoproteins is
virtually
nonexistent
Impaired assembly and

secretion of
chylomicrons with
chylomicron retention
in intestinal mucosa
Fat
malabsorption
Absent
Present
Present
Present
Age of onset
Generally first
decade, adult onset
described
Early childhood
Early childhood
Early childhood
Other clinical
features
Retinitis pigmentosa,
skeletal deformities,
cardiomyopathy
Retinitis pigmentosa,
acanthocytosis, retarded growth,
steatorrhea
Impacts growth and

has gastrointestinal
manifestations but
acanthocytes are
essentially absent,
neuromuscular
manifestations are less
severe, and ocular
manifestations are
subclinical
Laboratory
findings
Very low serum

vitamin E (as low as
1/100 of normal)
Low serum vitamin E and other fat

soluble vitamins, low to
nondetectable circulating
lipoproteins (apoB, chylomicrons,
very low-density lipoproteins or
low-density lipoproteins); serum
cholesterol and triglycerides are
markedly reduced (the ratio of free
to esterified cholesterol in plasma is
normal in hypolipoproteinemia and
elevated in abetalipoproteinemia)
Hypocholesterolemia,
normal fasting
triglycerides, reduced
plasma low-density
lipoprotein, apoB,
absence of
chylomicrons after a
fat test meal
800 mg/d to 1200 mg/

d of vitamin E
(prompt
normalization of
plasma -tocopherol
concentration)
100 mg/kg to
200 mg/kg of
vitamin E
100 mg/kg to 200 mg/

kg of vitamin E
Disease
Treatment
100 mg/kg to 200

mg/kg of vitamin
E
Chylomicron
Retention Disease
AD autosomal dominant; AR autosomal recessive; apoB apolipoprotein B.
107

KEY POINT:
108
The term
tropical
myeloneuropathies
has been used
to describe a
multifactorial
condition seen
in several
developing
countries.
Associations
have included
malnutrition,
cyanide
intoxication due
to cassava
consumption,
lathyrism,
organophosphate
neurotoxicity,
malabsorption,
malnutrition,
and vegetarian
diets.
Subacute Myelo-Optic
Neuropathy
Subacute myelo-optic neuropathy
(SMON) is a myeloneuropathy with
optic nerve involvement that affected
individuals in Japan and, to a lesser
extent, elsewhere between 1955 and
1970 (Konagaya et al, 2004). Epidemiologic studies have suggested that
SMON was due to toxicity from the
antiparasitic drug clioquinol. SMON is
characterized by subacute onset of
lower limb paresthesias and spastic
paraparesis with optic atrophy. Tendon hyperreflexia and extensor plantar responses are seen, although at
times the ankle jerk is absent. The precise mechanism of action of clioquinol
has been unclear. Identification of a
myelopathy resulting from acquired
copper deficiency has led to the speculation that clioquinol-induced neurotoxicity could be a consequence of
copper deficiency because clioquinol
is a copper chelator (Kumar and
Knopman, 2005).
Tropical Myeloneuropathies
(Including Cuban
Myeloneuropathy)
The term tropical myeloneuropathies
has been used to describe a multifactorial condition seen in several developing countries. Associations
have included malnutrition, cyanide
intoxication due to cassava consumption, lathyrism, organophosphate neurotoxicity, malabsorption,
and vegetarian diets (Roman et al,
1985). Often the precise cause of the
syndrome is unknown but possibly
has been felt to be nutritional. Disorders that probably fall into this category include 19th century descriptions
of Strachan Jamaican neuropathy and
burning feet, and neurologic syndromes such as happy feet and Strachan syndrome seen in the Far East in
World War II prisoners. From 1991 to
1994, an epidemic in Cuba affected
more than 50,000 persons and caused

optic neuropathy, sensorineural deafness, dorsolateral myelopathy, dysautonomia, bulbar dysfunction, and axonal sensory neuropathy (Roman,
1994). Identified risk factors included
irregular diet, weight loss, smoking,
alcohol, and excessive sugar consumption. Patients responded to
B-group vitamins and folic acid. Overt
malnutrition was not present.
Two major categories recognized
in the past were patients with prominent sensory ataxia (tropical ataxic
neuropathy) and those with prominent spastic paraparesis (tropical spastic paraparesis). Intermediate forms
also were recognized. Human T-cell
lymphotropic virus I (HTLV-I) was
identified to be the etiologic agent of
adult T-cell leukemia/lymphoma and
HTLV-I myelitis. HTLV-I myelitis had
been called tropical spastic paraparesis in many equatorial regions and
HTLV-Iassociated myelopathy in Japan. HTLV-Iassociated myelopathy
and tropical spastic paraparesis are
now believed to be identical syndromes. HTLV-II also is recognized to
cause a chronic myelopathy that resembles tropical spastic paraparesis.
The term tropical ataxic neuropathy
currently is used to describe a broad
spectrum of neurologic conditions attributed to a toxic-nutritional cause. It
initially was used to describe a specific
neurologic syndrome seen in Nigeria
and attributed to cassava consumption.
METABOLIC MYELOPATHIES
DUE TO POSSIBLE TOXINS BUT
WITHOUT A GEOGRAPHIC
PREDILECTION
Chemotherapy-Induced
Myelopathy
Myelopathy has been reported after
administration of certain chemotherapeutic agents (Table 5-1), particularly
so with intrathecal administration.
Paraparesis after intrathecal chemo-
therapy may be related to toxicity of

the preservative used (Hahn et al,
1983). Two clinical patterns of paraparesis have been recognized (Hahn et
al, 1983). A transient, flaccid, areflexic
paraparesis with pain and anesthesia
may occur soon after the intrathecal injection. Rarely, the paralysis may ascend, with respiratory compromise and
death. This form localizes to the spinal
root. A less common form is a progressive spastic-ataxic paraparesis with
sphincteric dysfunction that is seen after
weeks of a series of intrathecal treatments. MRI in patients with intrathecal
chemotherapy-induced myelopathy
may show contrast enhancement limited to the lateral columns (Figure
5-8) (McLean et al, 1994). To prevent
intrathecal chemotherapy-induced paralysis, preservative-containing chemotherapeutic agents or diluents
should not be used intrathecally
(Hahn et al, 1983). Multiple and frequent intrathecal therapy should be
avoided.
Hepatic Myelopathy
Hepatic myelopathy (portosystemic myelopathy) is a rare complication of
chronic liver disease. It is associated
with cirrhosis and/or extensive portosystemic shunting (Conn et al, 2006).
Portosystemic myelopathy can be induced by portosystemic shunting of all
types: surgical, angiographic, or spontaneous. Preceding portosystemic encephalopathy is often, but not invariably, present. It has been suggested that
the neurotoxicity may be a consequence
of ammonia or other metabolites bypassing the liver. Hepatic myelopathy
with increased serum manganese and
MRI evidence of manganese deposition
in the basal ganglia without extrapyramidal manifestations or clinical evidence of decompensated cirrhosis also
has been reported (Gospe et al, 2000).
There is symmetric demyelination of the
lateral corticospinal tract and, less commonly, in the ventral pyramidal tracts,
posterior columns, and spinocerebellar tracts. The hallmark of hepatic myelopathy is progressive spastic paraparesis. Sensory disturbance, upper limb
involvement, and sphincteric dysfunction are minimal or absent. Variable
results have been reported after liver
transplantation.
Heroin Myelopathy
Acute myelopathy is a well-recognized
complication of insufflation of heroin
or IV heroin abuse. MRI resembles that
seen in transverse myelitis and may
show cord expansion due to an enhancing confluent cord lesion (Figure
5-9A and 5-9B) (McCreary et al, 2000).
More recently, inhalation of heroin vapor has been shown to result in a progressive myelopathy with selective involvement of the ventral pons and
lateral and posterior columns (Figure
5-9C and 5-9D) (Nyffeler et al, 2003).
The proposed mechanisms of the underlying pathophysiology include embolism of adulterants, hypotension
with border-zone infarction, vasculitis,
direct toxicity, or hypersensitivity reaction. Hypersensitivity as a possible
KEY POINT:
Hepatic
myelopathy is a
rare
complication of
chronic liver
disease. It has
been suggested
that it may be a
consequence of
ammonia or
manganese
toxicity.
109
MRI in a patient with chemotherapy-related

myelopathy. Sagittal MRI (A) and axial (B) T1
with contrast MRI showing an enhancing
intramedullary cervical cord lesion (A) (arrows), which on
axial sequences shows involvement of the lateral columns
(B) (arrows). The patient developed delayed-onset
progressive paraplegia a few weeks after intrathecal
administration of methotrexate and cytarabine.
FIGURE 5-8
Modified with permission from McLean DR, Clink HM, Ernst P, et al.
Myelopathy after intrathecal chemotherapy: a case report with unique
magnetic resonance imaging changes. Cancer 1994;73(12):30373040.
Copyright 1994, John Wiley & Sons, Inc.

KEY POINTS:
Acute or
progressive
myelopathies are
well-recognized
complications of
heroin abuse.
Rarely, a
myelopathy may
be the presenting
manifestation of
superficial
siderosis. A
history of prior
intradural surgery
or trauma is
common.
mechanism is suggested by the fact

that, not infrequently, the myelopathy
occurs after a period of abstinence followed by single use.
Superficial Siderosis-Related
Myelopathy
Superficial siderosis of the CNS results from hemosiderin deposition in
the subpial layers of the brain and
spinal cord. Patients present with
slowly progressive gait ataxia and
sensorineural hearing impairment.
Additional manifestations include
anosmia, cognitive decline, and myelopathy. Rarely, a myelopathy may
be the presenting manifestation of
superficial siderosis. A history of
MRI in heroin myelopathy. A and B, Cord

MRI in a patient with acute heroin
myelopathy. A, Axial gradient-echo image
shows a mildly expanded cord with abnormal
hyperintensity. B, Sagittal T1-weighted cord MRI with
contrast shows that abnormal enhancement involves a
long segment of midthoracic cord. C and D, MRI in a
patient with progressive heroin myelopathy. C, Axial T2weighted MRI of the caudal pons showing bilateral
hyperintense signals in the pyramidal tract (arrows). D,
Axial T2-weighted cord MRI at the craniovertebral junction
shows bilateral hyperintense signal in the dorsal column
(arrows) and lateral columns (arrowhead).
FIGURE 5-9
110
Reprinted with permission from McCreary M, Emerman C, Hanna J, Simon

J. Acute myelopathy following intranasal insufflation of heroin: a case
report. Neurology 2000;55(2):316 317. Copyright 2000, AAN
Enterprises, Inc.
Reprinted from Nyffeler T, Stabba A, Sturzenegger M. Progressive
myelopathy with selective involvement of the lateral and posterior columns
after inhalation of heroin vapor. J Neurol 2003;250(4):496 498. With kind
permission of Springer Science and Business Media.
prior intradural surgery or trauma is

common. Despite extensive investigations, the cause of bleeding is often not apparent. T2-weighted MRI
may show a characteristic hypointensity around the brain, brain stem,
and spinal cord results (Figure
5-10). Cerebellar and spinal cord atrophy are often present (Figure
5-10A, 5-10C, and 5-10D). Some patients may show an intraspinal fluidfilled collection of variable longitudinal extent (Figure 5-10E1 and
5-10E2) (Kumar, 2007b).
Organophosphate Toxicity
Triorthocresyl phosphate is an organophosphate compound that has
been used as an adulterant. Pathologic studies have shown involvement of the anterior horn cell, corticospinal tracts, and peripheral
nerves. An outbreak of triorthocresyl
phosphate-related neurologic toxicity affecting adolescent girls occurred in a tea plantation in Sri Lanka
during 1977 and 1978 (Senanayake
and Jeyaratnam, 1981). The cause
was attributed to triorthocresyl phosphate present as a contaminant in a
type of cooking oil that, because of
its presumed nutritive value, was
given in large amounts to pubertal girls
in the postmenarche period. Contamination likely occurred when the oil was
transported in containers previously
used to store mineral oils. Sensory abnormalities were minimal. A distal axonopathy and pyramidal tract dysfunction
were
present.
Significant
improvement was noted over a 3-year
period.
The signs and symptoms of acute
organophosphate toxicity are due to
acetylcholinesterase inhibition and resulting muscarinic and nicotinic dysfunction. Pralidoxime, a reactivator of
inhibited acetylcholinesterase, is the
specific antidote. It is used in conjunction with atropine in the acute stages.
In some patients, after resolution of
FIGURE 5-10 MRI in superficial siderosis. Axial T2 (A, B, C, E2), sagittal T1 (D), and sagittal T2 (E1) MRI of the brain
(A, B) and cord (C, D, E1, E2) in different patients with superficial siderosis. A, Cerebellar atrophy and
hemosiderin deposition along the cerebellar folia. B, Hemosiderin deposition around the brainstem. C,
Hemosiderin deposition around the spinal cord (arrow) with cord atrophy (dotted arrow). D, Hemosiderin deposition
along the spinal cord (arrow) with severe cord atrophy (dotted arrow). E1 and E2 (inset), A longitudinally extensive
fluid-filled intraspinal collection in addition to cord atrophy and hemosiderin deposition.
the cholinergic crisis, an intermediate

syndrome develops (Senanayake and
Karalliedde, 1987). This is likely a neuromuscular junction defect, characterized by weakness of neck flexors and
proximal limb and respiratory muscles.
Organophosphate-induced delayed
neurotoxicity is a well-recognized
complication of some organophosphorus compounds and is possibly
due to phosphorylation and subsequent aging of neurotoxic esterase in
the nervous system (Lotti et al, 1984).
It occurs 1 to 3 weeks after acute
exposure and after a more uncertain
duration after chronic exposure. Organophosphate-induced delayed neurotoxicity may occur in the absence of
the cholinergic or intermediate phase.
The symptoms include distal paresthesias, progressive leg weakness and
wasting, and cramping muscle pain.
Upper limb involvement and pyramidal tract dysfunction may be evident.
Sensory loss, when present, is mild.
The red blood cell cholinesterase activity is less rapidly depressed than the
serum cholinesterase activity and is a
measure of chronic exposure to organophosphates.
111

CONDITIONS PRESENTING AS A
METABOLIC MYELOPATHY BUT
OFTEN ASSOCIATED WITH
ADDITIONAL EVIDENCE OF CNS
INVOLVEMENT
Adult Polyglucosan Body
Disease
Adult polyglucosan body disease is a
rare neurologic disorder characterized
by central and peripheral nervous system dysfunction (Robitaille et al,
1980). The pathologic hallmark is the
presence of polyglucosan bodies in
the brain, spinal cord, peripheral
nerves, and other organs. Polyglucosan bodies are periodic acid-Schiff
positive cytoplasmic spheroids composed of branching polysaccharides.
They also can be seen in healthy older
subjects (corpora amylacea), glycogen
storage disease type IV, phosphofructokinase deficiency, and progressive
myoclonic epilepsy. Reduced glycogen
branching-enzyme activity may be
present in some patients with adult
polyglucosan body disease. Despite re-
duction in the enzyme, mutations in the

gene may not be present, suggesting the
possibility of polygenic environmental
or genetic factors (Klein et al, 2004).
Adult polyglucosan body disease
presents with progressive upper and
lower motor neuron dysfunction, peripheral neuropathy, sphincteric disturbances, and occasionally dementia
(Klein et al, 2004; Robitaille et al,
1980). The typical age of symptom onset is from the fifth to seventh decades.
Adult polyglucosan body disease also
can present as a progressive myelopathy (Klein et al, 2004). The polyglucosan bodies may be seen on axillary
skin or sural nerve biopsy. MRI findings include cerebral, cerebellar, and
spinal cord atrophy with extensive,
confluent, nonenhancing areas of increased T2 signal involving the
periventricular and subcortical white
matter (Figure 5-11) (Klein et al,
2004). Nerve conduction studies show
a predominantly axonal sensorimotor
peripheral neuropathy. Somatosen-
112
FIGURE 511 MRI from a patient with adult polyglucosan body disease. A, Midline sagittal T1-weighted MRI with
moderate generalized cerebral atrophy and more severe cerebellar atrophy, with particular involvement
of the vermis (arrow). There is atrophy of the pons and medulla, with preservation of the characteristic
appearance of the pons, and cervical cord atrophy. B, Axial T2-weighted spin-echo image at the level of the midpons
demonstrates extensive cerebellar and vermian atrophy (long arrow). There is markedly increased T2 signal
symmetrically involving the dentate nucleus (arrow) bilaterally and abnormal signal involving the anterior midpons
and cerebellar peduncles (arrowhead). C, Axial fluid-attenuated inversion recovery image at the level of the midbrain
with diffuse abnormal increased signal within the midbrain (arrowhead), as well as confluent signal abnormality
involving the periventricular white matter adjacent to the temporal horns.
Reprinted with permission from Klein CJ, Boes CJ, Chapin JE, et al. Adult polyglucosan body disease: case description of an expanding genetic and
clinical syndrome. Muscle Nerve 2004;29(2):323328. Copyright 2004, John Wiley & Sons, Inc.
sory evoked potential studies may

show central conduction delay.
DIFFERENTIAL DIAGNOSIS
A compressive etiology should be aggressively sought in patients presenting with a myelopathy. Dural arteriovenous fistulas can present as a
progressive myelopathy. Intramedullary tumors, progressive multiple sclerosis, and, rarely, transverse myelitis
are included in the differential diagnosis of a metabolic myelopathy. When
dealing with a myelopathy in the setting of malignancy, the possibilities of
compressive myelopathy, paraneo-
plastic myelopathy, or myelopathy

as a delayed effect of radiation need
to be considered. Hereditary spastic
paraparesis can mimic adrenomyeloneuropathy and other leukodystrophies. A progressive myelopathy
also can be seen in some mitochondrial disorders. Vitamin E deficiency
can mimic hereditary ataxias such as
Friedreich ataxia and spinocerebellar
degeneration. The clinical presentation of the chronic form of hexosaminidase A deficiency may suggest
a possible diagnosis of spinocerebellar
degeneration, Friedreich ataxia, or
ALS.
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115
KEY POINT:
Rapid diagnosis
and referral to a
surgeon are
critical in
improving
outcomes for
compressive
myelopathy.
COMPRESSIVE AND
TRAUMATIC
MYELOPATHIES
Jeremy L. Fogelson, William Krauss
ABSTRACT
There is a broad spectrum of causes of compressive myelopathies. Resulting neurologic deficits may not improve after decompression. Early diagnosis and treatment are paramount to ensuring long-term functional outcome, and errors in
diagnosis with resultant delays in treatment can have drastic consequences. The
history, including patient demographics and the onset and progression of the
disease, and physical examination are critical tools in arriving at a correct diagnosis.
Very often, the diagnosis is obvious.
After the history and physical examination have concluded that a myelopathy is
present, imaging is necessary to evaluate for a compressive etiology. Spinal MRI,
including gadolinium-enhanced images, is the diagnostic study of choice and
should be obtained expediently. Major advantages of MRI include its multiplanar
capabilities and the ability to visualize nonosseous lesions.
Dependent on MRI findings, other radiologic evaluations may be necessary,
including noncontrast CT and plain x-rays. If an MRI is not obtainable because of the
presence of a pacemaker, claustrophobia, lack of availability, clinical situation, or a
multitude of other possible reasons, CT myelography is an excellent alternative tool.
Plain myelography can help in defining a compressive lesion. The goal of imaging
studies is to define the lesion and guide surgical decision making if cord compression is found.
later in this issue, is indicated by yellow shading throughout this chapter.
116
INTRODUCTION
Compressive myelopathy has innumerable causes. But, as a practical
matter, those encountered in routine
clinical practice are few. In many
cases, the diagnosis is obvious.
Causes of compressive myelopathy
fall into three major categories: neoplastic, non-neoplastic, and traumatic. The most common causes are
compression as a result of tumors
(most often metastatic), degenerative
discs, or bone fragments. This chap-
ter will focus on the more common

causes of myelopathy.
Neoplastic
Metastatic disease is a common cause
of cord compression encountered by
clinicians (Ecker et al, 2005). Primary
tumors of the spine and spinal cord
are rare causes of myelopathy when
compared with metastatic lesions.
Non-neoplastic
Degenerative spondylosis is a common feature of the aging spine. When
Relationship Disclosure: Drs Fogelson and Krauss have nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Fogelson has nothing to disclose. Dr Krauss
includes figures of, but does not discuss, the unlabled use of cervical pedicle screws.
disc degeneration occurs in certain locations in the cervical spine, cord compression and myelopathy may occur.
Cervical spondylotic myelopathy is the
most common non-neoplastic cause of
compressive myelopathy. Myelopathy is
seen as an uncommon manifestation of
connective-tissue disorders affecting the
spine. It also may result from unusual
congenital anomalies. Spinal epidural
abscess is another, albeit rare, non-neoplastic cause of myelopathy.
Traumatic
Whereas most compressive myelopathies occur as a result of relatively slow
processes, trauma is an explosive
event that results in cord compression
within seconds. In some cases, the
compression will last only for a few
seconds or less. In other cases, displaced bone fragments will continue
to compress the cord.
CLINICAL APPROACH
History
A complete and thorough history is
essential. The purpose of the history is
twofold: (1) It will help determine
whether compression exists and, if so,
its possible sources. (2) It will guide
the physical examination. In cases of
trauma, the patient or onlookers will
be able to provide details that should
make the cause obvious. In cases of
neoplastic compression, the patient
may have a known history of cancer.
Cases due to non-neoplastic causes
present a bigger challenge. Trauma is
typically seen in young males. Older
patients frequently have neoplastic or
non-neoplastic causes.
The rate of progression is important. As a rule, the sudden, abrupt onset of myelopathy is uncommon in
neoplastic and non-neoplastic causes.
If the onset is acute, compressive etiologies other than trauma are unlikely.
Many patients will complain of the insidious onset of gait problems. If the
lesion is located in the cervical spine,
patients may report the onset of hand

numbness. Involvement of nerve roots
by tumor or spondylosis may cause radicular pain, numbness, or weakness.
Bowel and bladder dysfunction may occur but are seen late in the clinical
course of most of these diseases.
Axial spine pain is a common
complaint and should not be overlooked. Very often, patients with neoplastic compression report night pain
in the spine. This occurs as a result of
tumor swelling when patients are supine. Frequently, the compression will
be located in the general region of the
axial spine pain.
Examination
Before the neurologic examination, it
is important that the clinician perform
a direct examination of the spine. The
vertebral column should be inspected,
palpated, and percussed over its entire
extent. Special attention should be
given to any spine region implicated
by the patients history. During inspection, the clinician should check for interspinous widening, skin ulceration
over the spine, or obvious deformities
of spinal alignment, which are all very
common in trauma. Gentle palpation
may find point tenderness, indicating
an underlying tumor. Percussion is
mainly an extension of palpation and
may also disclose point tenderness.
The physical examination should
encompass a complete neurologic examination with special attention to its
motor, sensory, and reflex components. Localization is based on sensory
and motor findings. Sensory levels are
quite common in traumatic and neoplastic causes, and identification of
them is extremely useful in ordering
appropriate imaging studies. Some patients will have diffuse sensory
changes that are difficult to ascribe to a
specific spinal level. The clinician
should attempt to differentiate motor
findings into upper and lower motor
neuron types. Findings consistent with
KEY POINTS:
Although the
words
compressive
myelopathy
conjure a large
differential
diagnosis, the
possibilities are
usually very
narrow with the
combination of
thorough
history, accurate
examination,
and MRI.
MRI is the
criterion
standard
imaging
modality in the
workup of
myelopathy and
should be
obtained
expediently.
117
COMPRESSIVE AND TRAUMATIC MYELOPATHIES

KEY POINTS:
118
Although back
pain is a
common
complaint, the
presence of
night pain is a
worrisome
finding,
suggesting
metastatic or
primary
involvement of
the spine by a
neoplasm.
The direct
examination of
the spine often
is neglected but
can be useful in
the workup of
myelopathy.
a lower motor neuron lesion are very

helpful; they may localize the compressive lesion to a specific nerve root.
The reflex examination plays a key
role in differentiating upper and lower
motor nerve root lesions. Furthermore,
the presence of lower motor neuron
findings can help differentiate compressive causes of myelopathy from
noncompressive causes. The latter
typically do not cause root involvement. Brown-Sequard syndrome is
commonly seen in neoplastic and nonneoplastic causes of compressive myelopathy. Central cord syndrome is
common in traumatic causes.
Imaging
MRI. MRI is a crucial study in the evaluation of any patient suspected of having a compressive myelopathy. Every
effort should be made to obtain a complete MRI of the region of interest. This
should include T1-weighted and T2weighted sequences. Coronal and sagittal sequences are extremely helpful
in both diagnosis and treatment. Gadolinium contrast is also very useful in
evaluating neoplastic causes of myelopathy.
Plain films. Unless they show obvious bony changes related to spondylosis or neoplastic disease (osteolytic
or osteoblastic activity), plain films are
not very helpful in the initial evaluation. If the patient has severe tenderness over a specific spine region, a
plain film may disclose a pathologic or
occult fracture. In some cases, plain
films obtained for complaints of axial
spine pain indicate the presence of a
more sinister lesion.
CT myelography. In some cases,
patients will not be able to undergo an
MRI. In these cases, CT myelography
is an excellent alternative study. CT
myelography is unparalleled in its ability to define bony anatomy. In cases of
cervical spondylosis, it is superior to
MRI in defining the pathologic anatomy. In neoplastic cases, it can demContinuum: Lifelong Learning Neurol 2008;14(3)
onstrate tumor as well as pathologic

bony changes such as fractures, osteolysis, and osteoblastic activity. Its major drawback is that it is an invasive
study requiring more resources than
the typical MRI study.
NEOPLASTIC COMPRESSION
Spinal Metastasis
Spine metastases occur in a large proportion of patients with metastatic
neoplasms. The most common malignancies that spread to the spine are
breast, lung, prostate, kidney, lymphoreticular, and myeloma (Ortiz Gomez, 1995). The spinal regions most
affected are the lumbar spine, then
thoracic, and then cervical, probably
related to the aggregate vertebral body
size. However, thoracic lesions are more
often neurologically symptomatic, followed by lumbar and cervical. This finding is attributed to the smaller space
available for the spinal cord in the thoracic canal compared with the cervical
canal and its marginal vascular reserve.
Clinical features. Ninety percent
of patients with spinal metastases describe pain at presentation, 50% to
77% demonstrate neurologic deficits,
31% to 46% are nonambulatory, and
38% have bowel or bladder difficulty
(Patchell et al, 2005; Sundaresan et al,
1985). Gokaslan and colleagues (1998)
described three types of pain: local
pain, axial spinal pain, and radicular
pain. Local pain is typically constant. It
is not positional because it is due to
stretching of the periosteum from expansion of the vertebral body by the
tumor. It may be present at rest or
while in bed. Axial pain is usually positional and is due to spinal deformity
or structural abnormalities such as
fractures, collapse, or instability. It also
localizes to the area involved. Radicular pain results from mass effect on the
nerve root and should fit a dermatomal distribution. Associated paresthesias or radicular deficits may be
present. The pain may be positional if

it is secondary to instability or loading.
Nonsurgical management, encompassing radiation or chemotherapy,
may improve local pain or radicular
pain by decreasing mass effect of the
tumor. Axial spinal pain will not be
alleviated by radiation or chemotherapy, however, whereas spinal stabilization is thought to be very effective.
Decompression of the nerve root may
be necessary to relieve radicular pain
(Gokaslan et al, 1998).
Investigations. After a detailed
history and physical examination raise
suspicion for myelopathy or metastatic
disease, a wide range of imaging is
used. Plain radiography may identify
fracture dislocations, osteoblastic and
osteolytic lesions, vertebral body collapse, and pedicle erosions. The disc
margins are usually unaffected, in
comparison with infectious processes,
which can cause extensive disc destruction and may erode through the
endplates. MRI is the standard for the
evaluation of spinal metastases. In patients with suspected metastases, Cook
and colleagues (1998) suggest that entire spinal MRI should be performed;
sensory levels may be misleading in
26% of cases, and asymptomatic disease may be present. CT scanning is
also necessary in metastatic workup
for evaluation of spinal stability and
for preoperative and intraoperative
planning. Radionuclide bone scans,
SPECT, and PET may be used but are
not part of the standard evaluation and
are not available at all centers. If the
diagnosis is not clear, CT-guided needle biopsy may be used, yielding diagnostic tissue in 95% of cases (Schiff
et al, 1997).
Management. Treatment of patients with spinal metastasis requires a
multidisciplinary team. The spectrum
of treatment can range from hospice
care, radiation, chemotherapy, and interventional radiologic procedures, including vertebroplasty or kyphoplasty,
to the most aggressive measures,

which could involve a neurosurgeon,
thoracic surgeon, general surgeon,
and orthopedic surgeon. From a neurologic perspective, the response to
radiation treatment is dependent on
pretreatment ambulatory status. Thus,
expediency of the evaluation and
treatment planning is paramount.
Steroids. Once the diagnosis is
confirmed, the first step in treatment
usually consists of high-dose steroids.
A standard dose regimen has not been
validated. Administration ranges from
10 mg of dexamethasone to 100 mg of
dexamethasone followed by 24 mg every 6 hours, or even to traumatic spinal
cord injury dosing (30-mg/kg bolus
followed by 5.4 mg/kg/h of methylprednisolone for 23 hours), until the
start of definitive treatment. The doses
may be reduced in patients with severe diabetes or other contraindications when deemed appropriate
(Ecker et al, 2005; Patchell et al, 2005).
Radiation. In patients destined for
radiation therapy, treatment usually is
started within 24 hours. In radiationsensitive tumors, including lymphoproliferative malignancies, multiple
myeloma, and germ cell tumors, radiation improves pain and functional
status in the majority of patients. The
radiation treatment parameters for epidural spinal metastases vary, but a
common schedule is to deliver 30 Gy
in 10 fractions. Typically, the radiation
portal is 8 cm wide, centered on the
lesion, and treated above and below
the lesion by one or two vertebral levels.
Stereotactic radiosurgery of lesions
located within the skull has reached
widespread use for tumors (both metastatic and intrinsic), vascular lesions,
and pain syndromes. The immobilization of the skull within a stereotactic
frame and minimal movement of the
intracranial structures allow high-radiation dose to the intended target while
minimizing exposure of surrounding
KEY POINT:
Current
literature
supports
aggressive
surgical
decompression
and stabilization
in select patients
with metastatic
spinal cord
compression,
and the first step
should be
surgical
consultation,
preferably
before
beginning
irradiation.
119

KEY POINTS:
120
Stereotactic
radiosurgery is a
promising
therapy for
spinal tumors;
until rigorous
comparison is
completed,
however, it
should be
considered
experimental.
Performing
surgery before
radiation
therapy is
preferred to
provide possible
benefits of
immediate
neural
decompression
and for the
purpose of
improved
wound healing,
which is more
problematic
after radiation.
healthy tissue. Until recently, physicians were unable to treat spinal lesions with stereotactic radiosurgery
because there has been no available
equipment that can immobilize the
spine. However, technologic advances
have resulted in radiation delivery systems that can adjust for patient movement. One method utilized periodically obtains orthogonal x-ray imaging
of the patient during the treatment session. A computer then uses those images to account for patient movement
and adjusts the targeting of the linear
accelerator
accordingly.
Another
method uses an on-board CT scanner so that the targeting is calculated
after the patient is positioned. The literature is growing regarding the experience of stereotactic radiosurgery of the
spine, with authors reporting positive
results (Degen et al, 2005; Gerszten et al,
2004; Gibbs et al, 2007). However, optimal dosing and patient selection, as well
as comparative efficacy with conventional radiation therapy, have not been
worked out. It seems likely that stereotactic spinal radiosurgery will follow in
the footsteps of cranial radiosurgery and
develop into a safe, effective, and less
onerous alternative than conventional
spinal irradiation. It seems clear that
treatment of spinal metastatic lesions in
the future will be based on some variation of current stereotactic spinal radiosurgical techniques.
Vertebroplasty or kyphoplasty. Although this chapter is focused on spinal cord compression, it is worth mentioning that painful metastatic spinal
disease without epidural compression
may be treated with vertebroplasty or
kyphoplasty. In a series of 56 patients
who underwent 65 vertebroplasty procedures and 32 kyphoplasty procedures, more than 80% of the patients
experienced pain relief without any
complications (Fourney et al, 2003).
Surgery. The role of open surgery in
the treatment of spinal metastatic disease has been clarified by a recent ranContinuum: Lifelong Learning Neurol 2008;14(3)
domized trial comparing surgery plus

radiation to radiation alone (Patchell et
al, 2005). The majority of patients who
undergo surgery and radiotherapy will
ambulate and survive longer than patients who receive only radiotherapy.
Surgery, therefore, should be a strong
treatment consideration in these patients
(Case 6-1).
Surgery consists of two phases: decompression and reconstruction. Decompression of the cord is a straightforward goal. It is best accomplished
by direct removal of tumor from its
interface with the dural tube. Until recently, many surgeons were overly dependent on laminectomy to decompress the cord. Laminectomy is a
posterior approach suitable for posteriorly situated tumor masses. In many
cases, the tumor is anterior to the cord,
making laminectomy an ill-suited
choice. Anterior and anterolateral approaches (retropharyngeal, transthoracic, transabdominal) to the spine are
better suited to decompress the dural
tube in the majority of metastatic lesions. In a recent review article,
Witham and colleagues (2006) recommended the following indications for
surgery in patients with metastatic epidural spinal cord compression: . . . the
need to establish a diagnosis, spinal instability, epidural cord compression
with cord dysfunction from bone or
from tumor that is not highly radiation
sensitive. Reconstruction means restoring structural stability to spinal elements that have been compromised by
tumor; frequently, the decompression
phase of the operation may also compromise spinal stability. Reconstruction
often entails the implantation of bone
grafts and metallic instrumentation.
Bracing may also be used to help assist
in restoring spinal stability. After the surgical wound has been allowed adequate
time to heal, radiation therapy is still
recommended to treat either gross or
microscopic residual disease. Usually, 2
to 3 weeks of recovery time is necessary
Case 6-1
A 55-year-old man presented with a 10-year history of renal cell carcinoma, which was found to
be metastatic 7 years previously. At that point, he had an asymptomatic left first rib lesion with
multiple additional metastatic lesions involving the liver, lung, and bone. Shortly after the
metastatic presentation, he had orthopedic procedures done for metastases in the humerus and
femur. This resulted in continued ambulation and decreased bone pain. He underwent
irradiation to the first rib lesion 3 years previously because of progression that had resulted in
extraforaminal left C7 root compression. The radicular pain improved until 1 year previously,
when he had progressive neck pain and right-sided T1 myotome weakness. He received
radiofrequency ablation, which relieved the pain for another 4 months. At this presentation, the
patient noted mild difficulty initiating urination, clumsiness of his hands, and gait unsteadiness.
These had become progressively worse over the previous several weeks. The pain at the base of his
neck had been increasing, requiring escalation of opioids. Examination demonstrated point
tenderness at the cervical/thoracic junction, wide-based gait, decreased strength in the intrinsic
muscles of the hands, and bilateral Babinski signs. MRI demonstrated increased size of the C7-T1
tumor, with severe cord compression (Figure 6-1A, 6-1B, and 6-1C). CT showed destruction of the
vertebral body (Figure 6-1C). No further radiation could be performed because of already
overlapping fields. He was started on dexamethasone, 10 mg IV load, followed by 6 mg every 6
hours. He underwent an anterior-posterior decompression/reconstruction of the C7/T1 segment
(Figure 6-1D).
121
FIGURE 6-1
Sagittal (A) and axial (B) cervical spine T1-weighted imaging after gadolinium demonstrating
infiltration of the T1 vertebral body with epidural extension of tumor and severe cord
compression. C, Axial cervical spine CT demonstrating erosion of the T1 vertebral body. D,
Anterior-posterior radiograph demonstrating posterior fusion and decompression.
Comment. Bony metastases can cause significant pain and morbidity. In certain circumstances,
resection and reconstruction can result in significant gain of function, retention of
independence, and improvement in pain. This patient received a total of 7 years of functional
survival after bony resection in the leg, arm, and spine. He remained ambulatory until his death
5 months after his spine surgery, secondary to widely progressive disease.

Case 6-2
122
A 55-year-old man was evaluated for a 2-month history of progressive leg weakness. He had
noted difficulty getting out of the car and a few days earlier had a fall because his legs gave
out. He also noted numbness of his legs and lower abdomen. He had two episodes of urinary
incontinence. On further questioning, he indicated that his baseline urinary frequency and
urgency were unchanged (history of benign prostatic hypertrophy), but instead that he had
difficulty
making it to
the
bathroom
because of
his leg
weakness.
Examination
revealed a
sensory level
at T8, below
which
superficial
pain
discrimination
was intact
but was not
as sharp.
He had
grade 4/5
weakness in
the proximal
muscles of
the leg and
normal
strength
A, Sagittal T2-weighted MRI of the thoracic spine demonstrating an
FIGURE 6-2
distally. A
intradural extramedullary lesion at the T8-9 interspace, dorsal to the
Babinski sign
spinal cord, with severe compression/deformation of the cord. B,
Intraoperative photograph demonstrating the T8-9 meningioma with the spinal cord
was present
visualized deep to the tumor. The dura is tacked up laterally.
on the left
and
equivocal on the right. Rectal tone and perineal sensation were normal. MRI revealed an
intradural-extramedullary enhancing lesion at T8-9 with severe mass effect on the spinal cord
(Figure 6-2A).
Comment. The patient underwent T8 and T9 laminectomy, and the tumor was resected.
Pathology revealed a meningioma. Neurologic examination was unchanged after surgery, and at
3-month follow-up the leg weakness had resolved (Figure 6-2B). Without resection, this patients
symptoms would have been progressive, eventually leading to paraplegia. Preoperative function
usually is the best predictor of neurologic function; thus prompt diagnosis and referral to a
surgeon are important to improving outcome.
before a standard course of radiotherapy may begin.

Nonmetastatic Neoplasms
Intradural tumors are a rare but treatable cause of myelopathy. The most
frequent extramedullary tumors include nerve sheath tumors (neurofibromas and schwannomas) and meningiomas (Case 6-2). They typically
involve the nerve roots, causing expansion of the nerve root foramen,
and may include an extraspinal component. Usually, extramedullary tumors are benign, and a curative resection is possible. The most frequent
intramedullary tumors are ependymomas and astrocytomas. Although usually not resectable, the prognosis for
astrocytomas is highly dependent on
the grade. On the other hand, although ependymomas do not have a
capsule, they usually do not invade
adjacent spinal cord tissue and can be
removed.
Clinical features. Primary tumors
of the spinal column are quite rare and
often present with pain in a similar
fashion to metastatic tumors (Table
6-1). Because of the nonspecific nature of back pain, the diagnosis may
be delayed. The pain is often present
at night or when the patient is at rest.
Depending on the size, tumors of the
axial spine and soft tissue can cause
myelopathy or radiculopathy. The
spectrum of tumor types is broad, owing to the multiple tissue origin of the
tumors. Malignant tumors are common
when patients are past age 20.
Investigations. Frequently, the
accurate characterization of spinal tumors requires multiple imaging modalities, including MRI, CT for bony
anatomy (without myelography if MRI
is available), dynamic radiographs to
check for stability, and spinal angiogram to assess vascularity and consider embolization.
Management. As with any tumor
involving the spine, considerations include compression of the neural elements, stability of the spine, and the
type of resection that is possible. Resection categories are: (1) en bloc: removal of the tumor with a wide margin
of normal tissue; (2) marginal resection: removal using a pseudocapsule
plane; and (3) intralesional: a debulking, incomplete removal (Sansur et al,
2007). Advances in technology, including preoperative embolization to
decrease blood loss, and newer spinal
stabilization techniques and hardware

have led to decreased morbidity and
mortality of primary spinal tumors.
NON-NEOPLASTIC
COMPRESSION
Pathophysiology. Cervical spondylotic myelopathy is the most common
cause of spinal dysfunction in elderly
persons and nontraumatic spastic
paraparesis and quadriparesis (Moore
and Blumhardt, 1997). Spondylosis is
defined as any degenerative disease of
the spine and occurs as part of the
aging process. This begins with disc
degeneration, which results in increased mechanical stress on the endplates and the adjacent vertebral body.
Subperiosteal bone formation occurs,
leading to osteophytic bars, which can
cause compression of neural structures. It is thought that the bone formation is an attempt to disperse the
load over a larger area, leading to
more stability. Repeated occupational
trauma, smoking, Down syndrome,
and genetic predisposition are risk factors for cervical spondylosis (Baron
and Young, 2007). As the spondylosis
worsens, myelopathy may develop
and is attributed to three mechanisms:
(1) static-mechanical, (2) dynamic-mechanical, and (3) cord ischemia. The
static-mechanical mechanism is due to
the hypertrophic anterior osteophytes
or disc extrusions, along with age-related hypertrophy of the ligamentum
flavum. In addition, if deformity occurs, such as kyphosis or subluxation
from instability, the stenosis may be
worsened. A congenitally small cervical canal predisposes patients to cervical spondylotic myelopathy. The absolute anterior-posterior diameter of
less than 14 mm is considered congenital stenosis. If axial reformatted images are not available, this can be estimated on lateral x-ray using a ratio of
the developmental sagittal canal diameter divided by the anteroposterior
123
TABLE 6-1
Primary Tumors of the Spine
True Bone Tumors
Associated Bone Tumors
Osteogenic
Vascular
Osteoma
Hemangioma
Osteoid osteoma
Aneurysmal bone cyst
Osteoblastoma
Hemangiopericytoma
Osteosarcoma
Hemangioendothelioma
Osteoclastic
Giant cell tumor
Chondroblastic
Chondroma
Enchondroma
Angiolipoma
Angiosarcoma
Notochord
Chordoma
Marrow
Osteochondroma
Plasmacytoma
Chondroblastoma
Myeloma
Chondrosarcoma
Ewing sarcoma
Fibroblastic
Adipose
Fibroma
Lipoma
Fibrosarcoma
Angiolipoma
Fibrous histiocytoma
Reprinted with permission from Camins MB, Jenkins AL, Singhal A, Perrin PG. Tumors of the vertebral axis:
benign, primary malignant, and metastatic tumors. In: Winn HR, ed. Youmans neurological surgery. 5th ed.
Philadelphia: WB Saunders, 2003:4836. Copyright 2004, Elsevier.
124
vertebral body diameter (Yue et al,

2001). The dynamic mechanism is due
to the normal flexion and extension of
the cervical spine. During extension,
the ligamentum flavum may buckle; in
flexion, the cord is draped over the
osteophytic bars. In the ischemic
model, venous congestion, compression of large vessels such as the anterior spinal artery, and reduced flow in
the pial plexuses may be present
(Baron and Young, 2007).
Clinical features. Symptoms generally develop insidiously and include
neck stiffness, neck and shoulder pain,
clumsiness of the hands, numbness
and tingling in the hands, and weakness or stiffness in the legs (Table
6-2). Patients may report difficulty
with fastening buttons or jewelry or

changes in handwriting. Unsteadiness
of gait, which may be most noticeable
while walking in the dark, is usually
present.
Hyperreflexia is common, and
Babinski sign, Hoffmann sign, Lhermitte sign, or ankle clonus may be
present. Some patients may have signs
and symptoms of myeloradiculopathy
(myelopathic and radicular symptoms). For example, a patient with
spondylosis at the C5-6 interspace may
have absent biceps and supinator reflexes due to radicular compromise
and hyperactive triceps reflex due to
myelopathy. Weakness and atrophy
also may be present. Typically, pa-
TABLE 6-2
Clinical
Presentation of
Cervical
Spondylotic
Myelopathy
Common Symptoms
Clumsy or weak hands
Leg weakness or stiffness
Neck stiffness
Pain in shoulders or arms
Unsteady gait
Common Signs
Atrophy of the hand
musculature
Hyperreflexia
Lhermitte sign (electric
shocklike sensation down the
center of the back following
flexion of the neck)
Sensory loss
Reprinted with permission from Young WF.

Cervical spondylotic myelopathy: a common
cause of spinal cord dysfunction in older persons [published erratum appears in Am Fam
Physician 2001;63(10):1916]. Am Fam Physician 2000;62(5):1064 1070, 1073. Copyright 2000, American Academy of Family
Physicians. All rights reserved.
tients present with weakness in the

intrinsic muscles of the hand, triceps,
iliopsoas, and quadriceps (Chiles et al,
1999) (Case 6-3).
Management. Few studies have
analyzed the natural history of cervical
spondylotic myelopathy. Some authors believe that patients treated nonoperatively will have progressive deterioration. A recent prospective trial
examining the outcomes after decompression for cervical spondylotic myelopathy showed significant improvements in neurologic function. More
than 71% of patients improved in sensory or motor function in both upper
and lower extremities or in sphincter
function. The improvement plateaued
at 6 months, and the mean follow-up
was 53 months (Cheung et al, 2007).

These results correlate with multiple
other studies demonstrating improvement in neurologic function after decompression (Carol and Ducker, 1988;
Chiles et al, 1999; Fessler et al 1998;
Yonenobu et al, 1992).
Nonoperative treatment for cervical
spondylotic myelopathy has not been
shown to alter the disease. Primarily,
anti-inflammatories and other medicines
can be used to treat the pain syndromes
that may be significant in cervical spondylotic myelopathy (Mazanec et al,
2007). Some authors claim that cervical
traction can improve the radicular symptoms and axial neck pain that may be
associated with myelopathy. In patients
with modest complaints, symptoms that
appear to be stable, no evidence of spinal instability, and no T2-signal change
within the cord, nonoperative management may be offered with serial follow-up and symptomatic treatment
(Matz et al, 2007). Patients with more
advanced signs and symptoms or those
who have demonstrated progression
over time are offered spinal cord decompression. In patients who choose
surgical treatment, anterior, posterior, or
combined approaches may be used.
The primary goal is decompression of
the spinal cord; however, other factors
are considered in determining the best
approach. Secondary goals include realignment of the cervical spine, stabilization and/or correction of instability,
and/or correction of deformity (Matz et
al, 2007). In patients with congenitally
short pedicles, with primarily posterior
mass effect, multilevel disease, and normal cervical lordosis, posterior decompression without fusion may be considered. Anterior approaches are useful for
single-level disease, compression that is
primarily ventral, angular interspace collapse, kyphotic deformities, loss of cervical lordosis, cervical instability requiring fusion, and spondylolisthesis (Matz
et al, 2007).
125

Case 6-3
126
A 68-year-old woman was referred to the neurology clinic for progressive hand weakness. Upon
questioning, she reported difficulty with buttoning her blouse to the point that her husband
needed to assist. She also had trouble with balance when walking in the dark. Review of systems
was remarkable for a 10-year history of neck pain. On examination she had atrophy of the
intrinsic muscles of the hands, bilateral Babinski signs, and weakly positive Romberg sign. MRI of
the cervical
spine showed
multilevel
cervical
spondylosis
with
moderate to
severe cord
compression,
most severe
from C3 to C7
(Figure 6-3A).
Comment.
The patient
underwent a
posterior
cervical
decompression
from C3 to
C7. The
technique for
cervical
decompression
is relatively
A, Sagittal T2-weighted cervical spine MRI demonstrating multilevel
straightforward. FIGURE 6-3
cervical spondylosis with the most severe cord compression/deformation
A midline
at the C3 to C7 levels. B, Intraoperative photograph after multilevel
incision is
cervical laminectomies.
extended
down to the
dorsal spinous processes, and the muscles are reflected laterally to expose the laminae. The laminae are
removed using drills, rongeurs, and curettes. At the end of the decompression, the cervical dura should have
a pulsatile motion in concert with the heartbeat, which usually confirms the flow of CSF around the spinal
cord (Figure 6-3B). This patient stayed two nights in the hospital and went home with a front-wheeled
walker. At 3-month follow-up, her balance had improved to independent ambulation, and finger
coordination had resolved to the point that she could dress herself.
Spinal Epidural Abscess

Pathophysiology. In the past, spinal
epidural abscess accounted for approximately 1 in 20,000 hospital admissions;
however, the incidence has doubled
over the past several decades for multiple reasons. An aging population, increasing frequency of spinal surgery,
more vascular access devices, and injection-drug use are all contributors to the
increased incidence. The majority of patients who develop spinal epidural abscess have one or more underlying conditions. Diabetes mellitus, IV drug use,
previous infection, history of spine injury, renal disease, multiple medical
problems, and history of spine surgery
are predisposing factors. The most common organism is Staphylococcus aureus, followed by coagulase-negative
staphylococcus, and then gram-negative

organisms. Tuberculosis is also common
in certain parts of the world (Pereira and
Lynch, 2005; Rigamonti et al, 1999;
Soehle and Wallenfang, 2002).
Clinical features and investigations. A typical triad of symptoms on
presentation is back pain, progressive
neurologic deficit, and fever. Laboratory analysis reveals a leukocytosis
and/or elevations of other inflammatory markers, such as erythrocyte sedimentation rate or C-reactive protein in
the majority of cases. On imaging, spinal radiographs may show erosion of
the vertebral endplates if an associated
discitis or osteomyelitis is present. MRI
is the criterion standard for diagnosis,
with sensitivity above 90%. CT myelography is just as sensitive when
MRI is not obtainable. Caution is advised, however, as the subdural and
subarachnoid space can be seeded
with organisms. MRI is preferred because it is less invasive and because the
soft tissues surrounding the spinal canal
also can be assessed. If a diagnosis of
spinal epidural abscess is entertained,
CSF analysis should not be performed.
Blood cultures nearly always reveal an
organism when CSF cultures are positive, whereas only 25% of CSF cultures
are positive in spinal epidural abscess
(Darouiche et al, 1992).
Management. The standard of
care is early diagnosis followed by
emergent surgical decompression, debridement, and IV antibiotics. The diagnosis can be confirmed only by obtaining a specimen for culture.
Nonoperative management can be
considered when minimal deficits,
small abscesses, extensive spinal involvement, or comorbidities precluding surgery are present (Curry et al,
2005). In most series, patients with
complete paralysis that already has
been present for 24 to 48 hours have
shown poor neurologic outcomes, and
this may be an indication toward nonsurgical management. If medical management is chosen, the pathogen may
be determined from systemic blood
cultures in 60% of cases. Occasionally,

CT-guided needle biopsy is necessary.
Evacuation of the abscess percutaneously has been reported, but this procedure is used only in rare circumstances (Lyu et al, 2002; Rust et al,
2005). One limitation of this technique
is that CT images without myelography are usually inadequate to confirm
that the spinal cord has been decompressed. Magnetic resonance guided
aspiration for spinal epidural abscess
has not been reported; however, MRI
has been used for needle aspiration of
suspicious breast lesions as well as lesions in the neck (Lai et al, 2003; Orel et
al, 2006). We predict that MRI-guided
aspiration could lead to more rapid decompression of the spinal cord, possibly
obviating the need for open surgical intervention in select cases.
TRAUMATIC COMPRESSION
Pathophysiology. Traumatic spine
injury with resultant myelopathy is the
most common cause of severe disability after trauma. Spinal cord injury affects approximately 10,000 new patients per year. Campaigning for injury
prevention is a cost-effective way to
deal with spinal cord injury, and, fortunately, prevention has been a target
for policy makers.
In traumatic myelopathy, a huge
amount of energy is delivered to the
cord in a short period of time, resulting
in mechanical disruption of axons, interruption of normal spinal cord blood
flow, and initiation of several pathways
of secondary injury. The neurologic effects are immediate and dramatic
Management. An important factor
in the immediate care of a trauma patient is the assumption that all trauma
patients have a spinal column and/or
spinal cord injury. Trauma patients must
undergo spinal immobilization until
spine injuries have been ruled out. Further displacement of spinal elements
can exacerbate injuries and worsen outcomes. This awareness starts in the
field, where extrication and transport
are completed using spinal precautions.
KEY POINTS:
Improvement
after surgery for
cervical
spondylotic
myelopathy is
not typical. The
primary goal of
surgery is to
prevent further
neurologic
progression.
However,
without surgery,
further
progression is
typical.
Nonsurgical
management of
a bacterial spinal
epidural abscess
is completely
dependent on
accurate
identification of
the involved
organism and its
antibiotic
sensitivities.
Considering the
current status of
spinal cord
regeneration/
recovery,
prevention of
spinal cord injury
remains a key
goal in public
health
education.
127

KEY POINT:
Maintenance of
spinal alignment
and
cardiopulmonary
function is critical
in the initial
management of
patients with
spinal cord injury.
Typically, a cervical collar should be applied before extrication. Then the patient is placed supine, and complete
spine precautions are instituted. Patients
are rolled with maintenance of spinal
alignment and transported on flat
boards. After extrication, the next step is
to attend to the ABCDEs of trauma:
airway, breathing, circulation, disability

(neurologic status), and exposure/environment. Studies have demonstrated
that the initial management of patients
with spinal cord injury is critical in optimizing outcome. Poor oxygenation,
anemia, and ischemia all correlate with
poorer outcomes (Case 6-4).
Case 6-4
128
An 18-year-old unrestrained female passenger was involved in a motor vehicle rollover accident.
She was ejected from the vehicle through the sunroof, landing 30 feet away. First responders
intubated her and transported her to a Level 1 trauma center. She was unable to move her legs
at the scene. Initial films in the emergency department (Figure 6-4A) showed a severe fracture
dislocation in the thoracic spine. She was noted to have a complete motor and sensory level at
the level of
the fracture
(T7-8). She
also had
severe
pulmonary
contusions
and marginal
oxygenation
on 100%
oxygen.
Comment.
This is an
unfortunate
case of acute
traumatic
myelopathy.
Compression
and probable
transection of
the cord
occurred over
a time period
of seconds.
Subsequent
management
of traumatic
myelopathy in
this patient
A, Midsagittal reconstruction from CT scan of the thoracic spine showing
centered on
FIGURE 6-4
severe fracture/dislocation at the T7-8 level. B, Sagittal reconstruction
surgical
from CT scan of the same patient after reduction and anterior and
decompression
posterior fusion.
and
reconstruction
of the spine (Figure 6-4B). Decompression involves removing bone, ligament, and disc to relieve
pressure on the cord parenchyma. Reconstruction depends on the use of bone grafts, spinal
instrumentation, and bracing to restore structural strength to the spine.
Hemodynamic stability. Resuscitation and maintenance of hemodynamic parameters are crucial. Patients
with spinal cord injuries typically will
become hypotensive because of neurogenic shock, which results from the
loss of sympathetic tone. Volume resuscitation along with vasoconstrictive
agents may be necessary, and it is important to maintain adequate blood
pressure, not only to limit ischemia to
the injured spinal cord, but also to
prevent multiorgan failure. Studies
have demonstrated that maintaining
mean arterial pressure above 85 mm Hg
to 90 mm Hg for 7 days after injury
improves neurologic outcomes. Unopposed vagal tone may lead to bradycardia, which in severe cases will require
atropine sulfate. In situations with combined hypotension and bradycardia,
combination agents with both chronotropy and inotropy may be utilized, such
as dopamine or norepinephrine.
Steroids. The use of high-dose
steroids in spinal cord injury is controversial. In summary, steroids may have
modest effect on spinal cord recovery
but result in a higher incidence of opportunistic wound and pulmonary infections (Table 6-3). They should be
viewed as a treatment option rather
than a standard recommendation.
Traction. Bony imaging is the first
step once the patient is stabilized in
the trauma bay. At our institution, CT
scan of the head, then cervical spine,
followed by IV-contrast CT of the
chest, abdomen, and pelvis (which includes reformats in the coronal and
sagittal planes of the thoracic and lumbar spine) is used in multi-trauma patients. With cervical spine fractures
that are dislocated, consideration is
given to immediate cervical traction to
realign the injury. Controversy exists
regarding obtaining a pretraction MRI
to evaluate for a disc extrusion, which
could lead to deterioration when the
dislocation is reduced. However, the
incidence is extremely low. Even in
TABLE 6-3
Steroids for
Spinal Cord Injury
Patient Criteria
Spinal cord injury (no
involvement of cauda equina
or isolated root injuries)
Exclude penetrating injuries,
such as stabbing or gunshot
wounds
Evaluation less than 8 hours
from the time of injury
Methylprednisolone
All patients receive a 30-mg/
kg bolus over 15 minutes
For patients treated less than
3 hours from time of injury
wait 45 minutes, then start
5.4 mg/kg/h IV for 23 hours
For patients treated 3 to 8
hours from time of injury wait
45 minutes, then start 5.4 mg/
kg/h IV for 47 hours
institutions where MRI is immediately

available, the risk of transporting to
the MRI suite and placing a multitrauma patient with a dislocated cervical spine injury in an MRI scanner may
be higher than simply proceeding with
a reduction attempt. On the other
hand, in patients who have a dislocated cervical fracture but have nearly
normal neurologic function, consideration can be given to obtaining MRI
before traction, as there is more to
lose. In cognitively intact patients with
complete spinal cord injuries and fracture dislocations of the cervical spine,
we recommend immediate reduction
with cervical traction. Specifically, patients with altered mental status
caused by brain injury, intoxication, or
the need for sedation for other reasons
necessitate an alternative method of
neurologic monitoring to minimize the
risk of further cord compression during traction/reduction, or to recognize
129

whether it does occur. Prereduction
MRI is considered mandatory in these
patients. Open reduction (surgery) of
the dislocation allows direct visualization of the neuro elements and is
sometimes used in patients with altered mental status.
Surgery. Patients with thoracic
and lumbar fractures represent a difficult group to treat because, in general,
the more caudal the injury, the more
excessive the biomechanical forces.
The patients tend to have multiple lifethreatening injuries, further complicating their care. Many systems are avail-
TABLE 6-4
able for evaluating spinal instability

and the need for surgery. All of these
systems attempt to quantify the extent
of ligamentous, bone, and neurologic
injury. In doing so, these systems try to
provide guidance in the management
of these injuries. One example of
these is a system developed by Vaccaro and colleagues (2006) (Table
6-4). Timing of surgery is also an important consideration and is the subject of ongoing investigations. Although logical thought would lead to
the conclusion that earlier decompression of spinal elements could result in
Thoracolumbar Injury Classification and Severity Score
(1) Injury mechanism: worst level is used and injury is additive (eg, a
distraction injury with a burst component without lateral angulation would
receive 1 [simple compression] 1 [burst] 4 [distraction] 6)
Description
Qualifier
Points
A. Compression
Simple compression
Lateral angulation
15
Burst
B. Translational/rotational
C. Distraction
(2) Posterior ligamentous complex disrupted in tension, rotation, or translation
Description
130
Qualifier
Points
A. Intact
B. Suspected/indeterminate
C. Injured
(3) Neurologic status
Description
Qualifier
Nerve root involvement

Cord, conus medullaris involvement
Cauda equina involvement
Points
2
Incomplete
Complete
2
3
The score is the total of three components : injury mechanism, neurologic status, and posterior
ligamentous complex disruption. A score of 3 suggests nonoperative treatment, 4 suggests
operative or nonoperative treatment, and 5 suggests operative treatment.
Reprinted with permission from Vaccaro AR, Baron EM, Sanfilippo J, et al. Reliability of a novel classification system
for thoracolumbar injuries: the Thoracolumbar Injury Severity Score. Spine 2006;31(11 suppl):62 69.
improved functional outcome, multiple factors need to be considered regarding timing of surgery. These include the hemodynamic status of the
patient and the expertise of the surgical team needed to treat these complex and rare fractures. Finally, patients with severe neurologic deficits
will require intensive rehabilitation
postoperatively to resume as independent a life as possible.
CONCLUSION
Compressive myelopathy is a potentially treatable cause of myelopathy.
Failure to recognize the most common
causes of compressive myelopathy

may lead to a delay in diagnosis and
treatment. Such delays may jeopardize
optimal neurologic recovery.
Neoplasms, spondylosis, and
trauma are the most common causes
of compressive myelopathy in a typical clinical practice. Diagnosis is usually straightforward. History and physical examination dictate the extent and
nature of spinal imaging. Imaging
studies are critical in establishing a diagnosis. Typically, preoperative status
is most predictive of functional outcome, raising the importance of
prompt diagnosis and treatment.
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133
DISEASES OF THE NERVE

ROOTS
Kerry Levin
ABSTRACT
Disorders of spinal nerve roots can give rise to disabling pain and weakness. Damage to nerve roots resulting from disc disease and spondylosis can be localized by
attention to anatomic principles and with appropriate testing. Management strategies vary, depending on the clinical situation. Autoimmune, infectious, diabetic,
infiltrative, degenerative, and hereditary disorders are also causes of nerve root
disease. Other neurologic conditions can masquerade as nerve root disease.
INTRODUCTION
134
Spinal nerve roots are formed from

sensory and motor axons as they exit
the spinal cord and shift from oligodendroglial myelination to Schwann
cell myelination. They continue
through the intraspinal canal and pass
through segmentally defined neuroforamina. Upon emerging, they are extraspinal and renamed anterior and
posterior primary rami. At the point
where individual anterior primary rami
from different segmental levels merge,
they lose their single nerve root segmental identities and become elements of the cervical or lumbar plexus.
Disease may affect individual nerve
roots, multiple nerve roots, or may involve nerve roots in a diffuse manner.
Nerve root lesions usually can be distinguished from plexus and peripheral
nerve trunk lesions on the basis of
characteristic clinical features. This
chapter will review the basic anatomy
of spinal nerve roots, the processes
that can produce nerve root disease,
and the disorders that may be difficult
to distinguish from nerve root diseases.

ANATOMY
In all, there are 31 pairs of spinal nerve
roots: 8 cervical, 12 thoracic, 5 lumbar,
5 sacral, and 1 coccygeal. Each spinal
nerve root is composed of a dorsal
(somatic sensory) root and a ventral
(somatic motor) root that join in the
intraspinal canal, just proximal to the
intervertebral foramen (Figure 7-1).
In the extraspinal region, just distal to
the intervertebral foramen, the nerve
root divides in two: a small posterior
primary ramus that supplies innervation to the paraspinal muscles and skin
of the neck and trunk, and a large
anterior primary ramus that supplies
sensory and motor innervation to the
limbs and trunk, including intercostal
and abdominal wall muscles. Cell bodies of the motor nerve fibers reside in
the anterior horns of the spinal cord,
while those of the sensory nerve fibers
reside in the dorsal root ganglia
(DRG). DRG are, in general, located
within the intervertebral foramina and
Relationship Disclosure: Dr Levin has nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Levin has nothing to disclose.
are, therefore, not strictly speaking intraspinal. However, at the lumbar and
sacral levels, the DRG tend to reside
proximal to the intervertebral foramina, in intraspinal locations. About 3%
of L3 and L4 DRG are intraspinal,
about 11% to 38% of L5 DRG are intraspinal, and about 71% of S1 DRG
are intraspinal, according to cadaver,
radiographic, and MRI studies (Hamanishi and Tanaka, 1993; Kikuchi et
al, 1994). At the cervical level, this is
less common but can be seen especially at the C5 and C6 levels (Yabuki
and Kikuchi, 1996).
The spinal canal is bound posterolaterally by laminae and the ligamentum
flavum, anterolaterally by pedicles, and
anteriorly by intervertebral discs and
vertebral bodies. The maximal anterior-posterior dimension of the canal at
the C1-C3 levels ranges from 16 mm to
30 mm, and at the C4-C7 levels from 14
mm to 23 mm. The diameter of the
spinal cord at C1 is about 11 mm, at
C2-C6 about 10 mm, and at C6-C7
about 7 mm to 9 mm. The cervical
canal diameter is reduced by 2 mm to
3 mm with extension.
Nerve roots are numbered according to their segmental location in the
spinal cord, while intervertebral foramina are numbered according to the
two vertebral bodies that frame the
intervertebral foramen from above and
below. A cervical root exits above the
vertebral body of the same number,
such that the C3 root exits the spinal
canal via the C23 intervertebral foramen. Since there are only seven cervical vertebrae, the C8 root exits through
the C7-T1 intervertebral foramen. As a
result of this incongruity, all thoracic,
lumbar, and sacral roots exit below the
vertebral body of the same number.
Nutrients reach spinal nerve roots
by a combination of arterial circulation
and diffusion from cerebrospinal fluid.
At each root level, the vascular supply
originates from the dorsal branch of a
segmental artery, which supplies a
FIGURE 7-1
Axial view of the spine at a midcervical level.

lig ligament.
Copyright 2008, Cleveland Clinic. All rights reserved.
Reprinted with permission.
longitudinal radicular artery and collateral radicular arteries, which course

along with the spinal nerve root and
give rise to corkscrewlike interfascicular arteries, stretching and contracting
along with nerve root during body
motion. These vessels supply intraneuronal capillaries that form a network, minimizing watershed zones
and risk of ischemia.
The blood-nerve barrier that protects peripheral nerves against a number of toxic exposures is not intact
around DRG, where open junctions
between and fenestrations within the
ganglionic vascular endothelial cells
have been documented (Jacobs et al,
1976). Hence, dorsal root ganglia are
prone to certain infections (such as
herpes zoster), immune disorders
(such as those associated with pure
sensory neuronopathy), and toxic exposures.
PATHOPHYSIOLOGY
Nerve root fibers are vulnerable to the
same types of injury as other peripheral nerves: entrapment, compression,
transection, invasion (malignancy, infection, inflammation), and ischemia.
Compression of a nerve root may reContinuum: Lifelong Learning Neurol 2008;14(3)
135
DISEASES OF THE NERVE ROOTS

KEY POINTS:
136
The blood-nerve
barrier that
protects
peripheral nerve
against a
number of toxic
exposures is not
intact around
dorsal root
ganglia.
Since the motor

nerve cell body
(anterior horn
cell, motor
neuron) is within
the spinal cord,
damage to the
nerve root at
any location will
lead to wallerian
degeneration.
Damage to the
dorsal root
ganglia (DRG)
itself or the
sensory axon
distal to the
DRG will result
in wallerian
degeneration of
the sensory
axon.
sult in focal demyelination leading to

conduction block or conduction velocity slowing along the demyelinated
nerve root segment. Conduction block
along sensory or motor fibers causes
motor and sensory deficits, but conduction velocity slowing alone is insufficient to produce weakness or significant sensory loss. However,
sensory pathways that function by
transmission of timed volleys of action
potentials, such as those serving vibration and proprioception, can be disrupted by desynchronization of conduction velocities.
Axon loss also interrupts electrical
impulse transmission from the spinal
cord, leading to sensory and motor
deficits. Wallerian degeneration of the
axon distal to the lesion occurs when
the axon has been disconnected from
its cell body. Since the motor nerve
cell body (anterior horn cell, motor
neuron) is within the spinal cord, damage to the nerve root at any location
will lead to wallerian degeneration.
DRG, in general, reside within the intervertebral foramen, relatively protected from compression from spondylosis and disc protrusion. Only
damage to the DRG itself or the sensory axon distal to the DRG will result
in wallerian degeneration of the sensory axon.
NERVE ROOT DISEASE FROM
DISORDERS OF THE SPINE
Pathologic Features
By far, the leading causes of nerve root
disease are intervertebral disc disease
and spondylosis. Damage to nerve
roots occurs as the result of degenerative change at three main points: the
disc, the uncovertebral joints, and the
zygapophyseal (facet) joints. Resulting
bony overgrowth (osteophytes) or
disc herniation at these points may directly impinge on spinal nerve roots or
the spinal cord. In addition, these
pathologic effects produce instability
and malalignment of the spine that in

turn produces pain and neurologic sequelae. Whether changes in these different structures are causally interrelated or occur independently is not
known.
It is generally thought that the cascade of spondylotic changes is led by
degenerative change in the nucleus
pulposus of the disc. As the disc degenerates, vertebral body endplates
adjacent to the disc undergo changes,
leading to endplate sclerosis, followed
by osteophyte formation at the margins of the vertebral bodies. Facet joint
degeneration may not be directly related to the above changes but often
coexists. Osteophyte formation at
those joints causes further narrowing
of the spinal canal and lateral recesses.
Risk Factors and Epidemiology
of Radiculopathy
In an epidemiologic study of cervical
radiculopathy in Rochester, Minnesota, physical exertion or trauma preceded onset of radiculopathy in almost
15% of the 561 patients, most often the
result of shoveling snow in the winter
and playing golf in the summer
(Radhakrishnan et al, 1994). Motor vehicle accidents were responsible for
radiculopathy due to spinal fracture,
but not due to disc protrusion. Of the
patients with cervical radiculopathy,
41% had had prior lumbar radiculopathy, and 31% had had prior cervical
radiculopathy.
Lumbosacral radiculopathy is a
very common condition. More than
75% of all disc protrusions causing radiculopathy involve the L5 or S1 nerve
roots. Lumbosacral disc herniation
may occur 10 to 20 times more frequently than cervical disc herniations.
However, cervical radiculopathy is
also a common condition with a maleto-female ratio of 1.7. In the Rochester
study, the annual age-adjusted rate
was 83.2 cases per 100,000, with a
peak frequency of 202.9 per 100,000
per year in the 50- to 54-year-old age

group. Of these cases, 46% involved
the C7 root, 17.6% involved the C6
root, and less than 10% involved each
of the other levels. The cause of radiculopathy was disc protrusion in 22%
and spondylosis, disc, or both in 68%.
Of those, 26% subsequently underwent surgical treatment, but at last follow-up 90% of all patients were
asymptomatic or only mildly affected
by their radiculopathy.
Clinical Localization of
Radiculopathy
Clinicians use reference charts to correlate specific distributions of weakness with the likely anatomic level of
nerve root involvement. Significant
variation exists among the published
reference charts. The lack of agreement from one myotomal chart to another relates to anatomic variations in
humans and differences in the nature
of the research material used in the
collection process. Anatomic charts
have been derived by tracing root and
peripheral nerve innervations of muscles from cadaver studies. Clinical
charts have been derived by correlating the distribution of clinical muscle
weakness in patients with specific
traumatic lesions. EMG charts have
been derived from patterns of muscle
denervation in patients with focal
nerve root lesions. Figures 7-2 and
7-3 show electromyographically derived myotomal charts for the main
cervical and lumbar root levels (Levin
et al, 1996; Tsao et al, 2003).
The Clinical Diagnosis of
Radiculopathy
The initial diagnosis of radiculopathy
rests upon the clinical assessment,
based on the history and physical examination. The anatomic localization
can be inferred in some cases by the
neurologic examination, but the precise structural cause can only be determined by neuroimaging procedures.
Patient history. Obtaining a history consistent with radiculopathy requires exploring the major symptoms
of arm and leg pain, paresthesia,
numbness, and weakness. Pain is
present in virtually all patients with
acute radiculopathy, but it is seldom of
localizing value. The diagnosis of cervical radiculopathy is supported by the
presence of a history of radicular pain
emanating from the neck or shoulder,
with extension into the arm (sometimes in a specific dermatomal distribution). The diagnosis of lumbosacral
radiculopathy is supported by radicular pain that begins in the back or
buttock with radiation into the leg or
foot. The diagnosis is further supported when the symptoms are exacerbated by Valsalva maneuvers
(cough, sneeze, or strain), indicating
stretching of the dura at an intraspinal
point of compression. Radicular symptoms in the arm may also be reported
with neck/head movement. Patients
with lumbosacral radiculopathy may
report the presence of a self-induced
straight-leg raising sign: radicular
symptoms in the leg occurring when
sitting up straight with the legs extended, or even when lying supine if
the symptoms are severe. In the latter
case, relief may be reported when the
knees are flexed.
Paresthesia and numbness are
present less often than pain. They are
usually nonspecific and therefore of
little localizing value. However, these
symptoms are seldom present with
nonradicular causes of neck and back
pain.
The presence of Lhermitte symptoms (spinal or radicular tingling,
shocklike paresthesia with neck flexion), supports dysfunction of the posterior columns of the spinal cord, possibly due to spondylotic cord
compression, but also potentially due
to intraspinal mass lesions or intramedullary processes such as multiple sclerosis. The presence of bowel
KEY POINTS:
The diagnosis of
a radiculopathy
is suggested
when symptoms
are exacerbated
by Valsalva
maneuvers
(cough, sneeze,
or strain),
indicating
stretching of the
dura at an
intraspinal point
of compression.
Paresthesia and
numbness are
present less
often than pain
and are usually
nonspecific.
Therefore, like
pain, these
symptoms are
not of great
localizing value.
The presence of
Lhermitte
symptom (spinal
or radicular
tingling,
shocklike
paresthesia with
neck flexion)
suggests
dysfunction of
the posterior
columns of the
spinal cord.
137

KEY POINTS:
138
The Spurling test

(neck
compression
maneuver) is
performed by
extending and
rotating the neck
to the side of the
pain, followed by
applying
downward
pressure on the
head.
The shoulder
abduction relief
sign is performed
by asking the
patient to lift the
symptomatic arm
over the head,
resting the hand
on the top of the
head.
The straight-leg
raising sign is
said to apply a
tug on the
sciatic nerve and
its connection
with the L5 and
S1 nerve roots,
where pain is
generated at
points of dural
compression.
Of all the
elements of the
clinical
examination, the
identification of
weakness in a
specific
myotomal
distribution has
the greatest
localizing value
for the diagnosis
of a solitary
cervical or lumbar
spinal nerve root
lesion.
FIGURE 7-2
Needle electrode examination results grouped by the surgically defined root level of
involvement. Closed circle: positive waves or fibrillation potentials, with or without
neurogenic recruitment and motor unit changes; half-closed circle: neurogenic
recruitment changes only; open circle: normal examination.
SUP supraspinatus; INF infraspinatus; DEL deltoid; BRAC brachioradialis; BIC

biceps; PT pronator teres; FCR flexor carpi radialis; TRIC triceps; ANC anconeus;
EDC extensor digitorum communis; EIP extensor indicis proprius; FPL flexor pollicis
longus; APB abductor pollicis brevis; FDI first dorsal interosseus; ADM abductor
digiti minimi; PSP paraspinal muscle.
Reprinted with permission from Levin KH, Maggiano HJ, Wilbourn AJ. Cervical radiculopathies: comparison of
surgical and EMG localization of single-root lesions. Neurology 1996;46(4):10221025. Copyright 1996, AAN
Enterprises, Inc.
or bladder urgency, incontinence, new

constipation, or urinary retention may
reflect cervical spinal cord or cauda
equina compression.
The patient may provide important
information regarding the underlying
cause of the symptoms. A history of
recent or remote trauma should be explored, including whiplash incidents
and injuries during contact sports.
Prior episodes of spine pain, prior
spine surgery, and a family history of
spine disease should be sought. A general medical review of systems and
medical history are important to exclude other possible factors, such as
the presence of malignant disease, collagen vascular disease, or infection.
Clinical examination. The initial
part of the examination should be a
limited general physical examination
as dictated by the findings during the
historical interview. A complete neurologic examination should be performed, including inspection and percussion of the spine. A classification of
the typical neurologic attributes of solitary cervical and lumbar root lesions
is listed in Table 7-1.
Specific bedside clinical maneuvers for the provocation of symptoms
of cervical radiculopathy have come
into use, although their accuracy and
safety have not been carefully studied.
Lhermitte sign can be elicited by actively flexing the patients head and
observing for the development of tingling paresthesia down the cervical
spine or into the symptomatic arm.
The Spurling test (neck compression
maneuver) is performed by extending
and rotating the neck to the side of the
pain, followed by applying downward
pressure on the head. This maneuver
may produce limb pain or paresthesia,
as neck extension causes posterior
disc bulging, while lateral flexion and
rotation cause narrowing of the ipsilateral neural foramina. It may be safer to
perform this maneuver by asking patients to actively extend their neck,
FIGURE 7-3
Needle electrode examination results

grouped by the surgically defined root level
of involvement.
AL adductor longus; IL iliacus; VL vastus lateralis;

RF rectus femoris; VM vastus medialis; PT tibialis
posterior; TA tibialis anterior; EDB extensor digitorum
brevis; PL peroneus longus; EHL extensor hallucis
longus; GMED gluteus medius; ST semitendinosus;
TFL tensor fascia lata; MG medial gastrocnemius;
LG lateral gastrocnemius; AD abductor digiti quinti;
BFSH biceps femoris (short head); BFLH biceps
femoris (long head); GM gluteus maximus; AH
abductor hallucis; PSP paraspinal.
Reprinted with permission from Tsao B, Levin KH, Bodner RA. Comparison
of surgical and electrodiagnostic findings in single root lumbosacral
radiculopathies. Muscle Nerve 2003;27(1):60 64. Copyright 2003, John
Wiley & Sons, Inc.
then laterally flex and rotate toward

the side of the pain, followed by application of pressure through the examiners hands on the vertex of the
head. When radiating pain or limb
numbness develops, the maneuver
should be stopped. This maneuver is
said to be rather specific but not sensitive. The shoulder abduction relief
139
TABLE 7-1
140
Typical Clinical Attributes of Solitary Root Lesions
Root
Pain
Numbness
Weakness
Reflex Loss
C5
Neck, shoulder
Axillary distribution
Shoulder abduction,
external rotation, elbow
flexion, forearm
supination
Biceps,
brachioradialis
C6
Neck, shoulder,
lateral upper arm,
lateral forearm,
thumb, and lateral
hand
Lateral forearm,
thumb, and index
finger
Shoulder abduction,
external rotation, elbow
flexion, forearm
supination and
pronation
Biceps,
brachioradialis
C7
Neck, shoulder,
middle finger, hand
Index and middle

finger, palm
Elbow and wrist (radial

aspect) extension,
forearm pronation, wrist
flexion
Triceps
C8
Shoulder, medial
forearm, fourth and
fifth digits, medial
hand
Medial forearm,
fourth and fifth
digits, medial hand
Finger extension, wrist

(ulnar aspect) extension,
distal finger flexion,
distal thumb flexion,
finger abduction and
adduction
Triceps
T1
Medial arm and

forearm, axillary
chest wall, medial
forearm
Medial forearm,
fourth and fifth
digits
Thumb abduction, distal

thumb flexion, finger
abduction and
adduction
L23-4
Back, anterior thigh,

occasionally medial
lower leg
Anterior thigh,
occasionally medial
lower leg
Hip flexion, hip

adduction, knee
extension
Patellar
L5
Back, buttock, lateral

thigh, dorsum foot,
great toe
Lateral calf, dorsum

foot, web space
between first and
second toe
Hip abduction, knee

flexion, foot
dorsiflexion, toe
extension and flexion,
foot inversion and
eversion
Medial hamstrings
(semitendinosus/
semimembranosus
tendons)
S1
Back, buttock, lateral

or posterior thigh,
posterior calf, lateral
or plantar foot
Posterior calf,
lateral or plantar
aspect of foot
Hip extension, knee

flexion, foot plantar
flexion
Achilles tendon
sign is performed by asking the patient

to lift the symptomatic arm over the
head, resting the hand on the top of
the head. Reports indicate this may be
a useful therapeutic maneuver, as well
as a diagnostic one, for lower cervical
radiculopathy (Fast et al, 1989).
The straight-leg raising sign is the
main clinical bedside maneuver for the
provocation of symptoms of lumbosacral radiculopathy. With the patient in

the supine position, the fully extended
leg is passively elevated until radicular
symptoms in the leg are reported, usually by 30 to 40 degrees of elevation.
This maneuver is said to apply a tug
on the sciatic nerve and its connection
with the L5 and S1 nerve roots, where
pain is generated at points of dural

compression. A reverse straight-leg
raising sign is performed by passively
elevating the leg when the patient is in
the prone position, applying a tug on
the femoral nerve and its connections
to the L2, L3, and L4 nerve roots. The
straight-leg raising maneuver may produce nonspecific back pain in patients
with mechanical or musculoskeletal
symptoms, but not radicular, radiating
symptoms. To explore the possibility
that leg and hip pain is due to hip joint
disease, the knee in the flexed and
elevated position is rotated medially or
laterally, a maneuver that is painful in
patients with hip joint disease.
Of all the elements of the clinical
examination, the identification of
weakness in a specific myotomal distribution has the greatest localizing
value for the diagnosis of a solitary
cervical or lumbar spinal nerve root
lesion. Limb weakness provides the
most reliable correlation with the anatomic level of spinal nerve root involvement. The presence of weakness
is strong support for a neurologic disorder, but the examination seldom
fully differentiates radiculopathy from
plexopathy or mononeuropathy. True
neurogenic weakness may be difficult
to distinguish clinically from reduced
voluntary effort due to pain.
Diagnostic Testing For
Radiculopathy
Neuroimaging procedures. For imaging of the lumbar spine, MRI and CT
myelography (CT scan after intrathecal
administration of contrast media) are
equally sensitive for the diagnosis of
disc herniation (Bischoff et al, 1993).
For routine initial assessment, MRI is
less invasive and more informative
than CT because it can also identify
other intraspinal pathologies, including inflammatory, malignant, and vascular disorders. However, MRI studies
also frequently identify asymptomatic
lesions (Boden et al, 1990). In one
study, 28% of normal subjects had MRI

evidence of disc herniation (Jensen et
al, 1994). CT myelography is indicated
in patients with implanted electrical
devices and is preferred over MRI in
patients with surgically placed spinal
hardware that produces magnetic artifacts.
Electrodiagnosis. The primary
electrodiagnostic (EDX) procedures
are nerve conduction studies (NCS)
and electromyography (EMG). These
procedures provide a high yield of
clinical information about radiculopathy when neurologic weakness is
present for at least 3 weeks. The yield
is much lower in patients with pain or
sensory loss as the only manifestations
of radiculopathy. EDX studies provide
no diagnostic information in patients
with nonspecific spine pain, except to
exclude the presence of muscle and
nerve pathology. In such patients,
EMG can distinguish pain-related reduced muscular effort from true neurogenic weakness. In patients with
weakness due to radiculopathy, NCS
and EMG together can provide excellent localization of the specific spinal
nerve root that is damaged, distinguish
between old and new axon loss nerve
damage, and provide indirect support
for the presence of demyelinating conduction block at the root level (Levin,
2000). Finally, EDX testing can identify
mimickers of radiculopathy, such as
mononeuropathy, plexopathy, and
motor neuronopathy.
A number of studies have assessed
the relative value of EDX studies in the
diagnosis of lumbosacral radiculopathy. EMG studies tend to have a low
false-positive rate of diagnosis compared with MRI (Khatri et al, 1984).
Studies tend to demonstrate that EMG
and imaging studies have a comparable diagnostic sensitivity, varying between 50% and 85%, depending on
the patient population (Kuruoglu et al,
1994; Nardin et al, 1999; Wilbourn and
Aminoff, 1998). Neither MRI nor EMG
KEY POINT:
In patients with
weakness due to
radiculopathy,
nerve
conduction
studies and EMG
together can
provide excellent
localization of
the specific
spinal nerve root
that is damaged,
distinguish
between old and
new axon loss
nerve damage,
and provide
indirect support
for the presence
of demyelinating
conduction
block at the root
level.
141

can stand alone in the diagnosis of
radiculopathy, as each provides
unique anatomic and physiologic information (Albeck et al, 2000).
Somatosensory evoked potentials
are another EDX technique, carried
out by repetitive stimulation of the tibial nerve at the ankle and recording of
the propagated sensory potentials up
the leg, into the cauda equina, through
central sensory pathways in the spinal
cord and brain, to the sensory cortex.
This procedure has been investigated
as a tool for the assessment of electrical conduction through the damaged
segment of spinal nerve root in the
intraspinal canal. Unfortunately, there
are conflicting results in the literature
regarding the ability of this technique
to localize specific nerve root compression, raising questions about its
clinical value (Aminoff et al, 1985;
Dumitru and Dreyfuss, 1996; Katifi and
Sedgwick, 1987).
142
Management of Radiculopathy
Approaches to the management of radiculopathy vary depending on the
acuity of illness and the degree of neurologic deficit. In general, the likelihood for spontaneous recovery is
high, except in situations with severe
neurologic impairment. For acute radiculopathy, treatment recommendations can be specified for the sensory/
painful radicular pattern, the mild
motor deficit pattern, and the marked
motor/progressive pattern of illness.
Treatment strategies are summarized
in Tables 7-2 to 7-4.
Acute sensory/painful radicular pattern. The management of the
sensory/painful radicular pattern is not
significantly different from the approach to acute mechanical back pain,
since the likelihood of spontaneous
resolution of all symptoms is very
high. Treatment includes rest for several days and avoidance of lifting and
activities that increase the pain. Radiculopathy is often extremely painful.
Nonsteroidal anti-inflammatory drugs

can be useful. Muscle relaxants do not
provide a significant benefit over nonsteroidal drugs (Bigos et al, 1994). Depending on the severity of pain, narcotic analgesia may be required during
the first 10 to 14 days, when radicular
pain is most intense.
Next in importance to analgesics
in the management of acute radiculopathy is modification of activity to
lessen active nerve root impingement.
The patient should avoid activities that
exacerbate pain. In general, physical
therapy in the first 1 to 2 weeks is not
recommended. Avoidance of activity
does not imply prolonged complete
bed rest, which may prolong disability
(Vroomen et al, 1999). Patients often
identify pain-relieving positions for
themselves. Some individuals commonly report that semi-sitting, reclining, or some positions in bed provide
a good degree of sciatic or femoral
pain relief. Other patients find recumbence in bed more painful, preferring
to be up and around, even performing
light work duties.
Patients with the sensory/painful
radicular pattern have no neurologic
deficits, aside from a segmental pattern of sensory dysfunction, so the
likelihood that neuroimaging will lead
to a consideration for surgery is very
low.
For patients with acute sensory
cervical radiculopathy, treatment with
cervical traction and spinal manipulation is not recommended in the presence of spinal cord compression or
large disc protrusion, and should not
be considered unless the intraspinal
anatomy has already been defined by
neuroimaging. In the patient with
acute cervical radiculopathy due to
neural foraminal stenosis from facet or
uncovertebral osteophytes, cervical
traction may provide temporary relief
by modestly increasing the separation
between vertebral bodies. This therapy can be self-administered with a
TABLE 7-2
Treatment Approaches for Acute Lumbosacral

Radiculopathy (Less Than 4 Weeks)
Painful/Sensory Pattern
Additional narcotic analgesia for severe pain
Brief (bed) rest (1 to 2 days)
Avoidance of aggravating activities
Consideration of a 10- to 14-day course of oral corticosteroids
Gradual mobilization
Medical follow-up if no improvement over 2 to 3 weeks
Mild Motor Deficit Pattern

Above strategies
Consideration of MRI scan of lumbar spine
EMG examination after 3 weeks if no or little improvement
Physical therapy assessment when pain has stabilized
Marked Motor Deficit

Urgent MRI scan of the lumbar spine
Neurosurgical or orthopedic consultation for compressive lesion
Above strategies
EMG at 3 weeks
Physical therapy assessment when pain has stabilized
TABLE 7-3
Treatment Approaches for Subacute Lumbosacral

Radiculopathy (Greater Than 4 Weeks)
Medical/Neurologic Reassessment
MRI Scan of the Lumbar Spine if Not Already Done

Neurosurgical or Orthopedic Consultation for Compressive Lesion
More Aggressive Mobilization
Medical Program of Rehabilitation
Consideration of gabapentin, pregabalin and/or duloxetine, and tricyclics
for neuropathic pain
Active physical therapy
Education
143

KEY POINTS:
144
For patients with

acute sensory
cervical
radiculopathy,
treatment with
cervical traction
and spinal
manipulation is
not
recommended in
the presence of
spinal cord
compression or
large disc
protrusion and
should not be
considered unless
the intraspinal
anatomy has
already been
defined by
neuroimaging.
In patients with
an acute
radiculopathy
the decision
regarding
surgery requires
the following
considerations:
(1) the likelihood
of spontaneous
improvement,
(2) the likelihood
of disability from
a fixed
neurologic
deficit, and (3)
the risk of
progression of
the deficit
without surgery.
Change in the
pain and
neurologic
deficits (for
better or worse)
over time will
help inform the
final decision.
TABLE 7-4
Treatment Approaches for Cervical Radiculopathy
Acute Radiculopathy With Sensory Symptoms and Signs

Perform cervical radiographs and MRI: with trauma, myelopathy, prolonged
symptoms
Avoid heavy lifting and activities that increase pain
Avoid bed rest and immobilization of the head and neck
Use nonsteroidal anti-inflammatory drugs for pain control
Consider high-dose, fast-taper corticosteroids for unresponsive symptoms
Consider cervical traction if pathology is limited to foraminal stenosis
Reassess in 1 month
Acute Radiculopathy With Neurologic Deficits

Perform MRI cervical spine
Refer for neurosurgical consultation for compressive myelopathy
Avoid heavy lifting and activities that increase pain
Avoid bed rest and immobilization of the head and neck
Use nonsteroidal anti-inflammatory drugs for pain control
Consider high-dose, fast-taper corticosteroids for unresponsive symptoms
Consider cervical traction if pathology is limited to foraminal stenosis
Reassess in 1 month
Subacute or Chronic Radiculopathy (Greater Than 4 Weeks)

Progressive mobilization
Physical therapy for mobility, posture
Consider transcutaneous electrical nerve simulation
Refer for neurosurgical/orthopedic consultation for structural and
continued clinical evidence of root or spinal cord compression
pulley system traction device. The initial counterweight should not exceed
5 to 7 pounds but can be increased as
tolerated to 15 or more pounds. Fifteen- to 20-minute episodes of traction
should be repeated throughout the
day as needed. Reports indicate that,
during cervical traction and for some
minutes after, some anterior cervical
vertebral separation does occur. In
one study, greater separation appeared with 50 pounds than with 30
pounds of traction, but traction applied for more than 7 seconds at a time
provided no further separation (ColaContinuum: Lifelong Learning Neurol 2008;14(3)
chis and Strohm, 1966). With 7 seconds of 30 pounds of applied traction

alternating with 5 seconds of rest,
maximal separation occurred at 25
minutes, but the effect was lost within
20 minutes of the last applied traction.
Although the efficacy of cervical traction has not been proven, it is a standard therapy, and many patients claim
benefit. If traction induces increased
symptoms or pain, it should be discontinued. A systematic review of the literature could not support firm conclusions on the efficacy of cervical
traction because of methodologic in-
adequacies in the published studies

(van der Heijden et al, 1995).
Acute mild motor deficit pattern. The management of the mild
motor deficit pattern also begins with
conservative measures as outlined
above. The likelihood of spontaneous
recovery is high. Systemic corticosteroids (1-week course of oral prednisone) have not been shown to be
more effective than placebo, based on
a single randomized controlled study
(Haimovic and Beresford, 1986). However, as a temporizing maneuver, and
for its effects as an anti-inflammatory
agent and mild mood raiser, corticosteroids may be beneficial in the early
phase of radiculopathy. A typical
course would be prednisone 60 mg to
80 mg daily for 5 to 7 days, followed
by a fast taper to discontinuation over
the next 7 to 14 days. Prophylaxis
against gastritis is recommended, and
special precautions are needed in diabetics, but otherwise the short course
of treatment is not likely to produce
complications.
With acute, mild motor deficits the
need for neuroimaging is dictated
more by the perceptions of the patient
and physician than by its value in clinical decision making. As the concern
about permanent or progressive deficits increases, the need for defining
the anatomic disease underlying the
radiculopathy becomes more acute.
Acute marked motor/progressive pattern. The management of the
marked motor/progressive pattern requires simultaneous treatment of the
pain symptoms and diagnosis of the
underlying anatomic cause of the condition. An MRI scan of the lumbosacral
spine will identify most pathologic
states that may require surgical intervention. EMG studies will not be of
value in the diagnosis of acute radiculopathy until at least 3 weeks have
passed from the onset of weakness.
The decision regarding surgery requires the following considerations:
(1) the likelihood of spontaneous improvement, (2) the likelihood of disability from a fixed neurologic deficit,
and (3) the risk of progression of the
deficit without surgery. Change in the
pain and neurologic deficits (for better
or worse) over time will help inform
the final decision. After 3 weeks, EMG
studies can help the decision-making
process by identifying the distribution
and extent of spinal nerve root damage, the degree of acute axon loss, and
the likelihood of conduction block. A
linear correlation does not exist between the size of disc herniation or
nerve compression and the amount of
spinal nerve root damage. Small compressive lesions can at times produce
severe, irreversible nerve damage if
they affect arterial blood supply to the
nerve. An ischemic nerve lesion, although severe, would not be likely to
improve as a result of removal of the
compressive lesion (Case 7-1).
Subacute radiculopathy. In general, radiculopathy has a monophasic
course with eventual improvement
(Cherkin et al, 1998). Patients with at
least moderate neurologic deficits may
have long-standing residual impairment. At 3 to 4 weeks after onset, unimproved patients who have not yet
had neuroimaging should have that
done to assess the underlying structural abnormalities. If a causative
structural lesion is identified, surgical
consultation should be considered.
Patients with continued spinal nerve
root compression or spinal nerve root
infarction are likely to have some degree
of persistent pain. Drugs with particular
effectiveness against neuropathic pain
should be considered, including gabapentin, pregabalin, duloxetine, and tricyclic antidepressants. Continuing narcotic
medications should be avoided but in
individual cases may be effective at a
specific dosage. Patients will respond to
mobilization and other physical therapy
techniques but may be limited by their
neurologic deficits. Physical therapy
KEY POINTS:
In patients with
acute
radiculopathy,
EMG studies will
not be of value
until at least 3
weeks have
passed from the
onset of
weakness. After
3 weeks, EMG
studies can help
the decisionmaking process
by identifying
the distribution
and extent of
spinal nerve root
damage, the
degree of acute
axon loss, and
the likelihood of
conduction
block.
A linear
correlation does
not exist
between the size
of disc
herniation or
nerve
compression and
the amount of
spinal nerve root
damage.
145

KEY POINT:
146
Small
compressive
lesions can at
times produce
severe,
irreversible nerve
damage if they
affect arterial
blood supply to
the nerve. An
ischemic nerve
lesion, although
severe, would
not be likely to
improve as a
result of removal
of the
compressive
lesion.
Case 7-1
A 65-year-old man with a history of L4 5 discectomy developed acute
severe back pain with radiation into the left posterior thigh and over the
dorsum of the foot. On examination, a left footdrop with weakness in
foot inversion and eversion, toe extension, and flexion was identified. The
pain improved over several weeks, but the footdrop persisted. The patient
was referred for electrodiagnostic testing 4 weeks after onset of
symptoms.
NCS demonstrated reduced amplitude of the left peroneal motor
responses when recording over the extensor digitorum brevis muscle in
the foot and over the tibialis anterior muscle, when compared with the
opposite side. The superficial peroneal sensory response was absent on
the left and normal on the right, while the sural sensory responses were
normal and symmetric. Needle EMG showed fibrillation potentials in the
left anterior tibialis, posterior tibialis, extensor hallucis longus,
semitendinosus, and gluteus medius muscles, with sparing of the biceps
femoris (short head and long head) muscles. Fibrillation potentials could
not be identified at left low lumbar and sacral paraspinal levels.
An MRI study of the lumbar spine showed advanced lumbar canal
stenosis at the L4 5 level with focal lateral disc herniation into the left
L5-S1 lateral recess.
Comment. This patient demonstrated clinical signs suggesting an L5
radiculopathy. EDX testing confirmed an L5 distribution of active motor
axon loss, with additional evidence of loss of the L5 sensory response on
NCS. Loss of the superficial peroneal sensory response is usually seen with
common peroneal neuropathy at or above the fibular head, sciatic
neuropathy, and sacral plexopathy. Loss of this sensory response,
however, can be seen with intraspinal canal lesions affecting the L5 root
when the L5 dorsal root ganglion is situated within the intraspinal canal
and vulnerable to compressive injury (Levin, 1998). For this patient, if pain
has subsided and there is no progression of weakness, surgery can be
deferred and physical therapy can be initiated on a trial basis.
should address issues of mobility and

strengthening of weak muscles.
In postoperative patients with continuing radicular pain, compressive
disease such as residual disc fragments, hematoma, and arachnoiditis
must be excluded. Neuroimaging is required to investigate treatable causes
of pain. In nonoperated patients with
continued radicular pain, several nonsurgical treatment modalities can be
considered.
Epidural corticosteroid injection. The American Academy of Neurology has a practice parameter that
addresses the issue of epidural steroid
injections to treat radicular lumbosacral pain (Armon et al, 2007) (AppenContinuum: Lifelong Learning Neurol 2008;14(3)
dix). Few placebo-controlled, prospective studies are available to assess

the value of epidural corticosteroid injections, and those that are available
have been criticized for design flaws
(Malanga and Nadler, 1999; Nelemans
et al, 2000). These procedures used an
interlaminar injection approach, often
without
fluoroscopic
guidance,
whereby a needle is advanced between the lamina of two adjacent vertebrae into the dorsal epidural space.
One meta-analysis found no trend favoring epidural steroids (Koes et al,
1995). Another study included patients
with radiculopathy from disc herniation and claudication from lumbar ca-
nal stenosis. It identified some effect

on pain and/or findings within days to
12 weeks after treatment, but found no
difference in pain or deficits when
compared with placebo at 12 weeks
(Cuckler et al, 1985). A randomized
double-blind trial studied 158 patients
with lumbar radiculopathy of 4 to 52
weeks duration, with evidence of radicular deficits on clinical examination
and CT evidence of disc herniation
(Carette et al, 1997). Six weeks after
three epidural injections of either corticosteroid or saline, patients having
received corticosteroid had somewhat
more improvement in leg pain, but at
3 months there was no significant difference between the two groups.
Twenty-five percent of patients in
both groups eventually went on to
lumbar spine surgery. With the interlaminar approach it has been shown
that only 70% of cases have epidural
delivery of steroid without fluoroscopic guidance (Karasek, 2001).
Transforaminal epidural injections
have been promoted as a more selective, and therefore more effective,
treatment technique. The likelihood of
steroid delivery at the root level is
thought to be higher, since the needle
is placed under fluoroscopic guidance
in the epi-radicular space just above
the dorsal root ganglion in the neural
foramen. One placebo-controlled
study of 55 patients assessed the need
for surgery for pain or neurologic deficits after treatment (Riew et al, 2000).
Eight of 28 treated patients ultimately
underwent surgery while 18 of 27 placebo-treated patients ultimately received surgery. Concerns raised with
this study included a non-homogeneous patient population (disc herniation and foraminal stenosis), atypical
pain scale assessment tools, and multiple surgeons making operative decisions (Joelson, 2001).
Epidural corticosteroid injections
at the cervical levels have been performed for several decades, but not to
the extent they have been used at the

lumbar levels. Epidural injection of a
combination of corticosteroid and anesthetic can lead to temporary reduction of pain in some patients. The few
trials that have been performed have
not been well controlled and have
lacked homogeneous study populations. One study involving injections
performed at the C5-6 and C6-7 interspaces produced pain relief for 1
month or longer in 38% of patients
(Shulman, 1986).
A retrospective study of 100 patients attempted to identify a patient
profile that predicted response to cervical epidural injection of a combination of corticosteroid and anesthetic
(Ferrante et al, 1993). Based on clinical
outcomes determined by subjective reports of pain relief and return to activities of daily living, only the presence
of radicular pain predicted a better
outcome from epidural injection.
Other measured predictors, including
age, abnormal sensory examination,
change in muscle stretch reflexes, motor changes on examination, and abnormal EMG findings, were not found
to be significant. Predictors of a poor
outcome included normal radiologic
examination findings and the presence
of a herniated disc. In those who experienced greater than 50% pain relief,
the response occurred irrespective of
the cervical level involved. In patients
with symptoms and neurologic signs
of true radiculopathy, whether or not a
structural abnormality was seen radiographically, the probability of at least
50% improvement was 62%, while the
probability was only 35% for patients
with only radicular pain symptoms
and radiologic structural changes. The
poorest probability was seen in patients with radicular symptoms without structural changes and in patients
with nonspecific axial pain symptoms.
One study described a 76% success
rate for paravertebral transforaminal
KEY POINT:
Potential
complications of
epidural steroid
injections
include spinal
headache,
epidural or
intrathecal
hematoma,
transient
worsening of
radiculopathy,
and steroid
effects. While
reported
complications of
cervical
injections are
rare, they can be
severe, including
spinal cord and
brainstem
infarction.
147

KEY POINT:
148
Diabetic
polyradiculopathy
may present as
an isolated L3-4
radiculopathy
but often
spreads over
weeks to
months into
other root
distributions.
Infections may
involve single or
multiple nerve
roots.
epidural steroid injections (Bush and

Hillier, 1996).
Potential complications of epidural steroid injections include spinal
headache, epidural or intrathecal hematoma, transient worsening of radiculopathy, and steroid effects. While reported complications of cervical
injections are rare, they can be severe,
including spinal cord and brainstem
infarction (Rathmell et al, 2004).
Surgical management. A number of carefully controlled, multicenter
trials have studied the value of surgery
for lumbosacral radiculopathy. In a recent study, patients with severe sciatica for 6 to 12 weeks with lumbosacral
radiculopathy confirmed by a neurologist were randomly assigned to receive either conservative treatment
(with or without eventual surgery) or
early minimal unilateral transflaval surgery with magnification (Peul et al,
2007). Patients with severe weakness
and cauda equina syndrome were excluded. At 1 year, outcomes were similar for the two groups, although the
rates of pain relief and of perceived
recovery were faster for those assigned to early surgery. In another
study, patients with lumbar spondylolisthesis, lumbar canal stenosis,
and neurogenic claudication with neurologic signs were randomly assigned
to conservative treatment or decompressive surgery with spinal fusion
(Weinstein et al, 2007). This study
demonstrated significantly greater improvement in pain and function
among the surgically treated patients,
but the analysis was complicated by
an unexpectedly high rate of crossover
from the conservative treatment group
to the surgery group. For both of these
studies, back pain did not improve as
much as leg pain, indicating that the
greatest benefit is likely to occur for
nerve rootrelated symptoms (Deyo,
2007).
The factors that increase the likelihood that surgery will be performed
for cervical radiculopathy include

identification of an anatomic lesion
that corresponds with the clinical picture in the presence of one or more of
the following: obvious neurologic deficit, progression of the deficit over
time, unresolved pain, and spinal cord
compression on neuroimaging in the
presence of associated myelopathic
neurologic deficits (Carette and Fehlings, 2005). In a Cochrane Database
of Systematic Reviews, only two studies met criteria for inclusion (Fouyas et
al, 2002). One study compared surgical and nonsurgical therapies in 81 patients with cervical radiculopathy
without myelopathy (Persson et al,
1997). At 3 months after therapy, there
was 42%, 18%, and 2% reduction in the
visual-analogue pain scores for surgical, physical therapy, and hard collar
patients, respectively. However, at 1
year, the three groups did not differ in
regard to any measure, including pain,
function, or mood.
OTHER DISORDERS OF NERVE
ROOTS
Few disorders, other than skeletal disease of the spine, present as a single
nerve root disorder. Diabetic polyradiculopathy may present as an isolated
L3-4 radiculopathy but often spreads
over weeks to months into other root
distributions. Infections may involve
single or multiple nerve roots. In particular, herpes zoster infection often
involves a single nerve root distribution when it manifests in an extremity.
Polyradiculopathy
Polyradiculopathy refers to damage to
multiple root segments simultaneously
or in progressive order, occurring in a
single limb, or more frequently bilaterally, and sometimes diffusely. The
causes are diverse and at times unclear. In general, this process affects
the lumbosacral segments, with the
cervical segments involved later or not
at all. In some neurologic disorders,
TABLE 7-5
Differential Diagnosis of Polyradiculopathies

Polyradiculopathy
Polyneuropathy
Myelopathy
Disorders with true root involvement

Arachnoiditis
Inflammatory polyneuropathy
Diabetes
HNPP
Procainamide polyradiculoneuropathy
Spondylosis
Radiation
Vascular malformation (conus medullaris)
Malignant invasion
Paraneoplastic syndromes
Sarcoidosis
Lyme disease
Viral infection (HZV, CMV, HSV, EBV)
Mycoplasma infection
Vasculitis
Angiotropic lymphoma
Pompe disease (-glucosidase deficiency)
Polyglucosan body disease (glycogenbranching enzyme deficiency)
Adrenal insufficiency
a
Disorders mimicking root involvement

Porphyric polyneuropathy
-Lipoprotein deficiency
X-Linked bulbospinal neuronopathy
Motor neuron disease
Juvenile monomelic amyotrophy
Spinal cord infarction
Multiple sclerosis
Syringomyelia
HNPP hereditary neuropathy with tendency to pressure palsy; HZV herpes zoster virus; CMV cytomegalovirus; HSV
herpes simplex virus; EBV Epstein Barr virus.
a
Data from Sahenk Z, Mendell JR, Rossio JL, Hurtubise P. Polyradiculopathy accompanying procainamide-induced lupus erythematosus: evidence for
drug-induced enhanced sensitization to peripheral nerve myelin. Ann Neurol 1977;1(4):378 384.
polyradiculopathy coexists with lesions in distal peripheral nerves, lesions in the CNS, or both. Table 7-5
lists some causes of polyradiculopathy

and disorders that fall into the differential diagnosis.
149
150
Compressive polyradiculopathies. Spondylosis of the spine is often multifocal, and multiple roots may
suffer compressive damage concurrently. This is especially true at the
lumbosacral level, where spondylosis
causes lumbar canal stenosis and multilevel neuroforaminal stenosis. With
lesions from L1 to the sacrum, a large
disc herniation or marked concentric
constriction of the canal from spondylotic stenosis may cause compression of
the cauda equina. This kind of lesion
can produce bilateral polyradiculopathy
at several levels simultaneously, at times
also affecting innervation of the urinary
and rectal sphincters.
At the cervical level, bilateral compressive polyradiculopathy may occur
due to diffuse spondylosis, perhaps
associated with congenital narrowing
of the intraspinal canal or hypertrophy
of the ligamentum flavum. This condition is often associated with cervical
myelopathy. Occasionally the occurrence of acute or subacute myelopathy
and motor axon loss in root distributions may not be due to direct compression, but rather to venous congestion in the spinal cord secondary to the
compression, leading to ischemia and
infarction of long tracts and anterior
horn cells. The effects of venous congestion span multiple segmental levels, explaining how a focal compressive lesion at one level of the cervical
spinal cord can produce anterior horn
cell loss at a number of levels distal to
the compression (Stark et al, 1981).
Other causes of polyradiculopathy. The polyradiculopathy associated with diabetes can be among the
most disabling of all the neuropathic
complications of that condition. Although almost always confined to the
thoracic, lumbar, and sacral segments,
in severe cases cervical myotomes are
also affected (Dyck et al, 1999; Riley
and Shields, 1984). Diabetic polyradiculopathy is usually associated with
underlying diabetic polyneuropathy
(so-called diabetic polyradiculoneuropathy), but may be seen in isolation

in as many as 25% of cases (Bastron
and Thomas, 1981). This condition is
often associated with damage at the
lumbosacral plexus level as well, leading some authors to refer to the condition as diabetic lumbar radiculoplexoneuropathy (Dyck et al, 1999)
(Case 7-2).
Any process that can infiltrate or
compress nerve roots or their sheaths
can lead to polyradiculopathy. Infectious causes include Lyme disease,
tuberculosis, syphilis, and fungal infections. Cytomegalovirus polyradiculopathy associated with underlying
HIV infection presents as a painful,
rapidly progressive paraparesis with
urinary and rectal sphincter dysfunction (Eidelberg et al, 1986). Malignancy produces polyradiculopathy by
compression and invasion. Malignancies with a predilection for bone (myeloma, metastatic breast, prostate,
lung cancer) are especially likely to
cause polyradiculopathy, myelopathy,
or both, because of their tendency to
spread into contiguous regions. Malignant cells may also gain entry into the
intraspinal canal by hematogenous
spread.
Polyradiculoneuropathies
The diagnosis of polyradiculoneuropathy indicates the presence of coexisting features of polyradiculopathy
and peripheral polyneuropathy. The
clinical presentation includes weakness in both proximal and distal root
distributions of the legs (and in some
disorders the arms as well), often in a
distal to proximal gradient, associated
with features of sensory axon loss.
Electrodiagnostically, the picture is
characterized by loss of sensory responses, combined with features of
motor axon loss, or demyelinating
conduction block in multiple root distributions, or both. The leading causes
include acute inflammatory demyeli-
KEY POINTS:
Case 7-2
About 4 weeks after total abdominal hysterectomy, a 58-year-old woman
developed back discomfort and pain in the right anterior thigh that
progressed in severity over a 2-week period of time. The patient was a
diet-controlled diabetic, but in the immediate postoperative period
glucose control deteriorated and insulin therapy was initiated. The pain
was burning and felt as though it was just under the surface of the skin.
Position changes did not affect the pain, and it was severe in bed at night.
Over the same period, the right knee began to give out and several falls
occurred. Over several weeks the leg failed to hold her up without
support of a walker. Over the subsequent 2 weeks, she reported a
progressive tendency to catch her foot and toes on rugs, and she noted
that she could not lift her foot to clear a curb.
The examination showed strength graded 3/5 in right knee extension,
4/5 in hip flexion, knee flexion, and foot dorsiflexion. Toe extension was
graded 4/5, and toe flexion and foot plantar flexion were nearly normal.
Sensation was blunted in the stocking distribution to light touch and pin
bilaterally, and more marked sensory loss was noted over the right
anterior thigh. Muscle stretch reflexes were graded 1 in the arms, 1 at the
left knee, and absent at the right knee and both ankles.
MRI studies of the lumbar spine demonstrated multilevel spondylosis
with mild canal stenosis at L3-L5. MRI studies of the pelvis showed
postoperative changes without discernible hematoma.
NCS showed absence of the sensory responses at both feet. Peroneal
and tibial motor responses recording over foot muscles were within
normal limits, but the right femoral motor response showed more than a
50% reduction of the amplitude compared with the opposite side. Needle
EMG showed prominent fibrillation potentials in the right quadriceps
muscles, the iliacus, adductor longus, tibialis anterior muscle, and extensor
hallucis longus. On the left, mild fibrillation potentials were identified in
the quadriceps muscles only. Laboratory studies identified a fasting
glucose of 155 mg/dL and the hemoglobin A1c level was 8.0.
Comment. A diagnosis of diabetic lumbar polyradiculoneuropathy was
made. Aggressive pain management was instituted, and diabetic control
was improved. Over the course of 6 months, improvement occurred in
right leg function with physical therapy, and the patient could ambulate
with a cane.
nating polyradiculoneuropathy (Guillain Barre syndrome) and chronic

inflammatory demyelinating polyradiculoneuropathy. Both demyelinating and pure axon loss forms of inflammatory polyradiculoneuropathy
are now recognized (Griffin et al,
1996). As noted above, diabetes produces a primarily axon-loss polyradiculoneuropathy.
Some hereditary disorders produce a picture of polyradiculoneuropathy. Hereditary neuropathy with
tendency to pressure palsy can present
in this fashion (Le Forestier et al,

1997). -Lipoprotein deficiency (Tangier disease) is associated with a motor
and sensory neuronopathy in a progressive segmental pattern that often
affects the upper extremities first, and
mimics a pattern of polyradiculopathy
(Case Records of the Massachusetts
General Hospital, 1996; Schmalbruch
et al, 1987). Porphyric polyneuropathy
is characterized by marked proximal
and distal weakness, sometimes asymmetric, affecting the arms more than
the legs. Sensory responses are variContinuum: Lifelong Learning Neurol 2008;14(3)
Some hereditary
disorders
produce a
picture of
polyradiculoneuropathy.
When a
polyradiculopathy
pattern is
associated with
corticospinal
tract deficits, the
differential
diagnosis
expands to a
consideration of
motor neuron
disease of the
ALS type,
cervical and/or
thoracic
polyradiculopathies, and
myelopathies.
151

ably affected, but the clinical presentation is predominantly motor.
A number of conditions mimic the
clinical picture seen with polyradiculopathy and should be considered
when making a diagnosis. Motor neuron disorders present with a picture of
asymmetric or symmetric progressive
segmental weakness, involving either
the cervical or lumbosacral myotomes
first. Disorders with only lower motor
neuron involvement include spinal
muscular atrophy, juvenile amyotrophy of the upper extremity, and progressive muscular atrophy (lower motor neuron variant of ALS) (Hirayama
et al, 1987; Suarez et al, 1997).
When a polyradiculopathy pattern
is associated with corticospinal tract
deficits, the differential diagnosis expands to a consideration of motor neuron disease of the ALS type, cervical
and/or thoracic polyradiculopathies,
and myelopathies. To distinguish
these disorders, neuroimaging, EDX
studies, and occasionally CSF analysis
are required. Several EMG features
may help distinguish one disorder

from the other. Compressive polyradiculopathy is a more chronic process,
and there may not be much evidence
of active motor axon loss (fibrillation
potentials). In contrast, in midstage
ALS, fibrillation potentials are prominent, as is motor unit configuration
instability as a feature of active reinnervation. Second, the degree of motor unit dropout is usually greater in
ALS than in most radiculopathies.
Other conditions that may fall into this
category include polyglucosan body
disease (glycogen-branching enzyme
deficiency) (Bruno et al, 2004) and
Pompe disease (-glucosidase deficiency) (Karpati et al, 1977; Moses and
Parvari, 2002).
Other disorders of the spinal cord
can mimic polyradiculopathy with
associated myelopathy. Examples include syringomyelia; radiation radiculo-myelopathy; severe demyelinating disease (multiple sclerosis);
intramedullary glioma, as well as other
malignancies; and arteriovenous malformations affecting the spinal cord.
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155
DISEASES OF THE
PLEXUS
Devon I. Rubin
ABSTRACT
Disorders of the brachial and lumbosacral plexuses are rare mimickers of spinal cord
and root diseases. The clinical manifestations consist of pain, weakness, and sensory
loss in the affected limb. The plexuses may be injured by several mechanisms,
including trauma, inflammation, structural compression, or infiltration. The use of
careful electrodiagnostic testing and neuroimaging studies, in addition to the identification of clinical clues, is important in diagnosing plexopathies and determining
etiology. Despite identification of the etiology of plexopathies, treatment is often
limited. Treatment of the underlying cause, as well as supportive and symptomatic
treatment, may lead to improvement of neurologic function.
156
INTRODUCTION
The brachial plexus and lumbosacral
plexus are uncommon sites of primary
neurologic dysfunction, and the diagnosis and treatment of plexopathies
can be challenging. Brachial and lumbosacral plexopathies may clinically
mimic disorders of the spinal cord or
the cervical and lumbosacral roots,
and because radiculopathies are much
more common than plexopathies, the
evaluating physician may overlook the
plexus as the source of a patients
symptoms. In addition, the complex
anatomy of the brachial and lumbosacral plexuses and the patchy nature of
the pathologic processes that affect
these structures can be daunting to a
physician and lead to difficulty in determining precise anatomic localization. Numerous types of diseases can
injure the plexus, including trauma, infiltrative and compressive lesions, and
inflammatory or immune-mediated
disorders. This chapter will review the
basic anatomy of the brachial and lumbosacral plexuses, review the diagnostic tools used to evaluate plexopathies,
and discuss the clinical presentation
and management of disorders affecting the plexus.
PLEXUS ANATOMY
The anatomy of the brachial and lumbosacral plexuses is complex. In the
brachial plexus, multiple roots and
branches converge and diverge to
form different segments, which contribute to multiple terminal nerves.
The lumbosacral plexus has fewer
connections and segments than the
brachial plexus but contains numerous
sensory and motor branches. A solid
knowledge of the different branches
and terminal nerves, as well as the
innervation of arm and leg muscles is
critical for the physician to be able to
adequately localize a lesion (Table
8-1). A detailed review of the anatomy
of the plexus is beyond the scope of
this chapter; however, the major com-
Relationship Disclosure: Dr Rubin has received royalty payments for contributing to an EMG educational
CD-ROM from AAN Enterprises, Inc., and the American Association of Neuromuscular and
Electrodiagnostic Medicine.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rubin has nothing to disclose.
TABLE 8-1
Muscle Innervation Through the Brachial Plexus by Trunk, Cord, and Nerve
Upper Trunk (C5-6)
Middle Trunk (C6-7-8)
Lower Trunk (C8-T1)
Supraspinatus (SSc)
Infraspinatus (SSc)
Lateral cord
Lateral cord
Biceps (MC)
Pronator teres (M)
Brachialis (MC)
Flexor carpi radialis (M)
Posterior cord
Posterior cord
Posterior cord
Brachioradialis (R)
Triceps (R)
Extensor indicis proprius

(R)
Supinator (R)
Anconeus (R)
Extensor carpi ulnaris (R)
Deltoid (Ax)
Extensor carpi radialis (R)
Teres minor (Ax)
Extensor digiti communis

(R)
Triceps (R)
Extensor carpi ulnaris (R)

Medial cord
Abductor pollicis brevis
(M)
First dorsal interosseus (U)
Abductor digiti minimi (U)
Flexor carpi ulnaris (U)
Flexor digitorum
profundus 45 (U)
Flexor pollicis longus (M)
SSc suprascapular nerve; MC musculocutaneous nerve; M median nerve; R radial nerve; Ax axillary nerve; U ulnar
nerve.
ponents of the brachial and lumbosacral plexuses will be reviewed.

Brachial Plexus
The brachial plexus is defined as the
group of nerves derived from the fifth
cervical through the first thoracic root
that extends approximately 15 cm
through the upper neck into the axilla.
This interlacing braid of nerves supplies all of the muscles in the upper
extremity. The plexus is traditionally
divided into roots, trunks, divisions,
cords, and terminal nerves (Figure
8-1).
Roots. In most patients, the brachial plexus is derived from the anterior primary rami of the C5 through T1
roots. Approximately 5% of individuals have a variation of root contribution to the plexus with significant contribution of C4 (prefixed) or T2
(postfixed). Following the formation
of mixed spinal nerves after exiting the
intervertebral foramen, the roots divide into posterior primary rami,
which innervate the paraspinal muscles, and ventral primary rami, which
course into the plexus. Although techContinuum: Lifelong Learning Neurol 2008;14(3)
157
DISEASES OF THE PLEXUS

KEY POINT:
The brachial
plexus anatomy
is complex; the
trunks, divisions,
and cords
converge and
diverge to form
the intertwining
plexus that
ultimately
terminates in
five major nerves
in the arm.
nically not a component of the plexus,

the roots provide the initial contribution to the plexus and may be injured
along with more distal components. In
some situations, an absolute distinction between a pure preganglionic and
postganglionic injury cannot be made,
such as occurs in traction, neoplastic,
or radiation injuries. The roots are
more susceptible to traction injury
than the plexus since they are shorter,
unprotected by adherent dura or
epineurium, and are less interwoven
within the nerve sheath. Several indi-
vidual nerves (long thoracic, dorsal

scapular, and phrenic) branch directly
off the roots prior to the formation of
trunks. Clinical involvement of these
nerves is helpful in determining the
proximal extent of a lesion.
Trunks. After the anterior primary
rami of the roots exit their respective
spinal segments, they join to form
three trunks in the supraclavicular
fossa at the lateral border of the anterior and medial scalene muscles: upper
(formed by the C5 and C6 roots), middle (formed predominantly by the C7
158
FIGURE 8-1
The brachial plexus.

Reprinted with permission from Mayo Foundation for Medical Education and Research. All rights reserved.
root with some contribution from C6

and C8), and lower (formed by the C8
and T1 roots). The trunks are located
in a relatively superficial region in the
lower anterior aspect of the posterior
triangle in the neck, thereby increasing
their susceptibility to traction and penetrating injuries. The suprascapular
nerve (innervating the supraspinatus
and infraspinatus) may branch directly
off the upper trunk.
Divisions. Although it is rare for a
process to solely affect the divisions of
the plexus and spare the trunks or
cords, the divisions are important clinically as a landmark used in the classification of plexopathies. With the
arm in the anatomic position, each
trunk separates into an anterior and
posterior division just beneath the
clavicle. Lesions involving the roots or
trunks occur in the supraclavicular
portion of the plexus, and lesions involving the cords or terminal nerves
occur in the infraclavicular plexus.
Pathologic studies have demonstrated
that the nerve fibers in the trunks (supraclavicular) are arranged in a segmental fashion, thereby producing
deficits in a myotomal or dermatomal
pattern. At the level of the cords (infraclavicular), the nerve fibers have divided into individual fascicles that ultimately form the terminal nerve
branches, thereby forming a pattern of
single or multiple peripheral nerve
lesions. Supraclavicular plexopathies
are more common than infraclavicular
plexopathies and less likely to demonstrate complete recovery in severe
injury than infraclavicular lesions. Although most etiologies of plexopathies can affect any region of the
plexus, some disorders are more likely
to affect the supraclavicular or infraclavicular portions (Table 8-2).
Cords and terminal nerves. Three
cords (lateral, medial, and posterior) are
formed at the level of the proximal axilla.
The cords are named according to their
anatomic relationship to the second por-
KEY POINT:
TABLE 8-2
Causes of Brachial
Plexopathies
According to
Anatomic Site
Supraclavicular
Trauma
Obstetric paralysis
Open heart surgery
Cervical ribs or bands
Separation of
brachial
plexopathies
into
supraclavicular
and
infraclavicular
localizations may
be helpful in
determining the
possible
etiologies.
Neoplastic
Inflammatory
Infraclavicular
Humeral head fractures
Penetrating injuries
Axillary arteriograms or blocks
Radiation
Neurovascular injuries
tion of the axillary artery, which they surround. The cords are the longest component of the brachial plexus. Each cord
terminates in one or more individual
nerves (Table 8-3).
Lumbosacral Plexus
The anatomy of the lumbosacral
plexus is less complex than that of the
brachial plexus. Although typically
considered a single structure, the lumbosacral plexus is actually composed
of two adjacent plexusesthe lumbar
and the sacral (Figure 8-2). The lumbar plexus is derived from the L1 to L4
roots. The anterior rami of these roots
pass downward from the vertebral column and join together to form several
branches within the psoas muscle (Table 8-4). Relatively minor branches include the iliohypogastric, ilioinguinal,
and genitofemoral nerves, which supply sensation to the inferior abdominal
wall and medial groin. The lateral
femoral cutaneous nerve is derived
from the upper to mid-lumbar plexus
159
TABLE 8-3
Cord
Terminal Nerve
Commonly Innervated
Muscles
Sensory Distribution
Posterior
Axillary
Deltoid, teres minor
Lateral shoulder
Radial
Triceps, anconeus,
brachioradialis, supinator,
wrist and finger extensors
Dorsal forearm
Dorsal-lateral hand
Subscapular
Teres major, subscapularis
Thoracodorsal
Latissimus dorsi
Musculocutaneous
Biceps, brachialis,
coracobrachialis
Lateral antebrachial
cutaneous
Lateral forearm
Median
Pronator teres, flexor carpi

radialis
Lateral pectoral
Pectoralis major
Median
Thenar muscles, first and

second lumbrical
Lateral hand
Ulnar
Interossei, flexor digitorum

profundus (45), flexor carpi
ulnaris
Medial hand
Medial antebrachial
cutaneous
Medial forearm
Medial pectoral
Pectoralis minor
Lateral
Medial
160
Terminal Nerve Branches of the Brachial Plexus
and supplies the sensation to the anterolateral thigh. The major branches
include the obturator nerve and the
femoral nerve. The obturator nerve is
derived from the L2, L3, and L4 roots
and passes medial to the psoas muscle, supplying the adductor longus
and a portion of the adductor magnus
muscles. The largest branch is the femoral nerve, which passes lateral to the
psoas muscle and supplies motor innervation to the iliopsoas and quadriceps muscles. The saphenous nerve is
the distal sensory branch of the femoral nerve and supplies sensation to the
anteromedial lower leg and medial
foot.
The sacral plexus is derived from
the L5, S1, S2, S3, and sometimes S4

roots, and consists of anterior and posterior branches. The sacral plexus lies
in the pelvis, adjacent to the piriformis
muscle. The major branches of the sacral plexus include the superior gluteal
nerve (innervating the tensor fascia
lata and gluteus medius), the inferior
gluteal nerve (innervating the gluteus
maximus), and the sciatic nerve. The
sciatic nerve innervates the hamstring
muscles and ultimately separates into
the common peroneal and tibial
nerves, which innervate the foot muscles. The sacral plexus also provides
contribution to the pudendal nerve,
which innervates the external anal
sphincter.
PATHOGENESIS OF DISEASES
AFFECTING PLEXUSES
The brachial plexus is a vulnerable
structure because of its length and relationship to surrounding structures.
The lung apex, lymph nodes, bones
(clavicle and ribs), and major vessels
may all be sites of disease that may
primarily or secondarily extend toward and involve the nerve bundles in
the plexus. In addition, the plexus is
susceptible to injury by traction because of mobility of the neighboring
shoulder joint, shoulder girdle, and
neck. In contrast to the brachial
plexus, the lumbar plexus lies deep in
the pelvis and therefore is relatively
shielded from direct or penetrating
trauma. However, its proximity to the
psoas muscle, hypogastric arteries and
veins, colon, and rectum predisposes
it to involvement from disorders involving these structures.
The underlying pathophysiology
of nerve injury in the brachial and
lumbosacral plexuses depends on
the mechanism and severity of injury. Different stages of nerve injury
have been proposed based on the
extent of anatomic disruption of the
nerve (Sunderland, 1990). In some
circumstances, typically in mild or
very early lesions, a neurapraxic
lesion characterized by focal demyelination of the affected segments is
the prominent pathologic feature. In
these cases, electrodiagnostic studies
may detect a focal block of conduction across the affected site. Because
the axon and supporting structures
remain intact, if the inciting cause is
removed without further nerve damage, recovery may occur within
hours to months, and the prognosis
is good. In more severe injuries in
which the continuity of the axons and
the supporting structures are disrupted
(axonotmesis, neurotmesis), wallerian degeneration of a disconnected
nerve segment occurs. In these stages,
FIGURE 8-2
The lumbar and sacral plexus.

Reprinted with permission from Mayo Foundation for
Medical Education and Research. All rights reserved.
effective recovery is poor or impossible

depending on the amount of separation
of the two ends of the nerve. In most
disorders, injury to the plexus, regardless of etiology, is substantial and axonotmesis or neurotmesis is the predominant mechanism.
CLINICAL MANIFESTATIONS OF
PLEXOPATHIES
The clinical manifestations of plexus
disorders vary according to the site of
involvement, the temporal profile of
injury, and the specific etiology. Furthermore, symptoms experienced are
not specific to injury to the plexus, and
a high clinical suspicion is important
in considering the diagnosis. Neurogenic and non-neurogenic disorders
that may clinically mimic plexopathies
are listed in Table 8-5.
Pain
Most patients with plexus disorders
experience pain. The pain is often
161

KEY POINT:
The lumbosacral
plexus has fewer
connections
between
components
than the brachial
plexus, but has
numerous
individual nerve
branches that
supply the
motor and
sensory
innervation to
the leg.
TABLE 8-4
Sensory
Distribution
Plexus
Nerve
Muscles
Lumbar
Iliohypogastric (L1-2)
Inferior abdominal
wall
Ilioinguinal (L1-2)
Medial groin
Genitofemoral (L1-2)
Medial groin
Lateral femoral cutaneous

(L3-4)
Anterolateral thigh
Obturator (L2,3,4)
Adductor longus
Adductor
magnus, gracilis
Femoral (L2,3,4)
Quadriceps
Medial leg and foot

(saphenous nerve)
Superior gluteal (L4-5)
Gluteus medius
Tensor fascia
lata
Inferior gluteal (L4-S1)
Gluteus maximus
Sciatic (L4-S2)
Anterior tibialis
Peronei
Gastrocnemius
Soleus
Foot muscles
Foot
Lateral leg
Pudendal (S2,3,4)
External anal
sphincter
Perineal
Sacral
162
Branches of the Lumbar and Sacral Plexus
prominent and severe and may be

described as having a deep, aching,
or burning quality. In brachial plexopathies, the pain may be located in
the shoulder, arm, or forearm, is precipitated or worsened by movement
of the arm or shoulder, and is rarely
exacerbated by Valsalva maneuvers,
which is more characteristic of radiculopathies. The pain often follows a
sclerotomal radiation pattern with
pain from lesions of the upper trunk
referred to the shoulder or upper
arm; pain from lesions of the middle
trunk to the forearm; and pain from
damage to the lower trunk, the axilla, medial arm or forearm, or hand.
When injury involves the lumbar
plexus, pain predominantly involves
the anterolateral and medial thigh reContinuum: Lifelong Learning Neurol 2008;14(3)
gion, and with sacral plexus involvement, the posterior thigh and the leg
and foot are predominantly involved. In many cases, patients cannot precisely localize the distribution
of their pain, which underscores the
importance of having a high index of
suspicion for an underlying plexopathy when evaluating patients with
arm or leg pain.
Sensory Loss and Paresthesias
Sensory disturbance is common in patients with brachial and lumbosacral
plexus disorders, although it may be
overshadowed or unnoticed when patients are experiencing a high degree of
pain and weakness. The sensory loss
generally follows a dermatomal distribution, although many patients have diffi-
KEY POINT:
TABLE 8-5
Disorders That Mimic Brachial or Lumbosacral

Plexopathy
Brachial Plexopathy
Cervical radiculopathy or spondylosis
Upper extremity mononeuropathy (median, ulnar, radial, axillary,
musculocutaneous)
Mononeuritis multiplex
Multifocal motor neuropathy
ALS
Cervical cord lesion (eg, transverse myelitis)
Orthopedic (shoulder) disorders
Rotator cuff injury
Acute calcific tendinitis
Adhesive capsulitis
Bursitis
The brachial
plexus is
vulnerable to
injury because of
its length and
relationship to
surrounding
structures, such
as the lung,
lymph nodes,
bones, and
major vessels;
the lumbosacral
plexus is less
susceptible to
stretch injury but
also lies close to
potential
pathologic
structures in the
pelvis.
Lumbosacral Plexopathy
Lumbosacral radiculopathy
Lower extremity mononeuropathy (femoral, peroneal, tibial)
Mononeuritis multiplex
Orthopedic disorders
Hip fracture
Hip osteoarthritis
Avascular necrosis
Bursitis
culty precisely identifying the distribution of sensory loss (Figure 8-3).

Patients with upper trunk brachial
plexus lesions experience sensory loss
in the lateral arm or forearm, middle
trunk brachial plexus lesions in the dorsal forearm and hand, and lower trunk
brachial plexus lesions in the medial
hand and forearm. In lumbosacral plexopathies, sensory loss most commonly
involves the thigh (lumbar plexus) or
foot (sacral plexus).
Weakness and Atrophy
Weakness and muscle atrophy are common in patients with plexopathies. The
weakness depends on the site of involve-
ment of the plexus and in many instances

may be patchy or incomplete, often complicating precise localization. In general,
the weakness follows a myotomal distribution, with weakness in brachial plexopathies predominantly affecting arm abduction, external rotation and arm flexion
in upper plexus lesions; arm and finger
flexion and extension with middle trunk
lesions; and intrinsic hand weakness with
lower plexus lesions. In lumbosacral plexopathies, weakness occurs in the quadriceps, hip flexors, hip adductors (lumbar
plexus), or the muscles involved in foot
movement and the glutei muscles (sacral
plexus).
163

KEY POINT:
The main clinical

manifestations
of plexopathies
include pain,
weakness,
atrophy, and
sensory loss in
the arm or leg.
The presence of
associated
clinical findings
such as Horner
syndrome or
palpable
inguinal mass
may help to
identify
etiologies of
plexopathies.
Associated Clinical Features

Other clinical features may also help
to provide a clue to disorders involving the brachial or lumbosacral plexopathies. In lesions of the lower trunk
of the brachial plexus or those involving the T1 root, a Horner syndrome,
with ipsilateral ptosis, miosis, and anhidrosis may be present. This classically occurs with Pancoast tumors in
the apex of the lung, but can occur in
any disorder involving the lower trunk
of the plexus. In suspected lumbosacral plexopathies, the presence of enlarged inguinal lymph nodes or a pulsatile femoral mass may provide a clue
to the etiology, such as neoplastic or
aneurysmal compression.
GENERAL EVALUATION OF
PLEXOPATHIES
Clinical History and
Examination
A thorough and comprehensive history and neuromuscular examination
are important first steps in evaluating
plexopathies. Important historical features to be considered include the date
of symptom onset; history of antecedent trauma, infections, or immunizations; history of underlying malignan-
164
FIGURE 8-3
Sensory involvement in brachial

plexopathies.
cies or radiation to the lung, chest, or

shoulder region; and recent surgical
procedures. A careful family history to
assess for similar episodes in other
family members, which may have
been diagnosed as radiculopathies or
mononeuropathies, may provide a
clue to a hereditary predisposition to
plexopathies. The neuromuscular examination should be comprehensive
and consist of a careful motor examination, noting the distribution of
weakness and atrophy in limb and
shoulder girdle muscles, any reduction
in reflexes, the distribution of sensory
loss, and the presence of other associated features, such as a Horner syndrome.
While a careful clinical assessment
and a high index of suspicion that the
disease involves the plexus are often
sufficient for localization, electrodiagnostic testing is useful to confirm localization and exclude other disorders
(Wilbourn, 1985). Furthermore, once a
plexopathy is confirmed, imaging and
other studies are necessary to identify
the etiology.
Electrodiagnostic Testing
Electrodiagnostic testing with nerve
conduction studies (NCS) and needle
EMG is an important step in the evaluation of plexopathies. EMG is useful
to confirm localization and determine
the site(s) of plexus involvement, exclude radiculopathies or mononeuropathy, define the severity of the injury, define the degree of recovery,
and occasionally identify the etiology.
The combination of findings on motor
and sensory NCS, in conjunction with
abnormalities on needle EMG, can localize the process to a specific trunk or
cord.
NCS are one of the electrodiagnostic tools used to distinguish a plexopathy from a radiculopathy. Motor NCS
assess the degree of motor axonal loss
or demyelination. Abnormalities on
motor NCS, such as low compound
muscle action potential (CMAP) amplitudes, are not specific and may occur
in severe radiculopathies, mononeuropathies, or diseases involving anterior horn cells, in addition to plexopathies. Abnormalities in different motor
conduction studies occur to a variable
degree depending on the site of the
plexus lesion (Table 8-6). In brachial
plexopathies, low median and ulnar
CMAP and ulnar and medial antebrachial amplitudes may occur in lower
plexus lesions, whereas low musculocutaneous and axillary CMAP amplitudes may be seen in upper plexus
lesions. In some instances, identification of focal demyelination with conduction block or temporal dispersion
with stimulation across the plexus is
useful to confirm localization and
identify focal demyelination as the
pathophysiologic process. In the
lower extremity, abnormalities in peroneal and tibial motor conduction
studies may occur with lower lumbar
or sacral plexopathies, but may also be
seen in L5 or S1 radiculopathies.
Sensory NCS are more useful than
motor NCS in separating a plexus from
a root lesion. In brachial plexopathies,
abnormal findings on sensory NCS
due to wallerian degeneration of the
post dorsal root ganglionic sensory fibers occur early and are helpful to
distinguish a postganglionic process
from a preganglionic (root) process.
Several sensory NCS can be used in
localization, including median, ulnar,
radial, and medial and lateral antebrachial cutaneous (Table 8-6). In contrast to the utility of sensory NCS in
evaluating brachial plexus lesions, few
reliable sensory conduction studies
are available to assess the lumbosacral
plexus, particularly in older patients
where sensory responses may be normally unobtainable. Identifying a
greater than 50% reduction in amplitude in the sural or superficial peroneal sensory response on the affected
side compared with the unaffected
side may be helpful in supporting a

sacral plexopathy.
Needle EMG is useful to more
precisely confirm the localization and
define severity and degree of nerve
regeneration in brachial and lumbosacral plexopathies. The sparing of abnormalities in the cervical or lumbosacral paraspinal muscles may be
supportive of a postganglionic lesion.
In rare instances, specific features during the needle examination, such as
the presence of myokymic discharges
in a patient who has received radiation
therapy, can determine the etiology of
the plexopathy.
Imaging Studies
While electrodiagnostic studies are
useful in confirming a plexopathy,
they provide little information regarding the etiology. In most instances, imaging studies of the brachial or lumbosacral plexus are necessary to assess
for compressing structural lesions or
neoplastic infiltration of the plexus. In
plexopathies due to trauma, imaging
may be useful in attempting to identify
root avulsion or hematoma formation
within the plexus, although in many
instances imaging will be normal.
In patients with brachial plexopathies, a routine chest radiograph is
useful as an initial screening study to
assess for a cervical rib or a Pancoast
tumor, although chest x-rays do not
adequately visualize the plexus and
patients should subsequently undergo
more detailed study of the plexus with
CT or MRI. CT or MRI can be useful to
assess for structural lesions within the
brachial and lumbosacral plexus. CT is
most useful at identifying a hematoma,
and in traumatic cases CT myelogram
may identify a pseudomeningocele
from root avulsion after trauma. However, in most instances, MRI is the imaging study of choice, since it is more
sensitive than CT at identifying subtle
infiltrative lesions or areas of enhancement.
KEY POINTS:
The evaluation
of plexopathies
should consist of
a careful and
thorough clinical
evaluation,
electrodiagnostic
testing to
confirm
localization and
define severity
and
pathophysiology,
and imaging
studies to assess
for structural
etiologies.
The combination
of findings on
motor and
sensory nerve
conduction
studies and
needle EMG can
be used to
confirm a
plexopathy and
localize the
process to the
specific site
within the
plexus.
165
TABLE 8-6
Nerve Conduction Studies Used in Brachial Plexus Evaluation
Upper Trunk
Middle Trunk
Lower Trunk
Suprascapular
Lateral cord
Lateral cord
Lateral antebrachial
Median (index)
Median (thumb)
Median (middle)
Median (index)
Median (middle)
Musculocutaneous
Posterior cord
Posterior cord
Radial sensory
Radial sensory
Axillary motor
Radial motor
Medial cord
Ulnar (fifth digit)
Dorsal ulnar cutaneous
Medial antebrachial
Median motor (APB)
Ulnar motor (ADM, FDI)
APB abductor pollicis brevis; ADM abductor digiti minimi; FDI first dorsal interosseus.
166
Laboratory Studies
In most cases of plexopathies, extensive laboratory studies are not necessary. Assessment for impaired glucose
metabolism or diabetes may provide a
clue to the cause of an inflammatory
process, particularly in patients with
lumbosacral plexus involvement. Inflammatory plexopathies have also
been associated with underlying connective tissue or rheumatologic disorders, and laboratory tests used to
screen for these conditions, such as
erythrocyte sedimentation rate, antinuclear antibodies, or other autoimmune markers, may be useful.
DISEASES OF THE BRACHIAL
AND LUMBOSACRAL PLEXUS
A wide variety of diseases may injure
the brachial and lumbosacral plexus
(Ferrante, 2004) (Tables 8-7 and 8-8).

Clues to determining the etiology of
the plexopathy are often identified
during the history and examination or
with ancillary testing.
Specific Disorders of the
Brachial Plexus
Trauma. Blunt and penetrating
trauma. The most common, and often
the most debilitating, etiology of brachial plexopathies is damage to the
plexus from blunt or penetrating
trauma. Traumatic injuries to the brachial plexus most often occur after
high-velocity vehicular accidents. Any
segment of the plexus may be injured,
and individual components may be involved in a nonuniform fashion. Furthermore, in cases of severe trauma,
simultaneous injury to the root, such
KEY POINTS:
TABLE 8-7
Etiologies of
Brachial
Plexopathies
Trauma
TABLE 8-8
Neoplastic
Thromboembolism
Primary
Vasculitis
Metastatic
Idiopathic neuralgic
amyotrophy
Hereditary neuralgic
amyotrophy
Inflammatory
Nondiabetic lumbosacral
radiculo-plexus neuropathy
Ischemia
Inflammatory
Neoplastic
Burner
syndrome or
rucksack palsy
occurs as a
result of forceful
or chronic
stretch of the
brachial plexus;
both disorders
are transient and
recovery is
possible if the
inciting cause is
eliminated.
Ischemia
Diabetic lumbosacral radiculoplexus neuropathy
Obstetric
Medial brachial fascial

syndrome
Trauma
Vasculitis
Shoulder dislocation
Blunt or
penetrating
trauma is a
common cause
of brachial
plexus injury;
concomitant
injury to the
roots is often
present.
Thromboembolism
Rucksack palsy
Postmedian sternotomy
Blunt, traction, penetrating
Blunt, traction, penetrating

Burner and stinger
syndrome
Etiologies of
Lumbosacral
Plexopathies
Radiation
Structural
Retroperitoneal hematoma
Aneurysm
Abscess
Primary
Metastatic
Radiation
Structural
Neurogenic thoracic outlet
syndrome
Displaced clavicular fracture
as root avulsion, may occur in conjunction with injury to the plexus. Distinguishing root avulsion from a pure
plexopathy can be difficult. Clinical
clues that point toward a suspected
avulsion are severe weakness and sensory loss of the entire arm, bony injury
to the cervical spine, evidence of spinal cord injury, or a Horner syndrome.
On electrodiagnostic testing, the sparing of the sensory nerve conduction
responses in the context of severe sen-
sory loss is indicative of a preganglionic lesion, such as occurs in root

avulsion. When the sensory conduction studies are abnormal, however,
concomitant root avulsion with a
plexus injury cannot be excluded.
Burner and stinger syndrome.
Burner or stinger syndrome refers
to a transient stretch injury to the
plexus that typically follows sudden,
forceful trauma to the shoulder, typically during contact-sports activities.
The upper portion of the plexus is
stretched from traction due to separation of the head and shoulder. Symptoms include sudden onset of pain and
paresthesias in the upper and distal
arm, with a variable degree of weakness. The symptoms are transient, typically lasting for several minutes, but
may be more prolonged.
167

KEY POINT:
168
Neuralgic
amyotrophy is
an immunemediated
plexopathy,
characterized by
the acute onset
of shoulder and
arm pain
followed by
weakness,
sensory loss, and
atrophy, which
is often
misdiagnosed as
another
disorder.
Rucksack palsy. Another form of

brachial plexopathy due to stretch or
traction injury is rucksack palsy, which
occurs as the result of traction on the
upper portion of the plexus after wearing a rucksack or other device over the
shoulder. Traditionally described in
military personnel, rucksack palsy can
also occur in other individuals who
wear backpacks, child-carrying devices, or other devices over the shoulder. The weight of the load, duration
of pressure on the shoulder, and characteristics of the device all may contribute to the development of brachial
plexus injury. The clinical presentation
is numbness, pain, and transient
weakness after use of the device. The
symptoms are transient and improve
after disuse of the device.
Neuralgic amyotrophy. Other
than trauma, neuralgic amyotrophy
may be the most common form of brachial plexopathy, although it may also
be the most misdiagnosed entity. Neuralgic amyotrophy is an immune-mediated plexopathy, characterized by
the acute onset of shoulder and arm
pain followed by weakness, sensory
loss, and atrophy. In 1948, Parsonage
and Turner detailed the clinical aspects of the syndrome in a large cohort
of 136 patients, and the disorder has
since become synonymous with their
names (Parsonage-Turner syndrome).
Numerous other terms have been used
to describe this disorder, including idiopathic brachial plexopathy, acute
brachial plexitis, shoulder-girdle neuritis, serum neuritis, acute multiple
brachial neuropathy, cryptogenic brachial plexus neuropathy, paralytic brachial neuritis, and brachial plexus neuropathy.
Etiology. Neuralgic amyotrophy
has been described in association with
numerous entities, including viral,
bacterial, or parasitic infections, immunizations, connective-tissue diseases, surgical operations, and pregnancy, although in many cases a
definite precipitating event is not identified (Parsonage and Turner, 1948;

Rubin, 2001) (Table 8-9). In patients
who develop symptoms after immunizations, the onset of symptoms occurs
between 3 and 21 days after the injections and may involve either the injected or noninjected limb (Tsairis et
al, 1972). Symptom onset has also
been described as between 3 and 14
days after minor procedures in the
postoperative period.
Neuralgic amyotrophy has traditionally been attributed to inflammation of the brachial plexus. However,
isolated or unequal involvement of individual nerves arising off the plexus
or of nerves that do not technically
arise from the brachial plexus but
branch directly off the cervical roots
(eg, long thoracic and phrenic nerves)
suggests that this disorder may not
technically be a true plexopathy. The
etiology of neuralgic amyotrophy is
unknown, although the most common
theory suggests an immune-mediated
mechanism. The most supportive evidence of an inflammatory process
stems from biopsy of the brachial
plexus in four patients, demonstrating
mononuclear, T-lymphocytic inflammatory infiltrates surrounding the
epineural and endometrial vessels of
the nerves (Suarez et al, 1996).
Clinical manifestations. Neuralgic amyotrophy classically begins
with the acute onset of shoulder or
arm pain. Pain is the initial symptom
in approximately 65% of patients,
and in 90% of these patients, it is
sudden and intense at onset (Tsairis
et al, 1972). Pain may occur in the
scapula, arm, forearm, elbow, or
hand; typically correlates with the location or distribution of the neurologic deficit; and is commonly aggravated by movement of the
shoulder or limb. As a result patients
support the affected limb in a characteristic elbow flexion-shoulder
adduction position to reduce the
TABLE 8-9
Disorders
Associated With
Neuralgic
Amyotrophy
Infectious Diseases
Influenza
Salmonella
Schistosomiasis
Malaria
Typhus
Tuberculosis
Hepatitis
Poliomyelitis
Yersinia enterocolitis
Parvovirus B19
Rheumatic fever
Escherichia coli sepsis
Osteomyelitis
Connective-Tissue Diseases
Systemic lupus erythematosus
Polyarteritis nodosa
Rheumatoid arthritis
Ehlers-Danlos syndrome
Immunizations
Tetanus toxoid
Swine flu vaccine
Botulinum toxin
Antiallergy injections
Hodgkin Disease
Postoperative
Pregnancy
Strenuous Exercise
Adapted with permission from Rubin

DI. Neuralgic amyotrophy: clinical features and diagnostic evaluation. Neurologist 2001;7(6):350 356.
degree of pain. The pain usually persists for several hours to several
weeks before subsiding, although in
some patients pain may persist for

more than 6 weeks (Parsonage and
Turner, 1948).
Muscle weakness and atrophy are
common and classically delayed in onset by days to weeks after the onset of
pain. In most cases, weakness begins
by 2 weeks after the onset of symptoms and characteristically worsens as
the pain subsides (Tsairis et al, 1972).
The distribution of weakness is variable and depends on the portion of
the plexus or individual nerves that are
affected. Weakness is most commonly
in shoulder girdle muscles but may
involve any distribution of the brachial
plexus and may even be confined to a
single nerve distribution in 6% to 41%
of patients (Tsairis et al, 1972). Isolated
involvement in the distribution of the
radial, long thoracic, suprascapular,
axillary, and anterior interosseus
branch of the median nerve has been
described (Rubin, 2001). In addition,
unilateral or bilateral diaphragm paralysis due to phrenic nerve involvement
may occur in isolation or in association
with other nerve involvement. Sensory
loss occurs in up to 66% of patients
(Rubin, 2001; Tsairis et al, 1972). Sensory symptoms are often overshadowed by the severe degree of pain and
weakness and may be identified only
after close scrutiny during the sensory
examination.
Symptomatic bilateral brachial
plexus involvement occurs in up to
29% of patients and is usually asymmetric (Tsairis et al, 1972). The interval
between symptoms on each side is
usually less than 24 hours but may be
as long as several months. In some
cases pain may be unilateral, with
weakness and atrophy developing bilaterally, and vice versa. In addition,
involvement of the clinically unaffected side may be found more often
on needle EMG than on clinical examination.
Evaluation. Electrodiagnostic testing is useful at identifying a plexopaContinuum: Lifelong Learning Neurol 2008;14(3)
KEY POINTS:
Neuralgic
amyotrophy has
been described
in association
with numerous
entities,
including viral,
bacterial, or
parasitic
infections,
immunizations,
connectivetissue diseases,
surgical
operations, and
pregnancy,
although in
many cases a
definite
precipitating
event is not
identified.
Pain is the initial

symptom in
neuralgic
amyotrophy in
approximately
65% of patients,
and in 90% of
these patients is
sudden and
intense at onset.
Weakness and
atrophy are
common but are
classically
delayed in onset
by days to
weeks following
the onset of
pain.
169

KEY POINTS:
170
No specific
treatments have
been
systematically
proven to be
helpful in
reducing the
degree of
neurologic
impairment or
improving the
prognosis in
neuralgic
amyotrophy.
The prognosis of
neuralgic
amyotrophy is
generally good,
with significant
improvement
occurring in
89% of patients
at 3 years after
onset; however,
many patients
are left with
some residual
pain or
weakness.
thy but may be complicated by the fact

that the disease is patchy. The EMG
findings are, therefore, patchy in nature and may demonstrate findings in
different segments of the plexus to different degrees or in individual nerves.
MRI is generally unremarkable but is
useful in excluding other disorders,
such as a Pancoast tumor. Laboratory
studies, including erythrocyte sedimentation rate and complete blood
count, are invariably normal unless the
disorder is associated with a systemic
infection or connective-tissue disease.
CSF studies may reveal a mild elevation in protein without abnormal pleocytosis but are usually normal (Rubin,
2001).
Treatment. No specific treatments
have been proven to be helpful in reducing the degree of neurologic impairment or improving the prognosis
in neuralgic amyotrophy. No controlled studies of corticosteroids, IV
immunoglobulin, or other immunosuppressants are available. Corticosteroids may reduce the degree of pain
but have not been clearly demonstrated to alter the course of the disease (Tsairis et al, 1972). Analgesic
medication, such as narcotics, may be
necessary but is often ineffective in
reducing the degree of pain early in
the course of the disease. Physical
therapy and regular range of motion
exercises have also been advocated to
prevent secondary complication, such
as shoulder immobility.
Prognosis. The prognosis of neuralgic amyotrophy is generally good in
most patients, with significant improvement occurring in 36% within 1
year, in 75% by the end of the second
year, and in 89% of patients at 3 years
after the onset (Tsairis et al, 1972).
Recovery begins with improvement in
pain usually several weeks after onset.
Depending on the severity of weakness and atrophy, the degree and temporal course of recovery vary and follow the pattern of reinnervation of
proximal muscles before distally affected muscles. More recent evidence

has suggested that the prognosis may
not be as good as had previously been
considered, and a relatively high percentage of patients demonstrate persistent deficits and a moderate degree
of pain more than 3 years after the
attack (van Alfen and van Engelen,
2006). Recurrent attacks are uncommon, but they have been reported in
1% to 5% of patients (Tsairis et al,
1972). The occurrence of multiple episodes over time, especially in younger
patients, should raise the possibility of
hereditary neuralgic amyotrophy.
Hereditary neuralgic amyotrophy. A hereditary form of neuralgic
amyotrophy is much less common
than sporadic neuralgic amyotrophy.
Hereditary neuralgic amyotrophy
(HNA) is an autosomal dominant disorder characterized by recurrent episodes of brachial plexopathy, typically
beginning in the second or third decades or even earlier in some patients.
In HNA, the temporal profile and clinical features of brachial plexus involvement are indistinguishable from
sporadic neuralgic amyotrophy. Associated phenotypic features, including
hypotelorism, cleft palate, short stature, or widely spaced teeth, may be
present (Dunn et al, 1978). In addition,
patients with HNA have a higher incidence of recurrent episodes of involvement, often experiencing three
or more attacks over many years. Genetic studies have mapped the gene
defect to chromosome 17q24-q25 in
some kindreds, although the absence
of pedigrees that do not demonstrate
linkage to this site indicates genetic
heterogeneity of the disorder (Watts et
al, 2001).
Neurogenic thoracic outlet syndrome and postmedian sternotomy. Thoracic outlet syndrome (TOS)
is a clinical syndrome characterized by
arm pain and numbness due to presumed transient compromise of the
subclavian vasculature from compression or narrowing of the vessels as

they course through the thoracic outlet. In the majority of cases of TOS, no
persistent neurologic deficits occur. In
rare instances, however, the lower
trunk or medial cord of the brachial
plexus is affected (true or classic
neurogenic TOS). True neurogenic
TOS was first described by in 1970 by
Gilliatt, who identified the characteristic motor and sensory deficits and attributed the characteristic features to
damage to the lower trunk/medial
cord of the plexus. In one populationbased study of workmens compensation patients diagnosed with TOS, true
TOS as shown by abnormal EMG studies was identified in only 7% of cases
(Franklin et al, 2000).
In true TOS, a band extending
from a cervical rib or elongated C7
transverse process to the first rib
stretches C8-T1 fibers in the lower
trunk of the plexus as it courses
through the thoracic outlet. This compression produces pain, weakness,
and numbness in the medial arm and
hand. Because of the anatomic distribution of the fibers in the lower trunk,
which lies just above the abnormal
band, the T1 fibers are classically more
affected than the C8 fibers. As a result,
atrophy and weakness affect the thenar muscles more prominently than
other C8-innervated muscles.
The classic electrodiagnostic findings of true neurogenic TOS are low
median and/or ulnar CMAP amplitudes, low ulnar or medial antebrachial sensory amplitudes, and sparing
of the median sensory response. The
medial antebrachial cutaneous sensory and medial motor responses have
been shown to be the most sensitive
conduction studies (Levin et al, 1998).
Surgical resection of the band or
removal of a cervical rib leads to improvement or resolution of the symptoms in most patients with true neurogenic TOS. In a review of a series of 33
surgically treated patients over a 25year period at a single institution, pain,

weakness, and sensory loss improved
in the majority of patients although
motor recovery was rarely complete
(Tender et al, 2004). This is in contrast
to patients with non-neurogenic TOS,
in whom retrospective studies have
shown no significant benefit of surgery compared to conservative management (Franklin et al, 2000). Surgical complications are rare in
experienced centers but may include
pleural tear, pneumothorax, hematoma, vascular insult, and the development of a more severe brachial plexopathy after transaxillary resection of
the first rib due to traumatic injury to
the plexus (Franklin et al, 2000; Tender et al, 2004).
A similar condition causing a
lower trunk plexopathy occurs after
surgeries requiring a median sternotomy, such as cardiac or thoracic surgeries (Levin et al, 1998). In these
cases retraction of the chest wall or
fracture of the first rib may compress
the C8 rami or lower trunk, producing
a traction injury. The clinical and electrodiagnostic features are similar to
those that occur in neurogenic TOS,
although the ulnar motor and sensory
responses are often more severely involved than the median motor or medial antebrachial sensory responses.
Compartment syndrome. The
infraclavicular portion of the brachial
plexus (cords) travels from the clavicle
to the axilla where the individual terminal nerves are formed. The medial
brachial fascial compartment is a section of the upper arm formed by the
medial intermuscular septum where
the axillary vessels and terminal
nerves of the brachial plexus travel.
Lesions located in this compartment,
such as hematomas after axillary arteriography, humerus fracture, or axillary artery aneurysms, may lead to an
increase in the intracompartmental
pressure and secondary compression
KEY POINTS:
True neurogenic
thoracic outlet
syndrome is
rare; a band
extending from
a cervical rib or
elongated C7
transverse
process to the
first rib stretches
C8-T1 fibers in
the lower trunk
of the plexus as
it courses
through the
thoracic outlet.
Surgical
resection of the
band or removal
of a cervical rib
leads to
improvement or
resolution of the
symptoms in
most patients
with true
neurogenic
thoracic outlet
syndrome.
171

KEY POINTS:
172
A lower trunk
plexopathy can
occur following
surgeries
requiring a
median
sternotomy due
to a traction
injury of the C8
rami or lower
trunk from
retraction of the
chest wall or
fracture of the
first rib.
Neoplastic
brachial
plexopathies are
most commonly
due to local
spread or
metastatic
disease rather
than primary
neoplasms in the
region. Lung,
breast, and
lymphoma
account for
approximately
75% of all
neoplasms
infiltrating the
brachial plexus.
and ischemia to the nerves within the

compartment. Any of the terminal
nerves (median, ulnar, radial, axillary,
musculocutaneous) may be affected to
different degrees, although the median
and ulnar are typically affected more
often than other nerves (Tsao and Wilbourn, 2003). Treatment with surgical
intervention and urgent decompression of the compartment within hours
of symptom onset is important to optimize recovery.
Neoplastic plexopathy. The
proximity of the brachial plexus to the
lung, breast, and neighboring lymphatic system predisposes it to tumor
spread and infiltration more than any
other peripheral nerve structure in the
body. As a result, neoplastic infiltration is one of the more common
causes of lesions involving the brachial plexus. In a review of patients
admitted to a large cancer center in the
1970s, 0.4% were found to have a lesion of the brachial plexus (Kori et al,
1981). Neoplastic plexopathies are
more frequently due to local spread or
metastatic disease rather than to primary neoplasms in the region. The
most common tumors to spread to the
brachial plexus are lung, breast, and
lymphoma, which account for approximately 75% of all neoplasms (Kori et
al, 1981).
The majority of patients initially
present with pain, which is often severe in quality and occurs in the shoulder girdle and radiates into the elbow
and medial arm. Progressive weakness, atrophy, and sensory loss follow
the onset of pain. The distribution of
plexus involvement varies, with the
lower trunk/medial cord or diffuse
plexus involvement most common
(Harper et al, 1989; Kori et al, 1981).
Other clinical features, such as the
presence of a Horner syndrome, were
found in half of the patients in one
series and favor neoplastic plexopathy
over radiation-induced plexopathy
(Kori et al, 1981).
One form of neoplastic plexopathy occurs from a Pancoast tumor, a

malignancy in the lung apex that extends rostrally to compress or infiltrate
the lower trunk of the plexus. In this
syndrome, pain and numbness in the
medial arm and progressive hand
weakness are the predominant clinical
features. The presence of a Horner
syndrome indicates involvement of
the T1 root or cervical sympathetic
ganglion and is a helpful localizing
sign.
Primary neoplasms of the brachial
plexus are rare and include schwannomas and neurofibromas. These neoplasms are typically slow growing, and
patients present with progressive paresthesias without significant pain. Imaging studies with MRI show enhancing solitary lesions within the plexus.
The electrodiagnostic features of
neoplastic plexopathies depend on
the distribution of involvement (Seror,
2001). Abnormalities in motor and
sensory conduction studies and during
needle examination are common. MRI,
the imaging study of choice, may demonstrate a distinct mass compressing
or nodular enhancement of the plexus
(Figure 8-4). MRI may also be useful
in helping to distinguish neoplastic
plexopathy, in which high-T2-signal
abnormality within the plexus is characteristic, from radiation plexopathy,
in which low-signal intensity is seen
on T2-weighted images. In addition,
hypermetabolism, as noted by increased uptake on PET imaging, may
also be helpful to suggest tumor infiltration (Luthra et al, 2006). Frequently,
surgical exploration and biopsy are
necessary to obtain pathologic confirmation of the neoplasm.
Treatment of neoplastic plexopathies is focused on the malignancy
with localized radiation or chemotherapy, which may improve pain but typically has little effect on improving
neurologic dysfunction (Kori et al,
1981).
MRI study (T1-weighted

with contrast)
demonstrating tumor
infiltration (arrows) into the brachial
plexus.
FIGURE 8-4
Radiation-induced plexopathy.
Radiation-induced brachial plexopathy is an uncommon delayed manifestation of radiation therapy. The incidence of development of brachial
plexus injury after radiation has been
reported to be as high as 9% of patients treated with radiation (Mondrup
et al, 1990). The clinical manifestations
include gradually progressive paresthesias, sensory loss, weakness, atrophy, and pain. Symptom onset ranges
from 1 month to 18 years after radiation exposure (Harper et al, 1989; Kori
et al, 1981) (Case 8-1). Several factors
have been associated with an increased risk of development of brachial plexopathy, including a higher
dose of radiation (greater than 5000
cGy), increased number of ports of
radiation administration, the use of adjunctive chemotherapy, and the extent
of axillary node dissection. Although
some studies report more selective involvement of the upper trunk of the
brachial plexus, others have shown
that the upper, lower, or entire plexus
may be involved (Harper et al, 1989;
Kori et al, 1981).
Electrophysiologic studies demon-
strate abnormal motor and sensory

NCS and large motor unit potentials
with reduced recruitment in the affected plexus segments. The presence
of myokymic discharges is a characteristic feature of radiation plexopathies,
occurring in up to 63% of patients, and
is helpful in distinguishing radiationinduced plexopathies from neoplastic
plexopathies (Harper et al, 1989).
Neuroimaging studies may be normal
or show increased or decreased signal
and fibrosis in the region of the brachial plexus (Wouter van Es et al,
1997).
The underlying pathophysiology
of injury to the brachial plexus is not
completely understood. Pathologic
studies have demonstrated loss of myelin, fibrosis and thickening of the
neurolemma sheath, and hyalinization
and obliteration of the vasonervorum
to the brachial plexus, suggesting either focal compression of the plexus
by fibrosis or chronic nerve ischemia
as possible underlying mechanisms.
The course of radiation plexopathy is typically one of steady progression or stabilization in 90% of patients,
although cases of improvement have
been reported (Killer and Hess, 1990).
No established treatment is available
to reverse or improve the nerve injury,
although surgical interventions, such
as neurolysis or neurolysis with omental grafting, have been performed in
some patients with variable improvement in symptoms. A report of resolution of conduction block after anticoagulation therapy suggested that
ischemic nerve injury may contribute
to the pathogenesis of radiation-induced nerve damage and strategies to
improve nerve perfusion may be effective (Soto, 2005). A recent phase 2
study of hyperbaric oxygen treatment
in radiation plexopathy did not demonstrate significant improvement in
functional outcome (Pritchard et al,
2001).
KEY POINTS:
Several factors
have been
associated with
an increased risk
of development
of radiationinduced brachial
plexopathy,
including a
higher dose of
radiation,
increased
number of ports
of radiation
administration,
the use of
adjunctive
chemotherapy,
and the extent
of axillary node
dissection.
The presence of
myokymic
discharges on
electrodiagnostic
testing is a
characteristic
feature of
radiation
plexopathies and
is helpful in
distinguishing
radiationinduced from
neoplastic
plexopathies.
173

Case 8-1
A 58-year-old right-handed woman presented with progressive right arm pain and hand
weakness. She was diagnosed with right breast infiltrating ductal carcinoma with positive lymph
nodes 11 years earlier and had been treated with a modified radical mastectomy, chemotherapy,
and adjuvant radiation to the right axilla and chest wall. Six years after the initial diagnosis
recurrent metastatic cancer was found in contralateral axillary lymph nodes, and she was treated
with additional chemotherapy. Beginning 1 year ago (10 years after her initial diagnosis), she
experienced progressive burning pain in her right hand, arm, and shoulder and tingling in her
fingers. She experienced diffuse weakness and atrophy of the muscles in her right arm. She had
no neck pain or left arm symptoms. Her examination demonstrated mild weakness of right
deltoid, biceps, triceps, and wrist flexors and moderately severe weakness of wrist extensors,
finger extensors, finger flexors, interossei, and thenar muscles. The right triceps reflex was mildly
reduced, and there was decreased pinprick in palm and dorsum of right hand. EMG
demonstrated findings of a diffuse right brachial plexopathy. Occasional myokymic discharges
were noted during the needle examination (Figure 8-5).
FIGURE 8-5
Myokymic discharge.
Comment. This case demonstrates findings of a diffuse right brachial plexopathy, involving
predominantly the lower trunk/medial cord, and less severely the upper and middle trunks.
The presence of myokymic discharges is strongly indicative of a radiation-induced plexopathy;
however, a concomitant neoplastic infiltration could also be present. This patient underwent
MRI of the brachial plexus, which showed no masses, enhancement, or infiltration of the
brachial plexus. The patient was felt to have a radiation-induced plexopathy.
174
Specific Disorders of the
Lumbosacral Plexus
Trauma. The lumbosacral plexus is a
relatively shielded structure that is located deep in the pelvis, neighbors no
highly mobile structures, and is less
prone to stretch injury. As a result,
traumatic lumbosacral plexopathies
are rare, and trauma accounts for only
a small percentage of all lumbosacral
plexopathies. The majority of traumatic plexopathies are the result of
penetrating trauma (eg, gunshot or
puncture wounds) or severe high-veContinuum: Lifelong Learning Neurol 2008;14(3)
locity injuries. In most cases, concomitant pelvic or hip joint injuries, such as
fractures, are present, which may confound the clinical examination and localization of the lesion to the plexus.
Diabetic and nondiabetic lumbosacral radiculo-plexus neuropathy. One of the more common causes
of lumbosacral plexopathies is an immune-mediated or inflammatory process involving the lumbosacral plexus.
This commonly occurs in the context
of diabetes, although an identical syndrome can occur in nondiabetics. Also
referred to by many names, including

diabetic amyotrophy, Bruns-Garland
syndrome, proximal diabetic neuropathy, as well as several other terms, this
condition has been shown to have a
multifocal localization involving segments of the plexus, individual nerves,
and roots, leading to the anatomically
driven term lumbosacral radiculoplexus neuropathy (LRPN) (Dyck and
Windebank, 2002).
The clinical features of diabetic
LRPN are fairly stereotypic. The syndrome occurs in middle- or older-aged
patients with type 2 diabetes, usually
during a period of relatively well-controlled diabetes and without other
long-term diabetic complications. It
often occurs in the context of marked
weight loss (Dyck and Windebank,
2002). Acute or subacute onset of pain
in the thigh, leg, buttock, and/or back
is the initial neurologic symptom. On-
set is predominantly and initially unilateral, although symptoms commonly

spread to the contralateral limb, with a
median time to bilateral disease of
about 3 months (Dyck and Windebank, 2002). Weakness and atrophy
occur shortly after the onset of pain
and are usually the most prominent
and debilitating symptoms. In one
series, half of the patients were wheelchair bound during their illness because of weakness (Dyck and Windebank, 2002). Variable sensory loss
in the leg may also be present. Improvement in pain and weakness occurs in the majority of patients, although recovery is usually slow and
incomplete (Case 8-2).
The clinical features of nondiabetic LRPN are indistinguishable from
the diabetic form, with a subacute onset and progression of asymmetric leg
pain and weakness (Dyck et al, 2001).
KEY POINT:
Diabetic and
nondiabetic
lumbosacral
radiculo-plexus
neuropathy is an
immunemediated or
inflammatory
process involving
the lumbosacral
plexus that
occurs in
middle- or olderaged patients. It
presents with
weight loss,
asymmetric or
unilateral leg
pain, weakness,
and atrophy.
Case 8-2
A 67-year-old man with a 4-year history of type 2 diabetes mellitus
developed severe left thigh pain. Over the subsequent month, the pain
persisted and he noted progressive weakness of his legs, left worse than
right, and atrophy of his thigh muscles. He reported a 9.1-kg weight loss,
but no fevers or other constitutional symptoms. His examination
demonstrated severe weakness on the left side involving the quadriceps,
hip flexors, and hip adductors, with mild weakness of left foot
dorsiflexion, inversion, and eversion. There was sensory loss over his left
thigh and mild bilateral distal sensory loss to his ankles. Reflexes were
absent diffusely. He also demonstrated mild weakness of his right hip
flexors and quadriceps.
EMG demonstrated low peroneal and tibial motor amplitudes with
normal conduction velocities and an absent sural response. Needle
examination showed fibrillation potentials and long duration, polyphasic
motor unit potentials diffusely in the left leg muscles, but most
prominently in the quadriceps, iliopsoas, and adductor longus. Similar
findings were seen in right quadriceps and the lumbar paraspinals. MRI of
the lumbar spine and pelvis was normal.
Comment. This case demonstrates the features of a diabetic LRPN. The
onset and progression of symptoms, as well as the clinical features, are
consistent with this diagnosis. In many cases, the disease affects the nerves
in a widespread distribution, and bilateral involvement is common.
Structural causes of root or plexus compression were excluded by imaging
studies. This patient gradually improved over 6 months without specific
treatment but was left with moderate residual quadriceps and iliopsoas
weakness.
175

KEY POINTS:
176
Neoplastic
lumbosacral
plexopathies
most commonly
occur from local
invasion or
direct extension
from
neighboring
tumors, such as
colorectal,
urogenital,
prostate,
lymphoma, and
retroperitoneal
and pelvic
sarcomas.
Non-neoplastic
structural lesions
involving the
lumbosacral
plexus include
retroperitoneal
hematoma,
psoas abscess,
or femoral artery
aneurysms.
Long-term outcome is similar to diabetic LRPN, with a severe morbidity

associated with incomplete recovery
of weakness.
Laboratory studies are typically
unremarkable in diabetic and nondiabetic LRPN, apart from abnormal fasting serum glucose and glycosylated
hemoglobin in the former. CSF protein
may be elevated in either, although
pleocytosis is uncommon. EMG demonstrates abnormal motor and sensory
NCS amplitudes and fibrillation potentials and neurogenic motor unit potentials in a patchy distribution in the leg
muscles. In addition, similar needle
EMG findings are commonly seen in
the lumbar paraspinal muscles, further
indicating involvement of the roots in
addition to postganglionic components of the nerve. Histopathologic
studies of both diabetic LRPN and
nondiabetic LRPN demonstrate multifocal fiber loss, perineurial thickening,
neovascularization, segmental demyelination, and axonal degeneration, all
of which suggest ischemic nerve injury
from a micro-vasculitis as the underlying mechanism (Dyck and Windebank, 2002).
There is no systematically proven
treatment for diabetic LRPN or nondiabetic LRPN. Anecdotal reports of improvement with IV methylprednisolone or immunoglobulin suggest
that immunomodulating therapies
may be helpful (Triggs et al, 1997).
Neoplastic. Compression or infiltration of the lumbosacral plexus by
neoplasms is one of the more common
etiologies of lumbosacral plexopathies. Neoplastic plexopathies most
commonly occur from local invasion
or direct extension from neighboring
tumors; and colorectal, urogenital,
prostate, lymphoma, and retroperitoneal and pelvic sarcomas account for
over 80% of the tumors (Jaeckle et al,
1985). Extra-abdominal metastatic tumors from breast or lung occur in apContinuum: Lifelong Learning Neurol 2008;14(3)
proximately 25% of neoplastic plexopathies (Jaeckle et al, 1985).

The clinical manifestations of neoplastic lumbosacral plexopathies include pain and weakness. In a review
of 85 cancer patients with lumbosacral
plexopathy, the lower plexus was involved in 51%, upper plexus in 31%,
and entire plexus in 18% (Jaeckle et al,
1985). Approximately 70% of patients
present with insidious onset of pelvic
or radicular pain, and 15% present initially with paresthesias or weakness. A
careful physical examination may
identify an abdominal or rectal mass
that, along with leg pain, weakness,
leg edema, and hydronephrosis, is
highly suggestive of malignancy. In
neoplastic plexopathies, bilateral involvement, typically in an asymmetric
fashion, occurs in approximately twothirds of patients. MRI or CT showing a
mass compressing the plexus or thickening or enlargement of the plexus is
important in making the diagnosis.
MRI is more sensitive than CT (Taylor
et al, 1997).
Hematoma, abscess, and aneurysm. Compression of the lumbosacral plexus by non-neoplastic masses
or after a large retroperitoneal hemorrhage may cause acute or subacute
onset of symptoms. Medical conditions, such as anticoagulation or other
bleeding disorders, may predispose a
patient to the development of a spontaneous hemorrhage. Furthermore, iatrogenic retroperitoneal or groin hemorrhages account for 11% of all
complications of femoral artery catheterizations (Lumsden et al, 1994).
Hemorrhage into the iliacus or psoas
muscle may lead to a compartment
syndrome involving the lumbar
plexus. Patients present with pain and
weakness, particularly in the thigh region. Imaging studies, ultrasound, CT,
or MRI are diagnostic for hemorrhage.
Other lesions that may occur in
structures neighboring the plexus include retroperitoneal abscess or femo-
ral artery aneurysm. Isolated aneurysms of the common iliac artery are
rare in the general population; however, lumbosacral plexopathies have
been described in several patients
with aneurysms of the common iliac
artery (Gardiner et al, 2006). In these
cases, pain in the low back, buttock,
hip, or thigh may occur over weeks or
months, although expansion of the aneurysm may produce acute worsening
of symptoms.
Radiation-induced. The features
of radiation-induced lumbosacral
plexopathy are similar to those of radiation-induced brachial plexopathies.
Symptom onset may occur months or
years after the radiation exposure, typically after treatment for lymphomas,
testicular cancer, or gynecologic cancers (Aho and Sainio, 1983). In contrast to neoplastic plexopathies, pain is
often less prominent in radiation-induced plexopathies, and patients
present with slowly progressive weakness and sensory loss. The lumbar or
sacral plexus may be involved. EMG
demonstrates myokymic discharges in
approximately 60% of patients and,
when present, they typically occur in
only one or a few muscles. The presence of myokymic discharges is helpful to distinguish radiation plexopathies from neoplastic plexopathy (Aho
and Sainio, 1983; Thomas et al, 1985).
TREATMENT AND
MANAGEMENT OF
PLEXOPATHIES
Treatment of plexopathies may be
challenging, particularly because many
of the etiologies have no specific cure.
When a specific, treatable etiology is
identified, such as neoplastic compression or a cervical band, removal or
treatment of the cause may lead to

significant improvement. Supportive
management, with focus on pain control and physical therapy, is usually
the mainstay of treatment of patients
with brachial and lumbosacral plexopathies. Physical and occupational
therapy are important in preventing
contractures or overstretching of muscles and ankylosis of joints and directing rehabilitation.
In some cases of severe brachial
plexopathies, particularly those due to
trauma in which the nerve lesion is not
in continuity, surgical intervention
performed within days after the injury
as primary repair or after several
weeks to months as a secondary repair
may improve function (Spinner and
Kline, 2000). Immediate primary repair
is usually recommended when a clean
laceration of the nerve by a sharp object has occurred and where the nerve
endings are not injured by crush or
stretch. Secondary early surgical repair
after 2 to 4 weeks is generally recommended for blunt injuries or injuries
with extensive soft tissue damage
where the nerve injury appears to be
complete or very severe. Surgical options include internal neurolysis, resection and reanastomosis, or resection and grafting. In those cases in
which the nerve injury is so severe that
primary repair or grafting is impossible, neurotization with anastomosis of
one nerve to another may be another
option. Finally, if the above procedures fail and no reinnervation has occurred or many years have elapsed
since the injury, other secondary forms
of therapy can be attempted. These
include tendon transfers and joint stabilization.
KEY POINTS:
Radiationinduced
lumbosacral
plexopathies
occur months or
years following
radiation
exposure,
typically
following
treatment for
lymphomas,
testicular cancer,
or gynecologic
cancers.
Treatment of
plexopathies
consists of
treating or
removing the
underlying
etiology,
symptomatic
and supportive
management,
and occasionally
surgical
intervention
with primary or
secondary repair
of the nerve.
177
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179
ETHICAL PERSPECTIVES IN
NEUROLOGY
Thomas I. Cochrane
The practice of neurology presents a series of ethical challenges for the clinician.
These rarely have simple or straightforward solutions, but require careful
consideration by the neurologist. This section of
provides a case vignette
that raises one or more ethical questions related to the subject area of this issue. The
discussion that follows, written by colleague(s) with particular interest in bioethics,
should help the reader understand and resolve the ethical dilemma.
NOTE: This is a hypothetical case.
182
A 32-year-old woman slips and falls from a 10-foot ladder at work. Her coworkers
immediately find her awake and attempting to mouth words, but not capable of
moving her limbs and barely breathing. When paramedics arrive 5 minutes later, she is
unconscious and not breathing, and they intubate her using spinal precautions. At the
hospital, she opens her eyes spontaneously and appears to attend when spoken to. She
can blink when asked but cannot move her limbs. She has no sensation below the
neck. She is ventilated and not generating any spontaneous respiratory movements.
When asked about pain, she seems to indicate by using blinks and facial gestures that
her neck pain is severe.
Sedative medications and narcotic analgesics are administered while imaging
studies are obtained. CT of the cervical spine reveals a burst fracture of the atlas, with
bony fragments and soft tissue within the spinal canal. MRI obtained 3 hours after the
injury reveals severe compression of the upper cord, with T2-signal hyperintensity,
indicating severe cord edema.
She is admitted to the surgical intensive care unit (ICU). Because the patient has
been sedated, the ICU attending physician and neurosurgeon approach the patients
husband and her parents. The neurosurgeon indicates that the patients prognosis for
recovery is poor and that she is likely to be permanently quadriplegic. He recommends
urgent surgery to decompress and stabilize the upper cervical spine in order to
minimize the patients pain and to maximize the chances of some recovery.
To the neurosurgeons surprise, the patients husband and her parents unanimously
refuse surgery. Moreover, they express their certainty that under these circumstances
the patient would refuse all life-sustaining therapy. The patients husband has durable
power of attorney for health care decisions (health care proxy in some states) for his
wife and specifically requests that her ventilator be stopped and that she be allowed to
die. The patients husband and parents previously have had detailed conversations with
Relationship Disclosure: Dr Cochrane has nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Cochrane has nothing to disclose.
her about disability, and in the past she has specifically stated that she would rather be
dead than be a quadriplegic. When the surgeon suggests waking the patient and
discussing the matter with her, her family refuse, claiming, We know what she would
want, and were not going to put her through that. She would definitely not want to go
through the trauma of finding out about her condition. If she could comment right now,
shed tell you the same thing.
COMMENT
(1) When a patient lacks competence due to the administration of sedatives and narcotics,
and if competence can be restored by reversing the sedation, are there circumstances in
which it is ethically permissible for the surrogate to insist the patient remain sedated?
Are there circumstances in which it is ethically permissible for the health care team to
refuse the surrogates request?
(2) When is surrogate consent required, and what types of decisions can surrogates make
for patients?
(3) If a patient is competent, is it acceptable to conceal knowledge of her condition from
her, in order to spare her psychological harm?
SURROGATE DECISION MAKING WHEN PATIENT CAPACITY CAN BE RESTORED
It is a well-established principle that patients who lose decision-making capacity
(competence) retain all of the rights in regard to health care decisions they possessed
before they lost capacity (Meisel and Cerminara, 2004). Naturally, the challenge is to
estimate what the patients wishes would be. Ideally, patients will have specified their
wishes in advance. However, in practice there is often a mismatch between the
conditions in the advance directive and the patients actual clinical circumstance, so that
uncertainty or ambiguity exists. Physicians must usually rely on surrogates to make
decisions for patients who lack capacity. A surrogate is someone who knows the patient
well enough to try to estimate what the patient would want in a given situation. That is,
the surrogates job is to try to make the decision that the patient would have made, if
the patient were able. Patients can specify in advance who they wish to be their
surrogates through documents such as a durable power of attorney for health care
decisions. Surrogates do not have decision-making authority over competent patients
except in the rare circumstance in which a competent patient explicitly yields authority
to the surrogate.
In the case described above, the patient lacks decision-making capacity only because
she is sedated, and there is good reason to think that she would regain decision-making
capacity if the sedation were reduced. Respect for the patients autonomy requires the
physicians to attempt to restore her capacity (while simultaneously treating her pain) so
that they can inform her of her condition and ask her whether she wishes to make
decisions for herself, or whether she wishes for her husband to make decisions for her.
Especially when it comes to decisions with irreversible consequences, such as
withdrawal of life-sustaining therapies, physicians should not consider proceeding
without attempting to consult with the patient herself.
In the critical care setting, there is often a limited window of opportunity for a
treatment, such as surgical decompression of the spinal cord, to be beneficial. Thus
183
ETHICAL PERSPECTIVES IN NEUROLOGY
there are circumstances when the doctrine of emergency treatment will influence the
traditional beneficence/nonmaleficence analysis strongly in favor of treating. One will
not have the opportunity to reconsider later, since the surgery cannot significantly
impact neurologic recovery after this critical period has passed. Likewise, a decision to
continue the ventilator is reversible, but a decision to forgo it is not.
This explains why most health care professionals would consider it acceptable to
have the patients husband consent for surgery, but not acceptable to honor his refusal,
at least not without first consulting the patient. One certainly should be unwilling to take
the irreversible step of stopping the ventilator without consulting her.
184
PROTECTING THE PATIENT FROM PSYCHOLOGICAL HARM

This patients husband and her parents have argued that it is in the patients best
interests to discontinue her ventilator and allow her to die without consulting her
because knowledge of her spinal cord injury and awareness of her neurologic deficits
would cause significant psychological distress. This is a rationale that is sometimes
advanced by families to protect patients in the setting of conveying news about a fatal
illness like some cancers or neurodegenerative disease such as ALS. It is common in
some cultures to conceal a diagnosis from a patient out of concern for the patients
psychological well-being.
In the United States, most physicians and ethicists are uncomfortable with this
practice since it conflicts with the principle of respect for autonomy, and most consider
it unacceptable (Beauchamp and Childress, 2001). While such an approach might be
considered for patients from a culture where this practice is accepted, it cannot be
reasonably considered if the patient comes from a culture and tradition in which honesty
and disclosure directly to the patient is the norm, as it is in most of North America. In
the absence of a specific reason to think that disclosure would cause severe and
irreversible psychological harm, it should be the practice to include patients in their own
medical decision making and to be prepared to respond to any emotional or
psychological distress that the patient or family may have.
This does not mean that patients are required to make their own decisions in all
circumstances. Autonomous patients may legitimately choose not to have certain types
of information revealed and can ask that someone else make decisions for them. When
a concern is raised about the type of information a patient may want to know, one can
involve the patient in deciding what that information would be. For example, one is
permitted in some cases to ask the patient, How much specific information do you
want to know? This puts the patient in the position of controlling the flow of
information, so if the patient opts out of the decision-making process at this point, this
is still consistent with the principle of respect for autonomy.
COMPETENT REFUSAL OF LIFE-SUSTAINING THERAPY
Generally speaking, patients with decision-making capacity have the right to refuse any
medical therapies, including surgeries and life-sustaining therapies such as ventilator support. Physicians, in turn, are generally obligated to honor such refusals (Beauchamp and
Childress, 2001).
Certain conditions should apply, however, before refusal of life-sustaining therapy is
considered legitimate and informed. The patient must be able to understand her current
condition and its prognosis, as well as the treatment alternatives available to her. She must
be able to understand the potential risks and benefits of the alternatives and be able to make
a choice between the alternatives. Finally, the patients decision must not be coerced
(Bernat, 2002).
In the case described, the patients decision-making capacity has not been assessed, and
she has not been informed of her condition, her prognosis, or the treatment alternatives (eg,
surgery versus no surgery). But if she were awakened and found to be competent, and she
refused surgery and ventilator support as her family predicted she would, what should the
physicians response be?
There is no single or simple answer to this question. The most general response is to say
that such an important and irreversible decision should not be made until one can be very
confident that the patient fully understands her situation and has an accurate understanding
of what her prognosis actually implies. In the acute setting, one is wise to be cautious in
assessing the patients decision-making abilities even if she appears fully cognitively intact.
In the hours and even days after a sudden and unexpected serious illness, the psychological
stress of adjusting to the new situation can also cause patients to make decisions that they
may later consider hasty (Patterson et al, 1993). It is also well recognized that patients and
caregivers tend to underestimate quality of life with disability, so an argument can be made
that patients treatment refusals in the acute setting should be met with efforts to persuade
and educate, rather than immediate treatment withdrawal (Cushman and Dijkers 1990;
Peterson et al, 1993).
Much will depend on the particulars of a given case, but whenever concern about the
legitimacy of treatment refusal or consent exists, caregivers should seek input and assistance from other sources, including ethics consultants, social workers, chaplains, and
psychiatrists. Ethics consultation in particular is an effective way to ensure that all of the
parties that should be involved in decision making have had appropriate input.
CONCLUSION
When faced with a request by a surrogate to forgo life-sustaining therapy for a patient
who lacks decision-making capacity solely because of the administration of sedative
agents, physicians should not feel obligated to immediately honor the request without
discussion. Because the patient in the case lacks capacity only because of medication
effects, the team should attempt to restore her capacity before agreeing to the
irreversible decision to withdraw ventilatory support. The physicians should attempt to
persuade her surrogates of the need to wait until the patients capacity is restored and
assessed and the prognosis is better understood.
Because of the limited time window for surgical decompression, the physicians may
reasonably insist that surgical decompression and stabilization of the spine be
performed, as the risk of further harm to the spinal cord is small, and there is a real,
although small, chance of benefit. Since this would mean proceeding with surgery
despite the surrogates refusal (assuming the patient had not been awakened and
refused the surgery herself), the physicians should call for immediate advice and
consultation from the ethics service and the hospital counsel. It is very likely that an
emergency request for a judicial order to treat the patient would be needed.
Overriding the surrogates might, at first, seem to be a violation of the principle of
respect for autonomy. But in rare circumstances such as these, this action can be
properly viewed not only as protecting the patients life and health, but also as
defending the patients right to make informed decisions about life-sustaining treatments
for herself, which shows greater respect for her autonomy.
185
ETHICAL PERSPECTIVES IN NEUROLOGY
REFERENCES AND SELECTED READINGS

Beauchamp TL, Childress JF. Principles of biomedical ethics. 5th ed. New York: Oxford University Press,
2001.
Bernat JL. Ethical issues in neurology. 2nd ed. Boston: Butterworth-Heinemann 2002.
Cushman LA, Dijkers MP. Depressed mood in spinal cord injured patients: staff perceptions and patient
realities. Arch Phys Med Rehabil 1990;71(3):191196.
Ditunno JF Jr, Formal CS. Chronic spinal cord injury. N Engl J Med 1994;330(8):550 556.
Meisel A, Cerminara KL. The right to die: the law of end-of-life decision making. 3rd ed. New York: Aspen
Publishers, 2004.
Patterson DR, Miller-Perrin C, McCormick TR, Hudson LD. When life support is questioned early in the care
of patients with cervical-level quadriplegia. N Engl J Med 1993;328(7):506 509.
Sensky T. Withdrawal of life sustaining treatment. BMJ 2002;325(7357):175176.
Whiteneck GG, Charlifue SW, Frankel HL, et al. Mortality, morbidity, and psychosocial outcomes of
persons spinal cord injured more than 20 years ago. Paraplegia 1992;30(9):617 630.
186
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TYPE A QUESTIONS (ONE BEST ANSWER)
1. A 50-year-old man is seen in consultation for acute low back and leg
188
pain of 2 days duration. He recalls developing sharp, shooting pain down

the left buttock and along the lateral aspect of the leg after opening a
sliding door. He has had difficulty finding a comfortable position since but
feels somewhat better when he gets up and stretches than when he sits. On
physical examination, strength is normal in the legs. There is diminished
pinprick over the dorsum of the left foot; reflexes are intact. Straight-leg
raise produces pain in the left buttock at 40. Naproxen sodium, taken at
500 mg twice daily, has provided only minor relief. Which of the following
is the next best step in management?
A.
B.
C.
D.
E.
Epidural steroid injection

Initiation of muscle relaxants
Physical therapy
Two weeks of bedrest
Use of narcotic analgesia
2. A 25-year-old woman in East Africa is seen in a local clinic after the

development of weakness in the legs that occurred over a 2-day period
2 weeks before. She does not describe having been ill with a fever and
reports no diarrhea, major weight loss, or problems controlling her urine.
Food stocks in her village have been very limited, with most people
surviving on a locally produced flour product made from a root vegetable.

Recently, due to drought, crop cycles have been shortened. On
examination, she has symmetric weakness of hip flexors, foot dorsiflexors,
and knee flexors. Reflexes are brisk throughout with bilateral extensor
plantar signs. Sensation is normal. The patient states that she has neither
worsened nor improved since the onset of the problem. Which of the
following conditions is most likely responsible for this patients problem?
A.
B.
C.
D.
E.
A mutation in the spastin gene

Antibody to aquaporin-4 water channel
Excessive cyanide exposure
Infection with HIV
Parasitic infection of the spinal cord
3. Which of the following is the most common presenting symptom of

spinal metastasis?
A.
B.
C.
D.
E.
Fecal incontinence
Numbness
Pain
Urinary retention
Weakness
4. Which of the following neurologic manifestations at presentation is most

typical of spinal cord ischemic events?
A.
B.
C.
D.
E.
Bladder distension
Isolated proprioceptive loss
Isolated upper extremity weakness
Preserved lower extremity reflexes
Preserved lower extremity strength
5. A 35-year-old man develops the acute onset of severe neck and left arm
pain associated with numbness 2 hours after a workout session. He has a
2-year history of chronic neck discomfort, previously relieved by ibuprofen.
Pain is described as radiating over the scapula and to the upper arm;
numbness and tingling are intermittent and felt in the same region.
Neurologic examination shows mild weakness in the left deltoid with
pinprick loss in the upper outer forearm. Deep tendon reflexes are
symmetric; plantar responses are flexor. Which of the following is of the
greatest value in localizing a root lesion?
A.
B.
C.
D.
E.
Lhermitte sign
Location of pain
Pinprick loss
Plantar response
Weakness
6. In the posterior columnmedial lemniscal system, first-order neurons,

after bifurcating, ascend in laminated tracts, the medial fasciculus gracilis
189
and more lateral fasciculus cuneatus. In which of the following structures
does the second-order neuron in this pathway originate?
A.
B.
C.
D.
E.
Contralateral medulla
Contralateral parietal lobe
Contralateral thalamus
Ipsilateral medulla
Ipsilateral thalamus
7. On the last day of a weeklong backpacking trip in the Alps, a 36-year-old

woman developed pain and numbness in a patch along the lateral aspect of
her proximal right upper extremity, with weakness of shoulder abduction.
She also reported some neck pain and low back pain. Her symptoms were
starting to improve the next day, so she did not seek medical attention. Her
symptoms had resolved completely by the time she returned home 3 days
later, but her husband insisted that she go to the emergency department,
where her examination is normal. Which of the following tests should be
scheduled?
A.
B.
C.
D.
E.
MRI of brachial plexus

MRI of cervical spine
Nerve conduction studies/EMG
No test necessary
8. A 58-year-old woman from Brooklyn developed a febrile illness and

severe weakness about 3 weeks after returning from a late summer camping
trip in Pennsylvania. She has had no previous medical illnesses, and she has
done no other traveling in the past year. She has never traveled outside the
United States. Examination reveals flaccid weakness and areflexia in all four
limbs, with normal sensation. Which of the following infections is most
likely?
190
A.
B.
C.
D.
E.
Borrelia burgdorferi
Taenia solium
Treponema pallidum
Varicella-zoster virus
West Nile virus
9. A 45-year-old man undergoes a protracted endodontic procedure for

multiple tooth abscesses. He has a history of drug and alcohol abuse.
Within a day after his procedure, he develops difficulty walking. He comes
to the emergency department, where he is noted to be ataxic. A blood
alcohol level is normal. Neurologic examination reveals a positive Romberg
sign and profound loss of position sense in the feet. Which of the following
studies is most likely to lead to a diagnosis in this patient?
A.
B.
C.
D.
E.
Human T-cell lymphotropic virus I antibody assay

MRI of the thoracic spine
Serum vitamin B12 level
Serum ceruloplasmin level
Urine toxicology screen
10. A 65-year-old man is seen in consultation for difficulty speaking and

walking, which has gotten progressively worse over a 6-month period. He
notes problems with enunciating words. He denies diplopia or ptosis. His
wife feels that he has been dragging the right leg for a few years. He has
had no cognitive problems, although he has noted more emotionality lately.
He has a history of a cervical laminectomy done for neck and left arm pain
5 years before, from which he recovered well. He has a family history of
Parkinson disease in a maternal uncle. On examination, he is oriented. No
fasciculations are noted; mild left triceps atrophy is seen. There is mild
bilateral facial weakness, poor tongue movement, and an exaggerated jaw
jerk. Eye movements are normal. There is a spastic paraparesis, with more
pronounced weakness on the right. MRI scan of the cervical spine shows no
evidence of cervical cord compression or myelomalacia. Electrical studies
reveal only a chronic left C7 radiculopathy. He is followed over an 18month period and develops weakness in all four limbs, without associated
atrophy or fasciculation. Which of the following abnormalities is associated
with this disorder?
A.
B.
C.
D.
E.
JC virus infection of brain

Presence of oligoclonal bands in CSF
Optic nerve degeneration
Sphincter involvement
Swallowing difficulty
11. Which of the following is the most common cause of intramedullary

spinal hemorrhage?
A.
B.
C.
D.
E.
Syringomyelia
Trauma
Tumor
Vascular malformation
Venous infarction
12. A 56-year-old woman reports that her gait has been deteriorating over
the past 6 months, and she has developed urinary urgency and
incontinence over the past month. She was born and raised in Mexico and
moved to the United States 25 years ago. Examination reveals spastic
paraparesis, and a spinal MRI scan reveals a large cystic lesion compressing
the cord at the T6 level, with several smaller cysts at the C2, C6, and T10
levels. An MRI scan of the brain reveals scattered small calcified cysts. This
condition was most likely acquired as a result of ingesting which of the
following?
A.
B.
C.
D.
E.
Food contaminated by fecal matter

Gluten
Inadequately cooked pork
Lead
Zinc
191
13. In a patient with spinal metastasis, which of the following treatments is
most likely to alleviate axial spinal pain?
A.
B.
C.
D.
E.
Chemotherapy
Physical therapy
Radiation therapy
Spine stabilization surgery
14. A 75-year-old man comes to the emergency department (ED) 1 day after
the onset of severe pain over the right thigh. He has generally been healthy
and is not diabetic. He has a history of moderate low back pain that he
attributes to arthritis. Initially in the ED, he is in a great deal of pain and is
given narcotic analgesics. The ED physician cannot get him to bear weight
on the right leg. Plain films of the lumbosacral spine demonstrate
degenerative disease without acute fracture. He is admitted to the hospital
where he is seen by a consultant the next day; at this point, his pain is
considerably better. On examination, there is 2/5 weakness of hip flexion
and knee extension on the right; the right knee jerk is absent. MRI scan of
the lumbosacral spine demonstrates a small herniated disc at L3-L4 on the
right; MRI of the pelvis shows only prostatic hypertrophy. Which of the
following choices most likely explains the discrepancy between the clinical
and radiologic findings?
A.
B.
C.
D.
E.
The disc is an incidental finding

An infiltrative process of roots is present
MRI is missing a bone lesion
A nerve infarct may be present
Weakness is due to incomplete effort
15. A 25-year-old woman has been followed since the first year of life for
192
an abnormal gait. She was known to be the product of a normal pregnancy,

although the obstetrician did have to unravel the umbilical cord at her birth.
Her examination reveals increased tone in the legs with upper motor
neuron involvement but without evidence of cognitive or bulbar
abnormalities. Her parents have no such problems. It was assumed after her
birth that she had experienced a birth accident. MRIs of the brain and
spinal cord done at age 20 were normal. She has remained largely stable
since birth. Her 2-year-old son has been seen for delayed walking and
spastic legs. What is the probability of this disorder occurring in a
subsequent child born to this mother?
A.
B.
C.
D.
E.
0% as it is not a hereditary problem

0% if the child is a girl
25%
50%
Not known
16. A 40-year-old woman is referred for consultation for numbness of the

feet and increased difficulty walking over a 6-month period. Past medical
history is significant for morbid obesity (150 kg) treated 18 months ago with
gastric bypass surgery. One year after her surgery, she had lost
approximately 50 kg. Prior to her surgery, she had been treated for type 2
diabetes mellitus and hypertension; both of these conditions normalized
after weight loss. Three months after her surgery, she developed diarrhea
that has persisted. On physical examination, tone is increased in the legs.
Strength is normal in all four limbs except for mild bilateral hamstring
weakness. Position and vibratory sense in the toes is markedly impaired.
Ankle jerks are absent, but arm and knee reflexes are increased with
bilateral extensor plantar signs. Her gait is wide based and stiff. Which of
the following signs is associated with this disorder?
A.
B.
C.
D.
E.
Hand muscle atrophy

Involvement of spinothalamic tracts
Lower extremity fasciculation
Positive Romberg sign
Sparing of two-point discrimination
17. Which of the following procedures increases the risk of spinal cord
ischemia as a consequence of aortic aneurysm repair?
A.
B.
C.
D.
E.
CSF fluid drainage

Distal aortic perfusion
Endovascular techniques
Intraoperative somatosensory evoked potentials
Open surgery
18. Which of the following is more common in neoplastic brachial

plexopathy than in radiation-induced brachial plexopathy?
A.
B.
C.
D.
E.
Horner syndrome
Low signal on T2-weighted MRI
Muscle atrophy
Myokymic discharges on EMG
Sensory nerve conduction abnormalities
19. In a patient with a first episode of myelitis, which of the following signs
would suggest that neuromyelitis optica is more likely than multiple
sclerosis?
A.
B.
C.
D.
E.
Abnormal visual evoked responses

Antecedent infection
Enhancing lesions on brain MRI
Lesions longer than three vertebral segments on spine MRI
Oligoclonal bands in the spinal fluid
20. A 3-year-old child with known malabsorption is seen for impaired gait.
There is no family history of a similar problem. She has been followed by a
pediatric gastroenterologist since the first year of life and was noted to have
fatty stools. On physical examination, she is at the 10th percentile for height
and weight. Neurologic examination demonstrates mild spasticity in the legs
along with areflexia; position sense in the feet is severely impaired, and gait
193
is wide based and lurching. Which of the following abnormalities is likely to
be found upon further investigation of this childs problem?
A.
B.
C.
D.
E.
Accumulation of very long chain fatty acids

Multivitamin overdose
A mutation in the frataxin gene
Ragged red fibers on muscle biopsy
Undetectable serum vitamin E levels
21. A 65-year-old man is seen in urgent consultation because of increasing

midback pain over the past 3 weeks. He describes shooting pain from the
back over the right abdominal wall. In the past week, he has had more
difficulty arising from a chair. On the day before being seen, he had two
episodes of urinary incontinence. Past medical history is significant for
hypertension and a recent rise in serum prostate-specific antigen, for which
he has been scheduled for a prostate biopsy. On physical examination,
upper extremities are normal. Weakness is present in the legs (right greater
than left), hamstrings, hip flexors, and foot dorsiflexors. There is no muscle
atrophy. Reflexes demonstrate patellar clonus on the right, 3 knee jerk on
the left, and bilateral ankle clonus and bilateral extensor plantar responses.
A sensory level to pinprick is elicited at T10; position sense in the great toe
is impaired on the right. An emergent MRI is requested. What is the most
likely finding on MRI?
A.
B.
C.
D.
E.
Cauda equina compression

Compressive extramedullary lesion at L1
Compressive extramedullary lesion at T7
Expansile intramedullary lesion at C7
Expansile intramedullary lesion at T7
22. Which of the following treatments is associated with the best outcome
in most patients with spinal metastasis?
194
A.
B.
C.
D.
E.
Radiation therapy alone

Radiation therapy alone or surgery alone (depending on age)
Radiation therapy alone or surgery alone (equivalent results)
Surgery and radiation therapy
Surgery alone
23. A 45-year-old man with a history of AIDS is brought to the emergency

department because of a 2-day history of increasing difficulty walking. He
has been treated in the past for pneumonia and cerebral toxoplasmosis,
from which he made a good recovery. He reports severe radiating lower
back pain and pain in both legs. On examination, he is afebrile. There is
minimal tenderness to percussion along the spine. In the legs, there is
asymmetric weakness with right hip flexion, knee extension and flexion 3/5,
right dorsiflexion and plantar flexion 1/5; left hip flexion and knee
extension is 4/5 with dorsiflexion and plantar flexion on the left 3/5. No
lower extremity reflexes are elicited. Which of the following findings is most
likely to be associated with this condition?
A.
B.
C.
D.
E.
Babinski signs
Loss of sphincter control
Lumbar canal stenosis
Segmental sensory loss
Upper extremity weakness
the acute onset of neck pain and right shoulder and arm pain. He states that
he has had an ongoing problem with neck pain and stiffness but that these
symptoms worsened markedly after he played tennis on the previous day.
An ED resident finds mild right biceps weakness and a depressed biceps
and brachioradialis jerk on the right. The patient is stabilized and brought
back for an outpatient MRI scan of the cervical spine. He is told that his
scan shows a large herniated disk at one level and some degenerative
changes at several other levels, but he forgets to note at which level he has
the most serious problem. Between which vertebral levels is the most likely
level of greatest involvement in this patient?
A.
B.
C.
D.
E.
C3 and C4
C4 and C5
C5 and C6
C6 and C7
C7 and T1
25. A 60-year-old woman is examined for an exacerbation of low back

pain. She had previously noted pain in the lumbar region and right buttock
for a period of 3 months. In the past 2 weeks, she has noted worsening of
her pain and the appearance of numbness over the anterior thigh after
having been ill with bronchitis. On physical examination, there is mild (4/5)
weakness of knee extension on the right, with a diminished knee jerk on
that side. Pinprick loss is found over the center of the thigh and the knee.
Which of the following maneuvers on physical examination is most likely to
exacerbate this patients symptoms?
A.
B.
C.
D.
E.
Flexed position of the lumbar spine

Inward rotation of the knee with the hip flexed
Outward rotation of the knee with the hip flexed
Reverse straight-leg raise
Straight-leg raise (supine position)
26. Which of the following MRI findings is most specific for dural
arteriovenous fistulae of the spinal cord?
A.
B.
C.
D.
E.
Blood flowrelated signal abnormalities in subarachnoid space

Enhancement of the cord on postcontrast T1 sequences
Hyperintensity in cord parenchyma on T2 sequences
Scalloped cord boundaries on sagittal images
Widened cord
195
27. The feasibility of stereotactic radiosurgery for the treatment of spinal
tumors will most likely depend on development of techniques to control or
correct for which of the following?
A.
B.
C.
D.
E.
Aortic blood flow

Bony artifact
Intestinal gas patterns
Patient movement
Teratogenic effects
28. A 40-year-old woman who has been on weekly methotrexate for a year
for rheumatoid arthritis is seen for numb feet and an unsteady gait that
became noticeable 3 months ago. On examination, she has multiple joint
deformities. There is mild spasticity in the legs along with position sense
loss and a stocking pinprick loss. Folic acid deficiency is suspected, and she
is placed on oral replacement therapy. Which of the following tests is most
useful to monitor response to folate therapy?
A.
B.
C.
D.
E.
L-Methionine level
Complete blood count
Methylmalonic acid level
Plasma homocysteine level
Serum folate level
29. A 20-year-old college student comes to the physician because of
196
clumsiness and tingling in the feet that has been going on for a year. He
has been generally healthy and is treated only for depression. Three years
later, while a graduate student, he is seen because of an inability to
concentrate. This is attributed at first to his depression. Within a year he
begins to notice graying of his vision and more trouble walking. On
examination, he has bilateral optic atrophy and brisk reflexes throughout.
Family history reveals multiple sclerosis in a female first cousin. Over the
next 3 years, he becomes increasingly disabled, both cognitively and
physically. Which of the following abnormalities is likely to be found in this
patient?
A.
B.
C.
D.
E.
Accumulation of long chain fatty acids

Antibodies to aquaporin-4 water channel
Antibodies to HIV
Expanded trinucleotide repeat in frataxin gene
Presence of JC virus in brain
30. Which of the following processes tends to affect the infraclavicular

portion of the brachial plexus more often than it affects the supraclavicular
portion?
A.
B.
C.
D.
E.
Cervical rib
Neoplastic infiltration
Obstetric trauma
Open heart surgery
Radiation injury
31. Which of the following tests is most useful in predicting the likelihood
that a patient with partial myelitis will subsequently experience a second
clinical attack that will establish the diagnosis of multiple sclerosis?
A.
B.
C.
D.
E.
MRI of brain
MRI of cervical spinal cord
Spinal fluid immunoglobulin G index
Spinal fluid oligoclonal bands
Spinal fluid white blood cell count
32. The value of decompressive surgery for lumbosacral radiculopathy has

been studied extensively in controlled multicenter trials. In one recent study
involving patients with lumbar spondylolisthesis, canal stenosis, and
neurogenic claudication, there was randomization to either conservative
treatment or decompressive surgery with fusion. Which of the following was
a significant finding of this study?
A.
B.
C.
D.
E.
Conservatively treated patients had improved ambulation

Neurogenic claudication is always a surgical indication
One-year outcomes for surgical versus nonsurgical patients was the same
Pain of root origin responded well to surgery
Surgical patients had greater improvement in back pain
33. A patient reports pain and numbness in the fourth and fifth fingers and
the medial aspect of the forearm and hand. Examination reveals weakness
of the intrinsic hand muscles. Which of the following electrodiagnostic
findings would make a lower trunk brachial plexopathy more likely than a
C8/T1 radiculopathy due to disk herniation?
A.
B.
C.
D.
E.
Focal slowing of ulnar motor conduction velocity at the elbow

Neurogenic motor units in the abductor digiti minimi muscle
Reduced amplitude of ulnar motor response
Reduced amplitude of ulnar sensory response
Spontaneous activity in the first dorsal interosseous muscle
34. A 35-year-old man is referred to a physician for burning pain and

dysesthesias in both arms and shoulders of 1 years duration. He states that
over the past month he feels as though his hands have become somewhat
weak and clumsy. Past medical history is significant for a motorcycle
accident 3 years ago, during which he sustained a cervical fracture stabilized
by traction. On examination, pinprick and temperature sensation are
reduced over the shoulders and upper arms with preservation of position
sense. Atrophy of intrinsic hand muscles with accompanying weakness is
found bilaterally. Pinprick over the legs and anal region is normal. Reflexes
are reduced in the arms. A lesion of the central aspect of the spinal cord is
suspected. Which of the following best explains the examination findings in
this patient?
A.
B.
C.
D.
E.
Bilateral involvement of dorsal columns

Cervical enlargement of the spinal cord
Partial involvement of lateral corticospinal tracts
Somatotopic organization of lateral spinothalamic tracts
Sparing of anterior horn cells
197
35. Patients who have experienced a prolonged cardiorespiratory arrest are
most likely to sustain ischemic damage to the spinal cord at which of the
following levels?
A.
B.
C.
D.
E.
High cervical
Low cervical
Low thoracic
Lumbosacral
Midthoracic
36. A 50-year-old man comes to his physician for follow-up on a

progressive problem with coordination. At about age 40, he began to notice
stiffness and slowness of movement along with slurred speech. He
continued to work but had several falls on the job and found himself
hugging the walls. Over the next few years, he developed increased tone
in the limbs with spasticity noted on examination, as well as wasting of his
intrinsic hand muscles. By his late 40s, he was noted to have lid retraction,
severe dysarthria, and gait ataxia, along with hand and proximal lower
extremity weakness. At that time, no reflexes could be elicited. Studies
obtained included brain MRI, which revealed moderate cerebellar atrophy,
as well as EMG, which showed an advanced axonal sensorimotor
neuropathy. At age 50, he remained cognitively intact but could no longer
walk. The patients 25-year-old daughter is concerned about the possibility
of inheriting her fathers condition; the patients mother was in a wheelchair
by age 50 and died 5 years later. What is the probability of this occurring?
A.
B.
C.
D.
E.
No chance because it is sporadic in occurrence

No chance because it is X-linked
Low probability because it is a recessive trait
Fifty percent chance because it is autosomal dominant
Greater than 50% chance because of anticipation
37. A 41-year-old previously healthy woman began to notice a tendency to
198
stumble while walking. Over the next 2 months, her gait disturbance gradually
progressed to the point where it was obvious even when walking short
distances, and she developed urinary urgency and occasional incontinence.
Examination reveals spastic paraparesis, with a sensory level at T6. Spine MRI
reveals an intramedullary enhancing lesion extending from T4 to T8, with
several enhancing pial nodules in the cervical and thoracic cord. Brain MRI is
normal except for meningeal enhancement around the brainstem. Spinal fluid is
notable for a protein level of 66 mg/dL and 24 white blood cells/L, all
mononuclear. Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Sarcoidosis
Syphilis
Vacuolar myelopathy
38. A 40-year-old man is referred for neurologic evaluation for difficulty

walking that began about 6 months ago and has progressively worsened.
One year ago, he underwent gastric bypass surgery for morbid obesity; he
has lost a total of 60 kg. He had been treated for type 2 diabetes, but after
weight loss his last hemoglobin A1C was 6.2. However, prior to surgery, he
had a history of paresthesias in the feet and a stocking loss to pinprick. He
has been faithful to his prescribed regimen of B vitamin replacement. For
the first 2 months after surgery, he had intermittent diarrhea, but that
stabilized shortly thereafter. On examination, he has increased tone in the
legs with mild bilateral footdrops. There is patellar clonus, but no ankle
jerks are elicited. Plantar signs are extensor. Profound vibratory loss as well
as impaired position sense is found in the legs. The previously described
stocking loss to pinprick is evident. He has mild low back pain, which has
been chronic. Serum methylmalonic acid level is normal. Which of the
following studies is most likely to lead to a diagnosis in this patient?
A.
B.
C.
D.
E.

Genetic testing for -tocopherol transfer protein gene mutation
MRI of the cervical spine
Serum copper level
39. A patient with a 3-month history of progressive myelopathy was found

to have an enhancing intradural-extramedullary lesion on MRI. There were
no bony abnormalities. Which of the following tumor types is most likely?
A.
B.
C.
D.
E.
Astrocytoma
Ependymoma
Meningioma
Myeloma
Tuberculoma
40. A 54-year-old man with a history of hypertension, diabetes, and prostate

cancer developed severe pain and weakness in his left thigh, which became
progressively more severe over the course of a week, to the point where he
could walk only with a walker. Over the next 2 weeks, his left lower
extremity symptoms stabilize while he develops similar (but milder)
symptoms in his right lower extremity. He also reports that he has no
appetite, and he has lost 9 kg. Motor examination is notable for marked
weakness and atrophy of the left knee extensors, moderate weakness of the
left hip adductors, mild weakness of left ankle dorsiflexion, left ankle
plantar flexion, and left knee flexion, and mild weakness of right knee
extension. He has a reduced right patellar reflex, and absent reflexes at the
left knee and both ankles. Electrodiagnostic testing reveals abnormal motor
and sensory nerve conductions and both acute and chronic denervation in a
patchy distribution in both lower extremities, worse on the left; there are
fibrillation potentials in the lumbar paraspinal muscles. MRI of the
lumbosacral spine is normal, as is an MRI of the left lumbosacral plexus.
Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Diabetic lumbosacral radiculo-plexus neuropathy

Metastatic spine disease
Neoplastic lumbosacral plexopathy
Spinal epidural abscess
199
PATIENT MANAGEMENT PROBLEM

Dean M. Wingerchuk
The following patient management problem was chosen to reinforce the subject matter
presented in this issue. It emphasizes decisions facing the practicing physician. At each
decision point determine how you, as the neurologist, would respond. Then answer the
questions provided. The weight or value indicates the relative strength or weakness of the
response as determined by the faculty. Use these values, as well as the critical comments, to
assess your own understanding and handling of the problem. A review of all responses, not
merely the ones you select is recommended.
Educational Objective
To understand the process of investigation, acute therapy, and long-term management of

acute transverse myelitis.
Case History
A 49-year-old Hispanic woman presents to the emergency department with a 2-day history
200
of radicular right upper extremity pain and numbness, progressive bilateral lower extremity
weakness, imbalance, and urinary urgency. She reports several falls and is transported in a
wheelchair for safety. She also notes stereotypic, painful right arm spasms lasting 30 to 45
seconds and recurring 15 to 20 times daily.
She was recently ill with a nonspecific upper respiratory tract infection. Her medical
history includes Grave disease with posttreatment hypothyroidism, hypertension, and
hyperlipidemia. She takes no prescription medications, does not smoke or use alcohol or
recreational drugs, and has no family history of neurologic disease. She has no history of
trauma, cancer, or HIV risk factors. Review of systems reveals occasional diarrhea but is
otherwise negative.
Her general examination reveals no vital sign or systemic abnormality and no rash. Two
30-second events of painful involuntary movements of the right upper extremity, consisting
of elbow and wrist flexion, forearm and wrist pronation, and digit extension, are witnessed
during the examination. The face and lower extremities are unaffected, and consciousness
is maintained during the spells. Neck flexion elicits Lhermitte sign. Neurologic examination
reveals normal cranial nerve function, moderate pyramidal weakness of the right upper and
both lower extremities, bilateral extensor plantar responses, a T4 sensory level, and
Relationship Disclosure: Dr Wingerchuk has received personal compensation for activities with Genentech, Inc. Dr Wingerchuk
has received research support to Mayo Clinic from the National Multiple Sclerosis Society and Genzyme Corporation.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Wingerchuk discusses the unlabeled use of methylprednisolone,
plasmapheresis, and cyclophosphamide for the treatment of myelitis attacks; carbamazepine for tonic spasms; and prednisone,
azathioprine, mycophenolate mofetil, cyclophosphamide, mitoxantrone, intravenous immune globulin, and rituximab for
prevention of relapse of certain inflammatory myelitides.
moderate impairment of vibratory and proprioceptive sensation involving the right hand
and lower extremities. She is unable to ambulate without assistance.
Decision Point A. What diagnoses need to be considered?
A1. Compressive myelopathy
A2. Multiple sclerosis
A3. Herpes zoster myelitis
A4. Epileptic seizures with postictal weakness
A5. Postinfectious transverse myelitis
A6. Neuromyelitis optica
A7. Spinal cord infarction involving the anterior spinal artery
Decision Point B. What diagnostic tests should be obtained to guide immediate
therapy?
B1. MRI of the spinal cord with and without gadolinium
B2. Lumbar puncture
B3. EEG
MRI of the spinal cord (Figure 1) reveals a longitudinally extensive lesion involving the
spinal cord and lower medulla; additional sequences demonstrate slight gadolinium
enhancement of the lesion. There is no compressive lesion. Spinal fluid examination
shows 120 white blood cells (15% polymorphonuclear cells and 85% lymphocytes;
201
FIGURE 1
Sagittal T2-weighted MRI of the cervical

spinal cord demonstrates a longitudinally
extensive spinal cord lesion with increased
signal extending from the cervical cord into
the lower medulla.
negative cytology), elevated protein of 85 mg/dL, and negative Gram stain and initial
bacterial cultures.
Decision Point C. What therapy should be considered for this spinal cord lesion?
C1. Oral prednisone
C2. IV methylprednisolone
C3. IV acyclovir
Decision Point D. What therapy should be considered for the episodic spasms?
D1. Anticonvulsants such as carbamazepine or gabapentin
D2. Oral baclofen
Over the next 2 days, despite IV methylprednisolone therapy the patients neurologic
deficits worsen such that she becomes triplegic (sparing the left upper extremity) and
mildly dyspneic. CSF PCR tests for varicella zoster and herpes simplex viruses are
negative. Laboratory abnormalities include positive antinuclear antibody and high titers
of transglutaminase and endomysial antibodies. HIV serology is negative.
Decision Point E. What therapy should be considered for the worsening neurologic
deficits?
E1. IV immunoglobulin
E2. Plasmapheresis
E3. IV cyclophosphamide
Plasmapheresis treatment results in marked improvement over the next 4 days. She
receives seven courses over a 14-day period, at which time she is ambulating with a
cane and continuing to note improvement.
202
Decision Point F. What tests or consultations should be performed to establish the

overall diagnosis?
F1. MRI of the brain with and without gadolinium
F2. Determination of oligoclonal bands in the CSF
F3. Paraneoplastic antibody panel
F4. Neuromyelitis opticaimmunoglobulin G (NMO-IgG) serology
F5. Visual evoked potentials
F6. Spinal cord biopsy
F7. Serum vitamin B12 levels
F8. Rheumatology consultation
F9. Gastroenterology consultation
Brain MRI (Figure 2) reveals numerous nonspecific white matter lesions, none of which
enhances with gadolinium. The CSF studies reveal normal IgG index and no oligoclonal
bands. The paraneoplastic antibody panel and visual evoked potentials are normal.
NMO-IgG serology is positive. Rheumatologic consultation is unrevealing. A
gastroenterologist recommends a small bowel biopsy to evaluate for possible celiac
disease. The patient is diagnosed with an NMO spectrum disorder (longitudinally
extensive transverse myelitis with NMO-IgG seropositive status and coexisting systemic
autoimmunity) (Wingerchuk et al, 2007).
FIGURE 2
Axial MRI of the brain (fluid-attenuated

inversion recovery [FLAIR] sequence) reveals
several nonspecific subcortical white matter
lesions scattered throughout the cerebral
hemispheres.
Decision Point G. What preventive therapeutic strategy should be considered?

G1. No therapy; observation for development of new lesions on brain MRI to be
performed in 3 months
G2. Interferon beta injections
G3. Immunosuppression
The patient is treated with prednisone and azathioprine and remains relapse free for 3
years. Small bowel biopsy confirms coexisting celiac disease, and she also maintains a
gluten-free diet. She stops azathioprine therapy after 16 months in order to conceive a
child. Six months after delivering a healthy infant, she experiences right optic neuritis,
confirming a diagnosis of NMO. She has remained relapse free for 13 months since
initiating rituximab therapy.
203
WEIGHTS AND COMMENTS

EXPLANATION OF WEIGHTS
Unequivocally required for diagnosis or effective treatment, without which management

would be negligent
Important for diagnosis and treatment but not immediately necessary
Potentially useful for diagnosis and treatment (routine studies fall into this category)
Neutral impact, neither clearly helpful nor harmful under given circumstances
Not harmful, but nonproductive, time-consuming, and not cost-effective
Nonproductive and potentially harmful
Totally inappropriate and definitely harmful; may threaten life

The differential diagnosis of acute myelopathy is broad, but when urgent spinal cord
imaging excludes a compressive lesion, a systematic evaluation for inflammatory and
infectious causes is necessary. It is important to determine whether there is evidence to
support an inflammatory myelitis to establish whether a specific diagnosis can be
achieved and to formulate acute and long-term treatment plans.
A1. Compressive myelopathy

The presentation of an acute myelopathy is a neurologic emergency that requires
immediate neuroimaging to exclude a compressive etiology.
1
A2. Multiple sclerosis
Although multiple sclerosis may present with almost any CNS symptoms and signs, the
rapid and severe nature of this myelitis attack, relatively late age of onset for a first
attack, and non-white racial background make this diagnosis less likely.
204
1
A3. Herpes zoster myelitis
It is reasonable to consider herpes zoster myelitis in the differential diagnosis because it
is a potentially treatable infection and may present as a radiculomyelitis. In most
instances, the infection occurs in an immunocompromised host and after the zoster skin
eruption is evident or resolving.
3
A4. Epileptic seizures with postictal weakness
This patients bilateral symptoms and signs are all referable to the spinal cord. The
repetitive spells are paroxysmal tonic spasms, a hallmark of CNS demyelinating disease.
Failure to recognize these events as part of the myelitis syndrome may lead to
inappropriate tests or delayed necessary investigations.
5
A5. Postinfectious transverse myelitis
The symptoms and signs are all compatible with acute transverse myelitis. The patient
experienced a recent upper respiratory tract infection, which may have triggered an
autoimmune myelitis.
A6. Neuromyelitis optica

The presentation of a severe inflammatory myelopathy should always suggest the
possibility of NMO, especially in a middle-aged woman of non-white racial origin.
3
A7. Spinal cord infarction involving the anterior spinal artery
Although this patient has vascular risk factors, the symptoms and signs are not
compatible with anterior spinal artery syndrome. Pursuit of vascular investigations could
lead to delays in obtaining appropriate diagnostic studies and initiating treatment for
more likely disorders.
5
B1. MRI of the spinal cord with and without gadolinium
MRI is the study of choice for immediate exclusion of compressive myelopathy and to
obtain information helpful in narrowing the differential diagnosis of noncompressive
causes.
3
B2. Lumbar puncture
Lumbar puncture, if deemed safe after exclusion of a compressive etiology, is very
helpful for investigation and confirmation of inflammatory and infectious myelopathies.
The presence of polymorphonuclear cells in the CSF suggests the possibility of a severe
inflammatory myelitis or, less likely, an infection.
3
B3. EEG
An EEG is not necessary in this case. The patients spells are typical paroxysmal tonic
spasms, and this test may result in delays for more valuable investigations.
C1. Oral prednisone

It is unlikely that usual doses of oral prednisone will produce an important antiinflammatory effect in the setting of this severe demyelinating syndrome.
C2. IV methylprednisolone
Parenteral corticosteroids are the standard therapy for inflammatory myelitis and may
reduce the likelihood of progression and speed recovery.
0
C3. IV acyclovir
IV acyclovir is unlikely to be harmful, but a primary viral infection is less likely than
noninfectious inflammatory myelitis in this setting, and this therapy should not take the
place of corticosteroids.
3
D1. Anticonvulsants such as carbamazepine or gabapentin
Oral anticonvulsants, such as carbamazepine 100 mg to 200 mg 2 to 3 times a day or
gabapentin 100 mg to 300 mg 3 times a day, are usually very effective for eliminating
paroxysmal tonic spasms. In this setting, one might consider administering IV phenytoin
because of the potential risk for ascending myelitis causing neurogenic respiratory
failure and a desire to keep the patient free from taking medication by mouth in case
artificial ventilation is required. Bolus IV fosphenytoin, as used for status epilepticus, is
not required and carries additional cardiovascular risks, especially hypotension.
0
D2. Oral baclofen
Oral baclofen is of unclear benefit for tonic spasms. It could be tried if other treatments
fail but more often is used when the spasms are mistaken for spasticity.
E1. IV immunoglobulin
There is no evidence to support the use of IV immunoglobulin for severe attacks of
demyelinating disease.
205
3
E2. Plasmapheresis
Controlled evidence supports the use of plasmapheresis for severe, acute,
corticosteroid-refractory attacks of CNS demyelinating disease, including multiple
sclerosis, transverse myelitis, and NMO (Weinshenker et al, 1999). It should be instituted
as soon as it is evident that the attack is not responding to corticosteroids.
1
E3. IV cyclophosphamide
Retrospective, uncontrolled data suggest that combination therapy with IV
methylprednisolone, plasmapheresis, and IV cyclophosphamide may result in better
outcome from very severe myelitis attacks, but more studies are needed (Greenberg et
al, 2007).
F1. MRI of the brain with and without gadolinium

Brain MRI is very helpful in detecting lesions suggestive of MS or signature lesions of
NMO (see Figure 27). The presence of white matter lesions on brain MRI does not
exclude a diagnosis of NMO or an NMO spectrum disorder.
1
F2. Determination of oligoclonal bands in the CSF
Although oligoclonal banding is common in multiple sclerosis, it may also occur in NMO or
transiently in monophasic transverse myelitis; its diagnostic value is therefore limited.
F3. Paraneoplastic antibody panel

Paraneoplastic myelopathy is rare but has been reported in conjunction with CRMP-5
and amphiphysin antibodies.
5
F4. Neuromyelitis opticaimmunoglobulin G (NMO-IgG) serology
Serum NMO-IgG is very useful because it is highly specific for NMO spectrum disorders
and its detection also alters the treatment plan.
F5. Visual evoked potentials

Visual evoked potentials might detect subclinical anterior optic pathway lesions that
support a diagnosis of NMO.
206
3
F6. Spinal cord biopsy
This patient does not require a spinal cord biopsy because the clinical and laboratory
features of the event, together with the favorable response to plasmapheresis, suggest
that inflammatory demyelinating myelitis is the most likely etiology and the procedure
would probably result in permanent additional neurologic deficits. Patients with
progressive myelitis that does not respond to empiric therapy or is associated with
unusual imaging features, such as prolonged gadolinium enhancement, may require
biopsy to rule out disorders such as CNS lymphoma.
1
F7. Serum vitamin B12 levels
Serum vitamin B12 levels are inexpensive and might be valuable in detecting coexisting
disorders, including autoimmune pernicious anemia.
F8. Rheumatology consultation

Rheumatologic consultation may be helpful in cases where there are several positive
serum autoantibody studies or symptoms or signs suggestive of rheumatologic
disorders. In most cases, including the current scenario, the systemic autoimmune
disorders or abnormal autoantibodies coexist with the transverse myelitis syndrome
rather than cause it, but a treatable disorder may be detected.
3
F9. Gastroenterology consultation
Gastroenterologic consultation was helpful in this individual case because of the high
titers of transglutaminase and endomysial antibodies together with a history of diarrhea.
Celiac disease coexists with, but did not cause, the myelitis syndrome. This is an
example of the need to screen for coexisting treatable disorders in patients with NMO
spectrum disorders.
G1. No therapy; observation for development of new lesions on brain MRI to be

3
performed in 3 months
Patients with a first-ever episode of longitudinally extensive transverse myelitis who are
found to be NMO-IgG seropositive are at high risk of myelitis relapse or development
of NMO (56% risk at 12-months follow-up) (Weinshenker et al, 2006). Preventive
immunotherapy is therefore recommended. Furthermore, there is no role for brain MRI
surveillance in NMO spectrum disorders.
3
G2. Interferon beta injections
Evidence from case series suggests that interferon beta therapy, which is approved for
multiple sclerosis, is not effective or deleterious for NMO (Papeix et al, 2007; Warabi et
al, 2007).
3
G3. Immunosuppression
Numerous case series show that drugs that suppress humoral immune function reduce
the rate of future clinical relapses in NMO and relapsing transverse myelitis compared
with pretreatment rates. Such therapies include azathioprine, mycophenolate mofetil,
mitoxantrone, and rituximab (Cree et al, 2005; Mandler et al, 1998; Weinstock-Guttman
et al, 2006). It is not clear whether one agent is superior to the others. Randomized
controlled trials are needed.
207
REFERENCES
Cree BA, Lamb S, Morgan K, et al. An open label study of the effects of rituximab in neuromyelitis optica.
Neurology 2005;64(7):1270 1272.
Greenberg BM, Thomas KP, Krishnan C, et al. Idiopathic transverse myelitis: corticosteroids, plasma
exchange, or cyclophosphamide. Neurology 2007;68(19):1614 1617.
Mandler RN, Ahmed W, Dencoff JE. Devics neuromyelitis optica: a prospective study of seven patients
treated with prednisone and azathioprine. Neurology 1998,51(4):1219 1220.
Papeix C, Vidal JS, de Seze J, et al. Immunosuppressive therapy is more effective than interferon in
neuromyelitis optica. Mult Scler 2007;13(2):256 259.
Warabi Y, Matsumoto Y, Hayashi H. Interferon beta-1b exacerbates multiple sclerosis with severe optic
nerve and spinal cord demyelination. J Neurol Sci 2007;252(1):57 61.
Weinshenker BG, OBrien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central
nervous system inflammatory demyelinating diseases. Ann Neurol 1999;46(6):878 886.
Weinshenker BG, Wingerchuk DM, Vukusic S, et al. Neuromyelitis optica IgG predicts relapse after
longitudinally extensive transverse myelitis. Ann Neurol 2006;59(3):566 569.
Weinstock-Guttman B, Ramanathan M, Lincoff N, et al. Study of mitoxantrone for the treatment of recurrent
neuromyelitis optica (Devic disease). Arch Neurol 2006;63(7):957963.
Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol
2007;6(9):805 815.
208
PREFERRED RESPONSES
Following are the preferred responses and critiques for the multiple-choice items in
issue. The questions and answer selections are repeated, and the
this
preferred response appears in bold print. In most cases, this is followed by an
explanation and, in some instances, a reference with which you may seek more
specific information. No score will be assigned to the answer form you mail in,
since the emphasis of this program is on self-assessment. You are encouraged to
review the responses and explanations carefully to evaluate your general
understanding of the course material.
TYPE A QUESTIONS (ONE BEST ANSWER)
1. A 50-year-old man is seen in consultation for acute low back and leg
pain of 2 days duration. He recalls developing sharp, shooting pain down
the left buttock and along the lateral aspect of the leg after opening a
sliding door. He has had difficulty finding a comfortable position since but
feels somewhat better when he gets up and stretches than when he sits. On
physical examination, strength is normal in the legs. There is diminished
pinprick over the dorsum of the left foot; reflexes are intact. Straight-leg
raise produces pain in the left buttock at 40. Naproxen sodium, taken at
500 mg twice daily, has provided only minor relief. Which of the following
is the next best step in management?
A.
B.
C.
D.
E.
Epidural steroid injection

Initiation of muscle relaxants
Physical therapy
Two weeks of bedrest
Use of narcotic analgesia
The correct answer is E. This patient typifies the scenario described as

acute sensory/painful radicular pattern by the author of the chapter
Diseases of the Nerve Rootsa presentation of acute pain and radicular
sensory symptoms without a motor deficit. The author suggests that an
initial course of nonsteroidal anti-inflammatory drugs (NSAIDs) may be
useful but cites a study showing that use of muscle relaxants confers no
benefit over NSAID use. Physical therapy done acutely is felt to potentially
exacerbate a radicular syndrome while, conversely, prolonged bedrest is
also not indicated. Randomized trials of epidural corticosteroid injection
have not established a lasting benefit that exceeds noninterventional
treatment. Narcotic analgesia may be useful in the intensely painful period
of acute radicular pain.
2. A 25-year-old woman in East Africa is seen in a local clinic after the

development of weakness in the legs that occurred over a 2-day period
209
PREFERRED RESPONSES
2 weeks before. She does not describe having been ill with a fever and
reports no diarrhea, major weight loss, or problems controlling her urine.
Food stocks in her village have been very limited, with most people
surviving on a locally produced flour product made from a root vegetable.
Recently, due to drought, crop cycles have been shortened. On
examination, she has symmetric weakness of hip flexors, foot dorsiflexors,
and knee flexors. Reflexes are brisk throughout with bilateral extensor
plantar signs. Sensation is normal. The patient states that she has neither
worsened nor improved since the onset of the problem. Which of the
following conditions is most likely responsible for this patients problem?
A.
B.
C.
D.
E.
A mutation in the spastin gene

Antibody to aquaporin-4 water channel
Excessive cyanide exposure
Infection with HIV
Parasitic infection of the spinal cord
The correct answer is C. The patient above appears to have an acquired,

not a hereditary, myelopathy, as evidenced by rapid onset and progression.
Infection as a cause of the myelopathy is not explicitly excluded; however,
very rapid onset, stabilization without any treatment, absence of sensory
involvement, and no history of systemic illness make this very unlikely.
Antibody to aquaporin-4 water channel, found in neuromyelitis optica,
would typically involve sensory as well as motor dysfunction, involves optic
nerves, and is unlikely to occur so rapidly. Excessive cyanide exposure is
found in konzo, which, according to the author of the chapter Metabolic
and Toxic Myelopathies, is an acquired rapid-onset myelopathy widely
attributed to toxic accumulation of cyanide from poorly processed cassava
root.
3. Which of the following is the most common presenting symptom of

spinal metastasis?
210
A.
B.
C.
D.
E.
Fecal incontinence
Numbness
Pain
Urinary retention
Weakness
The correct answer is C. At the time of presentation, 90% of patients with

spinal metastasis report pain, 50% to 77% have neurologic deficits, and 38%
have bowel or bladder problems.
4. Which of the following neurologic manifestations at presentation is most

typical of spinal cord ischemic events?
A.
B.
C.
D.
E.
Bladder distension
Isolated proprioceptive loss
Isolated upper extremity weakness
Preserved lower extremity reflexes
Preserved lower extremity strength
The correct answer is A. Weakness, sensory loss, acute back pain, and
urinary retention are the most common presenting symptoms of spinal cord
ischemia. Acute bladder distension is common. Preserved lower extremity

strength and reflexes are rare, and so is isolated proprioceptive loss. The
lower thoracic and lumbar spinal levels are most commonly affected, so
upper extremity weakness is uncommon.
5. A 35-year-old man develops the acute onset of severe neck and left arm
pain associated with numbness 2 hours after a workout session. He has a
2-year history of chronic neck discomfort, previously relieved by ibuprofen.
Pain is described as radiating over the scapula and to the upper arm;
numbness and tingling are intermittent and felt in the same region.
Neurologic examination shows mild weakness in the left deltoid with
pinprick loss in the upper outer forearm. Deep tendon reflexes are
symmetric; plantar responses are flexor. Which of the following is of the
greatest value in localizing a root lesion?
A.
B.
C.
D.
E.
Lhermitte sign
Location of pain
Pinprick loss
Plantar response
Weakness
The correct answer is E. The author of the chapter Diseases of the Nerve
Roots discusses several sensory maneuvers and findings that may be
present with a cervical radiculopathy, including the presence of pain and
paresthesias, the latter of which strongly suggest radicular disease. Lhermitte
sign may be elicited with neck flexion with the production of paresthesias
sometimes into the symptomatic arm; however, this is nonlocalizing as to
the specific root involved. Paresthesias and numbness, as well as pain,
according to the author, may be present (especially pain in acute cases) but
are poorly localizing. Plantar responses may be extensor in cases of cord
compression but are otherwise nonlocalizing. The author states that
weakness found in a particular myotomal distribution has the greatest
localizing value in root disease.
6. In the posterior columnmedial lemniscal system, first-order neurons,

after bifurcating, ascend in laminated tracts, the medial fasciculus gracilis
and more lateral fasciculus cuneatus. In which of the following structures
does the second-order neuron in this pathway originate?
A.
B.
C.
D.
E.
Contralateral medulla
Contralateral parietal lobe
Contralateral thalamus
Ipsilateral medulla
Ipsilateral thalamus
The correct answer is D. The primary projections of those posterior column

neurons that run in fasciculus gracilis (medial) and cuneatus (lateral) are to
their respective nuclei in the ipsilateral medulla. The second-order neuron
originating in the medulla then decussates to the contralateral thalamus,
where a third-order neuron originates and then terminates in the
somatosensory cortex.
211
PREFERRED RESPONSES
7. On the last day of a weeklong backpacking trip in the Alps, a 36-year-old
woman developed pain and numbness in a patch along the lateral aspect of
her proximal right upper extremity, with weakness of shoulder abduction.
She also reported some neck pain and low back pain. Her symptoms were
starting to improve the next day, so she did not seek medical attention. Her
symptoms had resolved completely by the time she returned home 3 days
later, but her husband insisted that she go to the emergency department,
where her examination is normal. Which of the following tests should be
scheduled?
A.
B.
C.
D.
E.
MRI of brachial plexus

MRI of cervical spine
Nerve conduction studies/EMG
No test necessary
The correct answer is D. This clinical scenario is typical of rucksack palsy,

which is the result of traction on the upper portion of the plexus after
wearing a backpack or other device over the shoulder. Symptoms are
typically transient. This patients neck pain and low back pain were
probably musculoskeletal and unrelated to her arm symptoms. Given that
her symptoms have resolved and her examination is normal, there is no
need for any further testing.
8. A 58-year-old woman from Brooklyn developed a febrile illness and

severe weakness about 3 weeks after returning from a late summer camping
trip in Pennsylvania. She has had no previous medical illnesses, and she has
done no other traveling in the past year. She has never traveled outside the
United States. Examination reveals flaccid weakness and areflexia in all four
limbs, with normal sensation. Which of the following infections is most
likely?
212
A.
B.
C.
D.
E.
Borrelia burgdorferi
Taenia solium
Treponema pallidum
West Nile virus
The correct answer is E. West Nile virus can cause a poliolike syndrome of
flaccid paralysis with sensory sparing. It is most common in summer or
early autumn, and outdoor activity is a risk factor because the virus is borne
by mosquitoes. Varicella-zoster virus is less likely in the absence of a rash
or immunosuppression. Camping is also a risk factor for B. burgdorferi
infection (Lyme disease), and patients with this infection may not be aware
of any rash, but neuroborreliosis usually does not cause a syndrome of
diffuse flaccid paralysis. Without risk factors, neurocysticercosis (T. solium)
and neurosyphilis (T. pallidum) are unlikely.
9. A 45-year-old man undergoes a protracted endodontic procedure for

multiple tooth abscesses. He has a history of drug and alcohol abuse.
Within a day after his procedure, he develops difficulty walking. He comes
to the emergency department, where he is noted to be ataxic. A blood
alcohol level is normal. Neurologic examination reveals a positive Romberg
sign and profound loss of position sense in the feet. Which of the following
studies is most likely to lead to a diagnosis in this patient?
A.
B.
C.
D.
E.
Human T-cell lymphotropic virus I antibody assay

MRI of the thoracic spine
Serum ceruloplasmin level
Urine toxicology screen
The correct answer is C. The above scenario highlights the key point made
by the author of the chapter Toxic and Metabolic Myelopathies that an
individual with unsuspected preexisting cobalamin deficiency who is then
exposed to nitrous oxide gas may present with an acute or subacute
neurologic syndrome with various phenotypes, including a
myeloneuropathy. A urine toxicology screen would only reveal exposure to
various drugs of abuse and probably would not be specific enough to be of
use. Serum ceruloplasmin level points to copper deficiency, which is
unlikely in situations not related to gastric surgery or zinc overdose. Human
T-cell lymphotropic virus I can produce a syndrome of spastic paraparesis
and sensory ataxia but would not present acutely. MRI of the thoracic spine
may indeed demonstrate an abnormality, such as high T2 signal in the
dorsal columns; however, it would not, in that case, be etiology specific.
Serum vitamin B12 level is correcta patient with probable compromised
vitamin B12 status to begin with then decompensates clinically after
exposure to nitrous oxide.
10. A 65-year-old man is seen in consultation for difficulty speaking and

walking, which has gotten progressively worse over a 6-month period. He
notes problems with enunciating words. He denies diplopia or ptosis. His
wife feels that he has been dragging the right leg for a few years. He has
had no cognitive problems, although he has noted more emotionality lately.
He has a history of a cervical laminectomy done for neck and left arm pain
5 years before, from which he recovered well. He has a family history of
Parkinson disease in a maternal uncle. On examination, he is oriented. No
fasciculations are noted; mild left triceps atrophy is seen. There is mild
bilateral facial weakness, poor tongue movement, and an exaggerated jaw
jerk. Eye movements are normal. There is a spastic paraparesis, with more
pronounced weakness on the right. MRI scan of the cervical spine shows no
evidence of cervical cord compression or myelomalacia. Electrical studies
reveal only a chronic left C7 radiculopathy. He is followed over an 18month period and develops weakness in all four limbs, without associated
atrophy or fasciculation. Which of the following abnormalities is associated
with this disorder?
A.
B.
C.
D.
E.
JC virus infection of brain

Presence of oligoclonal bands in CSF
Optic nerve degeneration
Sphincter involvement
Swallowing difficulty
The correct answer is E. This is an older patient who presents with

progressive deterioration in functions subserved by corticospinal and
corticobulbar tracts. Conspicuously absent is lower motor neuron
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PREFERRED RESPONSES
involvement (with the exception of mild left radicular findings) or any
sensory or cerebellar abnormality. Family history appears to be unrelated to
this patients disorder. The clinical presentation is one of primary lateral
sclerosis, sporadic in onset. Sphincter involvement, although not specifically
discussed, is not a typical feature of motor neuron disorders, nor is the
presence of oligoclonal bands in CSF. JC virus infection of brain is present
in cases of progressive multifocal leukoencephalopathy, but clinically this
would present with rapid, diffuse CNS involvement with prominent
cognitive deficits. Optic nerve degeneration, while seen in concert with
some disorders that may present with spastic paraparesis (eg,
leukodystrophies), is not seen in primary lateral sclerosis. The correct
answer is swallowing difficulty, which is a manifestation of corticobulbar
tract degeneration.
11. Which of the following is the most common cause of intramedullary

spinal hemorrhage?
A.
B.
C.
D.
E.
Syringomyelia
Trauma
Tumor
Vascular malformation
Venous infarction
The correct answer is B. Trauma is the most common cause of

intramedullary spinal hemorrhage. Spontaneous hematomyelia may occur
with bleeding into a syrinx or spinal tumor, rupture of a vascular
malformation, or venous infarction, but it is very uncommon.
12. A 56-year-old woman reports that her gait has been deteriorating over
214
the past 6 months, and she has developed urinary urgency and
incontinence over the past month. She was born and raised in Mexico and
moved to the United States 25 years ago. Examination reveals spastic
paraparesis, and a spinal MRI scan reveals a large cystic lesion compressing
the cord at the T6 level, with several smaller cysts at the C2, C6, and T10
levels. An MRI scan of the brain reveals scattered small calcified cysts. This
condition was most likely acquired as a result of ingesting which of the
following?
A.
B.
C.
D.
E.
Food contaminated by fecal matter

Gluten
Inadequately cooked pork
Lead
Zinc
The correct answer is A. The presence of multifocal cysts in the brain and
spinal cord, some of which are calcified, is very suggestive of
neurocysticercosis, especially in a patient from Mexico, where this condition
is endemic. Cysticercosis occurs when humans replace pigs in the life cycle
of the pork tapeworm, Taenia solium, and ingest the larvae excreted in the
feces of humans who harbor the adult worm. A slowly progressive
myelopathy can result from direct subarachnoid invasion of the organisms
or development of intramedullary cysts.
13. In a patient with spinal metastasis, which of the following treatments is

most likely to alleviate axial spinal pain?
A.
B.
C.
D.
E.
Chemotherapy
Physical therapy
Radiation therapy
Spine stabilization surgery
The correct answer is E. Spine stabilization surgery is thought to be very

effective for axial spinal pain from spinal metastases whereas chemotherapy
and radiation will not eliminate the pain. Physical therapy and nonsteroidal
anti-inflammatory drugs may be helpful as adjunct treatments, but they are
unlikely to be sufficient in and of themselves.
the onset of severe pain over the right thigh. He has generally been healthy
and is not diabetic. He has a history of moderate low back pain that he
attributes to arthritis. Initially in the ED, he is in a great deal of pain and is
given narcotic analgesics. The ED physician cannot get him to bear weight
on the right leg. Plain films of the lumbosacral spine demonstrate
degenerative disease without acute fracture. He is admitted to the hospital
where he is seen by a consultant the next day; at this point, his pain is
considerably better. On examination, there is 2/5 weakness of hip flexion
and knee extension on the right; the right knee jerk is absent. MRI scan of
the lumbosacral spine demonstrates a small herniated disc at L3-L4 on the
right; MRI of the pelvis shows only prostatic hypertrophy. Which of the
following choices most likely explains the discrepancy between the clinical
and radiologic findings?
A.
B.
C.
D.
E.
The disc is an incidental finding

An infiltrative process of roots is present
MRI is missing a bone lesion
A nerve infarct may be present
Weakness is due to incomplete effort
The correct answer is D. In this case, a small herniated disc at the level
appropriate to the clinical syndrome (L3-L4) is demonstrated, although the
pathology appears disproportionately small for the clinical deficit. Weakness
due to incomplete effort, although true in principle in some instances, is
unlikely to account for the discrepancy here, as the patient has weakness
where it should be and not diffusely, and he is examined when already
more comfortable. There is no suggestion on examination of involvement of
multiple roots, and the clinical syndrome is fairly abrupt for an infiltrative
process. A bone lesion missing on MRI is unlikely, given no such concern
on plain films. A nerve infarct explains how a relatively small (although
appropriately placed) lesion can affect arterial blood supply to a nerve root,
causing severe, and largely irreversible, nerve damage.
15. A 25-year-old woman has been followed since the first year of life for
an abnormal gait. She was known to be the product of a normal pregnancy,
although the obstetrician did have to unravel the umbilical cord at her birth.
Her examination reveals increased tone in the legs with upper motor
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PREFERRED RESPONSES
neuron involvement but without evidence of cognitive or bulbar
abnormalities. Her parents have no such problems. It was assumed after her
birth that she had experienced a birth accident. MRIs of the brain and
spinal cord done at age 20 were normal. She has remained largely stable
since birth. Her 2-year-old son has been seen for delayed walking and
spastic legs. What is the probability of this disorder occurring in a
subsequent child born to this mother?
A.
B.
C.
D.
E.
0% as it is not a hereditary problem

0% if the child is a girl
25%
50%
Not known
The correct answer is D. The patient above presented with infantile onset of
spastic diplegia that was initially attributed to mild cerebral palsy, although
no definite anoxic insult was demonstrated. The patient then gave birth to a
male child with the same phenotypic presentation. This is consistent with
hereditary spastic paraplegia with infantile onset, presenting much like
cerebral palsy but involving an autosomal dominant mutation, most
commonly in the SPG3A/atlastin gene. It is, in fact, a hereditary and not an
acquired disorder, is not X-linked or recessive, and the genetics have been
worked out.
16. A 40-year-old woman is referred for consultation for numbness of the
216
feet and increased difficulty walking over a 6-month period. Past medical
history is significant for morbid obesity (150 kg) treated 18 months ago with
gastric bypass surgery. One year after her surgery, she had lost
approximately 50 kg. Prior to her surgery, she had been treated for type 2
diabetes mellitus and hypertension; both of these conditions normalized
after weight loss. Three months after her surgery, she developed diarrhea
that has persisted. On physical examination, tone is increased in the legs.
Strength is normal in all four limbs except for mild bilateral hamstring
weakness. Position and vibratory sense in the toes is markedly impaired.
Ankle jerks are absent, but arm and knee reflexes are increased with
bilateral extensor plantar signs. Her gait is wide based and stiff. Which of
the following signs is associated with this disorder?
A.
B.
C.
D.
E.
Hand muscle atrophy

Involvement of spinothalamic tracts
Lower extremity fasciculation
Positive Romberg sign
Sparing of two-point discrimination
The correct answer is D. The syndrome of posterolateral spinal cord

degeneration here, on a presumed nutritional basistypically presents
with early paresthesias in the feet followed by dorsal column involvement
and lateral corticospinal tract degeneration. Spinothalamic tracts are spared,
as are anterior horn cells. Two-point discrimination is subserved by the
posterior columns and is therefore affected; a positive Romberg sign,
signifying loss of position sense, is consistent with the syndrome.
17. Which of the following procedures increases the risk of spinal cord
ischemia as a consequence of aortic aneurysm repair?
A.
B.
C.
D.
E.
CSF fluid drainage

Distal aortic perfusion
Endovascular techniques
Intraoperative somatosensory evoked potentials
Open surgery
The correct answer is E. Intraoperative monitoring of somatosensory evoked

responses, distal aortic perfusion, and CSF drainage may all lower the
likelihood of spinal cord ischemia during aortic aneurysm repair, although
there have been no randomized controlled trials of any of these
approaches. Because of prolonged clamping of the aorta above the renal
arteries, open surgical repairs are associated with a 5% to 10% risk of
significant neurologic deficit. Endovascular techniques appear safer than
open surgery, but they do not eliminate the risk of spinal cord ischemia.
18. Which of the following is more common in neoplastic brachial

plexopathy than in radiation-induced brachial plexopathy?
A.
B.
C.
D.
E.
Horner syndrome
Low signal on T2-weighted MRI
Muscle atrophy
Myokymic discharges on EMG
Sensory nerve conduction abnormalities
The correct answer is A. Horner syndrome is more common in neoplastic

brachial plexopathy than in radiation-induced brachial plexopathy.
Myokymic discharges on EMG and low signal on T2-weighted MRI are
characteristic of radiation-induced plexopathy. Pain, numbness, weakness,
atrophy, and sensory and motor nerve conduction abnormalities are
common in both conditions.
19. In a patient with a first episode of myelitis, which of the following signs
would suggest that neuromyelitis optica is more likely than multiple
sclerosis?
A.
B.
C.
D.
E.
Abnormal visual evoked responses

Antecedent infection
Enhancing lesions on brain MRI
Lesions longer than three vertebral segments on spine MRI
Oligoclonal bands in the spinal fluid
The correct answer is D. Brain MRI is typically normal at onset in patients

with neuromyelitis optica (NMO). Oligoclonal bands are present in the
spinal fluid of 85% of patients with multiple sclerosis (MS) but only 20% to
30% of patients with NMO. An infection may precede an attack related to
either MS or NMO. Because both MS and NMO commonly affect the optic
nerves, abnormal visual evoked responses would not differentiate between
them. Longitudinally extensive lesions (three vertebral segments or longer)
on spinal cord MRI are more common in NMO than in MS.
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PREFERRED RESPONSES
20. A 3-year-old child with known malabsorption is seen for impaired gait.
There is no family history of a similar problem. She has been followed by a
pediatric gastroenterologist since the first year of life and was noted to have
fatty stools. On physical examination, she is at the 10th percentile for height
and weight. Neurologic examination demonstrates mild spasticity in the legs
along with areflexia; position sense in the feet is severely impaired, and gait
is wide based and lurching. Which of the following abnormalities is likely to
be found upon further investigation of this childs problem?
A.
B.
C.
D.
E.
Accumulation of very long chain fatty acids

Multivitamin overdose
A mutation in the frataxin gene
Ragged red fibers on muscle biopsy
Undetectable serum vitamin E levels
The correct answer is E. This child presents with a gastrointestinal disorder

early in life suggestive of fat malabsorption resulting in retarded growth. A
mutation in the frataxin gene, found in Friedreich ataxia, would not be
associated with a malabsorption syndrome or growth retardation, although it
is similar in phenotype. Multivitamin overdose, while nonspecific, is less
likely to produce the above scenario than, for example, a vitamin
deficiency. Accumulation of very long chain fatty acids is found in
adrenoleukodystrophy/adrenomyeloneuropathy, which is X-linked. Ragged
red fibers on muscle biopsy are found in mitochondrial disease, which may
have diffuse nervous system involvement, including encephalopathy,
myopathy, and eye movement disorders without an associated
malabsorption syndrome. The patient described clinically has
abetalipoproteinemia (or a similar syndrome), which would produce
undetectable serum vitamin E levels on testing.
21. A 65-year-old man is seen in urgent consultation because of increasing
218
midback pain over the past 3 weeks. He describes shooting pain from the
back over the right abdominal wall. In the past week, he has had more
difficulty arising from a chair. On the day before being seen, he had two
episodes of urinary incontinence. Past medical history is significant for
hypertension and a recent rise in serum prostate-specific antigen, for which
he has been scheduled for a prostate biopsy. On physical examination,
upper extremities are normal. Weakness is present in the legs (right greater
than left), hamstrings, hip flexors, and foot dorsiflexors. There is no muscle
atrophy. Reflexes demonstrate patellar clonus on the right, 3 knee jerk on
the left, and bilateral ankle clonus and bilateral extensor plantar responses.
A sensory level to pinprick is elicited at T10; position sense in the great toe
is impaired on the right. An emergent MRI is requested. What is the most
likely finding on MRI?
A.
B.
C.
D.
E.
Cauda equina compression

Compressive extramedullary lesion at L1
Compressive extramedullary lesion at T7
Expansile intramedullary lesion at C7
Expansile intramedullary lesion at T7
The correct answer is C. This patient presents with thoracic radicular pain,
evidence of asymmetric corticospinal tract involvement in the legs,
spinothalamic tract involvement, and dorsal column impairment ipsilateral

to the long tract signs. The history and progression of this patients
syndrome plus the early presence of pain and long tract signs suggest an
extramedullary process. Cauda equina compression would likely present
clinically in a more subacute manner and with probable depressed lower
extremity reflexes. Both compressive extramedullary lesion at L1 and T7 are
correct in their identification of the pathophysiology, but a compressive
extramedullary lesion at T7 localizes to the sensory deficit found, making it
the correct answer.
22. Which of the following treatments is associated with the best outcome
in most patients with spinal metastasis?
A.
B.
C.
D.
E.
Radiation therapy alone

Radiation therapy alone or surgery alone (depending on age)
Radiation therapy alone or surgery alone (equivalent results)
Surgery and radiation therapy
Surgery alone
The correct answer is D. In a recent randomized controlled (but not

blinded) trial, patients who were treated with surgery plus radiation therapy
had better outcomes than those treated with radiation therapy alone.
Radiation therapy is usually recommended postoperatively in patients with
radiosensitive tumors, although controlled trials comparing surgery alone
(without radiation therapy) to other treatment approaches have not been
conducted.
23. A 45-year-old man with a history of AIDS is brought to the emergency

department because of a 2-day history of increasing difficulty walking. He
has been treated in the past for pneumonia and cerebral toxoplasmosis,
from which he made a good recovery. He reports severe radiating lower
back pain and pain in both legs. On examination, he is afebrile. There is
minimal tenderness to percussion along the spine. In the legs, there is
asymmetric weakness with right hip flexion, knee extension and flexion 3/5,
right dorsiflexion and plantar flexion 1/5; left hip flexion and knee
extension is 4/5 with dorsiflexion and plantar flexion on the left 3/5. No
lower extremity reflexes are elicited. Which of the following findings is most
likely to be associated with this condition?
A.
B.
C.
D.
E.
Babinski signs
Loss of sphincter control
Lumbar canal stenosis
Segmental sensory loss
Upper extremity weakness
The correct answer is B. A polyradiculopathy in patients with AIDS felt to

be secondary to Cytomegalovirus infiltration of nerve roots is well described
in the literature. The author of the chapter Diseases of the Nerve Roots
notes the painful and rapidly progressive nature of this condition with
resultant paraparesis. Babinski signs would not be expected from this
disorder of multiple roots, and the primary sensory complaint typically is
pain. The syndrome is generally confined to the legs and is based on an
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PREFERRED RESPONSES
infiltrative process in roots, not arthritic spondylosis. It involves rectal and
urinary sphincters.
the acute onset of neck pain and right shoulder and arm pain. He states that
he has had an ongoing problem with neck pain and stiffness but that these
symptoms worsened markedly after he played tennis on the previous day.
An ED resident finds mild right biceps weakness and a depressed biceps
and brachioradialis jerk on the right. The patient is stabilized and brought
back for an outpatient MRI scan of the cervical spine. He is told that his
scan shows a large herniated disk at one level and some degenerative
changes at several other levels, but he forgets to note at which level he has
the most serious problem. Between which vertebral levels is the most likely
level of greatest involvement in this patient?
A.
B.
C.
D.
E.
C3 and C4
C4 and C5
C5 and C6
C6 and C7
C7 and T1
The correct answer is C. The authors of the chapter Spinal Cord Anatomy
Localization, and Overview of Spinal Cord Syndromes review the anatomic
orientation of vertebrae to exiting spinal roots. In the cervical spine, the C1
root exits above the C1 vertebra (the atlas), and the following six spinal
nerves exit above their corresponding vertebrae. The clinical syndrome
above corresponds to encroachment upon the right C6 nerve, with the C6
nerve exiting between the C5 and C6 vertebrae.
25. A 60-year-old woman is examined for an exacerbation of low back
220
pain. She had previously noted pain in the lumbar region and right buttock
for a period of 3 months. In the past 2 weeks, she has noted worsening of
her pain and the appearance of numbness over the anterior thigh after
having been ill with bronchitis. On physical examination, there is mild (4/5)
weakness of knee extension on the right, with a diminished knee jerk on
that side. Pinprick loss is found over the center of the thigh and the knee.
Which of the following maneuvers on physical examination is most likely to
exacerbate this patients symptoms?
A.
B.
C.
D.
E.
Flexed position of the lumbar spine

Inward rotation of the knee with the hip flexed
Outward rotation of the knee with the hip flexed
Reverse straight-leg raise
Straight-leg raise (supine position)
The correct answer is D. The patient described has a radicular syndrome

localizable to the L3-L4 nerve roots. According to the author of the chapter
Diseases of the Nerve Roots, reverse straight-leg raise (patient prone, with
passive elevation of the leg) will place traction on the femoral nerve and its
root connections, L2, L3, and L4. Both inward and outward rotation of the
knee with the hip flexed are performed with the patient in straight-leg raise
position (supine) and are felt to elicit signs of hip joint disease. Straight-leg
raise is a useful clinical maneuver in eliciting symptoms of radicular disease
in the most common roots affected in the lumbosacral spineL5 and S1.
Finally, keeping the lumbar spine in flexed position generally relieves
radicular symptoms.
26. Which of the following MRI findings is most specific for dural
arteriovenous fistulae of the spinal cord?
A.
B.
C.
D.
E.
Blood flowrelated signal abnormalities in subarachnoid space

Enhancement of the cord on postcontrast T1 sequences
Hyperintensity in cord parenchyma on T2 sequences
Scalloped cord boundaries on sagittal images
Widened cord
The correct answer is A. While all of the MRI findings listed as choices can
be seen in patients with dural arteriovenous fistulae, blood flowrelated
signal abnormalities in the subarachnoid space are the most specific.
27. The feasibility of stereotactic radiosurgery for the treatment of spinal

tumors will most likely depend on development of techniques to control or
correct for which of the following?
A.
B.
C.
D.
E.
Aortic blood flow

Bony artifact
Intestinal gas patterns
Patient movement
Teratogenic effects
The correct answer is D. Stereotactic radiosurgery requires immobilization to

allow delivery of a high dose of radiation to the intended target while
minimizing exposure of surrounding healthy tissue. Inability to immobilize
the spine has made stereotactic radiosurgery impossible to date, but new
techniques to control for patient movement may eliminate this obstacle.
28. A 40-year-old woman who has been on weekly methotrexate for a year
for rheumatoid arthritis is seen for numb feet and an unsteady gait that
became noticeable 3 months ago. On examination, she has multiple joint
deformities. There is mild spasticity in the legs along with position sense
loss and a stocking pinprick loss. Folic acid deficiency is suspected, and she
is placed on oral replacement therapy. Which of the following tests is most
useful to monitor response to folate therapy?
A.
B.
C.
D.
E.
L-Methionine level
Methylmalonic acid level
Plasma homocysteine level
Serum folate level
The correct answer is D. The author of the chapter Metabolic and Toxic
Myelopathies discusses folate deficiency and notes that neurologic
complication from this condition is rare. Folate deficiency may present as a
subacute combined degeneration phenotypically. Serum folate level is not
the most sensitive way to monitor response to therapy because it varies
widely with short-term fluctuations in intake. Methylmalonic acid level may
be used to screen for cobalamin deficiency while L-methionine level is a
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PREFERRED RESPONSES
precursor to S-adenosylmethionine and has been studied in several trials to
treat AIDS-related myelopathy. Complete blood count may demonstrate
resolution of a megaloblastic anemia but would do so as well in treating
pure cobalamin deficiency; furthermore, resolution of the anemia has
limited correlation with improvement in neurologic status.
29. A 20-year-old college student comes to the physician because of

clumsiness and tingling in the feet that has been going on for a year. He
has been generally healthy and is treated only for depression. Three years
later, while a graduate student, he is seen because of an inability to
concentrate. This is attributed at first to his depression. Within a year he
begins to notice graying of his vision and more trouble walking. On
examination, he has bilateral optic atrophy and brisk reflexes throughout.
Family history reveals multiple sclerosis in a female first cousin. Over the
next 3 years, he becomes increasingly disabled, both cognitively and
physically. Which of the following abnormalities is likely to be found in this
patient?
A.
B.
C.
D.
E.
222
Accumulation of long chain fatty acids

Antibodies to aquaporin-4 water channel
Antibodies to HIV
Expanded trinucleotide repeat in frataxin gene
Presence of JC virus in brain
The correct answer is A. The male patient described presents as a young

adult with a peripheral sensory syndrome, followed by involvement of
upper motor neurons and optic nerves. Ultimately, he has diffuse cognitive
impairment. Although HIV might produce multifocal damage to the nervous
system, this patients course stretches over close to a decade, making HIV
an implausible choice. Similarly, progressive multifocal
leukoencephalopathy caused by JC virus is much more rapidly fatal and
would not present with symptoms of peripheral nerve disease.
Neuromyelitis optica is a rapidly progressive demyelinating disease of spinal
cord and optic nerves, which typically spares higher cortical functions and
peripheral nerve. Expanded trinucleotide repeat in frataxin gene is the most
common genetic mutation found in Friedreich ataxia. However, in that
autosomal recessive syndrome, which involves both corticospinal tracts and
peripheral nerve, optic nerves would not be involved, cognition is spared,
and dorsal column involvement is prominent. Accumulation of long chain
fatty acids is correct, with the clinical course typical of an X-linked disease
with diffuse central and peripheral nervous system involvement,
characteristic of adrenomyeloneuropathy.
30. Which of the following processes tends to affect the infraclavicular

portion of the brachial plexus more often than it affects the supraclavicular
portion?
A.
B.
C.
D.
E.
Cervical rib
Neoplastic infiltration
Obstetric trauma
Open heart surgery
Radiation injury
The correct answer is E. Radiation injury tends to affect the infraclavicular

portion of the brachial plexus more often than the supraclavicular portion.
Cervical ribs, neoplasms, obstetric trauma, and open heart surgery tend to
affect the supraclavicular portion more often.
31. Which of the following tests is most useful in predicting the likelihood
that a patient with partial myelitis will subsequently experience a second
clinical attack that will establish the diagnosis of multiple sclerosis?
A.
B.
C.
D.
E.
MRI of brain
MRI of cervical spinal cord
Spinal fluid immunoglobulin G index
Spinal fluid oligoclonal bands
Spinal fluid white blood cell count
The correct answer is A. The most useful test for predicting whether a
patient with partial myelitis will subsequently convert to multiple sclerosis is
the brain MRI. The presence of two or more white matter lesions is
associated with a 90% risk of conversion over the next 10 to 14 years.
32. The value of decompressive surgery for lumbosacral radiculopathy has

been studied extensively in controlled multicenter trials. In one recent study
involving patients with lumbar spondylolisthesis, canal stenosis, and
neurogenic claudication, there was randomization to either conservative
treatment or decompressive surgery with fusion. Which of the following was
a significant finding of this study?
A.
B.
C.
D.
E.
Conservatively treated patients had improved ambulation

Neurogenic claudication is always a surgical indication
One-year outcomes for surgical versus nonsurgical patients was the same
Pain of root origin responded well to surgery
Surgical patients had greater improvement in back pain
The correct answer is D. In reviewing the recent paper of Weinstein and

colleagues (2007), the author of the chapter Diseases of the Nerve Roots
cites several findings: with surgical treatment, back pain did not show as
much improvement as other symptoms, but leg pain, indicative of root
irritation, showed the best results with surgery. One-year outcomes for
surgical versus nonsurgical patients were looked at in the other major study
cited (Peul et al, 2007), which involved a different group of patients and a
different type of surgery and actually did show some differences in 1-year
outcomes for pain relief. Choice A is not discussed, and choice B is untrue,
as many patients randomized in the Weinstein and colleagues study and
treated nonsurgically had symptoms of neurogenic claudication.
Peul WC, van Houwelingen HC, van den Hout WB, et al. Surgery versus
prolonged conservative treatment for sciatica. NEJM 2007;356(22):22452256.
Weinstein JN, Lurie JD, Tosteson TD, Hanscom B, Tosteson ANA, Blood EA,
Birkmeyer NJO, Hilibrand AS, Herkowitz H, Cammisa FP, Albert TJ, Emery SE,
Lenke LG, Abdu WA, Longley M, Errico TJ, Hu SS. Surgical versus nonsurgical
treatment for lumbar degenerative spondylolisthesis. NEJM 2007;356(22):
22572270.
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PREFERRED RESPONSES
33. A patient reports pain and numbness in the fourth and fifth fingers and
the medial aspect of the forearm and hand. Examination reveals weakness
of the intrinsic hand muscles. Which of the following electrodiagnostic
findings would make a lower trunk brachial plexopathy more likely than a
C8/T1 radiculopathy due to disk herniation?
A.
B.
C.
D.
E.
Focal slowing of ulnar motor conduction velocity at the elbow

Neurogenic motor units in the abductor digiti minimi muscle
Reduced amplitude of ulnar motor response
Reduced amplitude of ulnar sensory response
Spontaneous activity in the first dorsal interosseous muscle
The correct answer is D. Disk herniations typically affect the central sensory
processes extending from the dorsal root ganglion into the spinal cord and
spare the processes extending from the dorsal root ganglion to the
periphery. Thus, even when sensory symptoms are prominent, sensory
nerve conduction studies are typically normal in patients with
radiculopathies due to disk herniation whereas they are abnormal in
patients with plexopathies. Motor nerve conduction studies and motor units
are abnormal in both conditions. Neither condition would produce a focal
slowing of conduction velocity at the elbow.
34. A 35-year-old man is referred to a physician for burning pain and

dysesthesias in both arms and shoulders of 1 years duration. He states that
over the past month he feels as though his hands have become somewhat
weak and clumsy. Past medical history is significant for a motorcycle accident 3
years ago, during which he sustained a cervical fracture stabilized by traction.
On examination, pinprick and temperature sensation are reduced over the
shoulders and upper arms with preservation of position sense. Atrophy of
intrinsic hand muscles with accompanying weakness is found bilaterally.
Pinprick over the legs and anal region is normal. Reflexes are reduced in the
arms. A lesion of the central aspect of the spinal cord is suspected. Which of
the following best explains the examination findings in this patient?
224
A.
B.
C.
D.
E.
Bilateral involvement of dorsal columns

Cervical enlargement of the spinal cord
Partial involvement of lateral corticospinal tracts
Somatotopic organization of lateral spinothalamic tracts
Sparing of anterior horn cells
The correct answer is D. The patients presentation, with early loss of pain
and temperature sensation in the proximal arms with spontaneous pain,
suggests early involvement of the lateral spinothalamic tracts. Dorsal
columns are spared, but anterior horn cells are involved with intrinsic hand
muscle wasting. No spasticity is described. The cervical enlargement of the
spinal cord, while present, is not the key to either the dissociated sensory
findings in the patient or the phenomenon of sacral sparing of
spinothalamic tract involvement. Somatotopic organization of lateral
spinothalamic tracts, which refers to sacral spinothalamic representations
being most lateral and cervical most medial in the cord, is correct and
explains early involvement of the upper body.
35. Patients who have experienced a prolonged cardiorespiratory arrest are

most likely to sustain ischemic damage to the spinal cord at which of the
following levels?
A.
B.
C.
D.
E.
High cervical
Low cervical
Low thoracic
Lumbosacral
Midthoracic
The correct answer is D. Contrary to the traditional teaching regarding the

midthoracic watershed region of the spinal cord, spinal cord damage after a
known hypoxic-ischemic event (whether due to primary hypotension or
cardiopulmonary arrest) is most prevalent in the lumbosacral levels, suggesting
that these lower levels are more prone to the effects of hypotension.
36. A 50-year-old man comes to his physician for follow-up on a

progressive problem with coordination. At about age 40, he began to notice
stiffness and slowness of movement along with slurred speech. He
continued to work but had several falls on the job and found himself
hugging the walls. Over the next few years, he developed increased tone
in the limbs with spasticity noted on examination, as well as wasting of his
intrinsic hand muscles. By his late 40s, he was noted to have lid retraction,
severe dysarthria, and gait ataxia, along with hand and proximal lower
extremity weakness. At that time, no reflexes could be elicited. Studies
obtained included brain MRI, which revealed moderate cerebellar atrophy,
as well as EMG, which showed an advanced axonal sensorimotor
neuropathy. At age 50, he remained cognitively intact but could no longer
walk. The patients 25-year-old daughter is concerned about the possibility
of inheriting her fathers condition; the patients mother was in a wheelchair
by age 50 and died 5 years later. What is the probability of this occurring?
A.
B.
C.
D.
E.
No chance because it is sporadic in occurrence

No chance because it is X-linked
Low probability because it is a recessive trait
Fifty percent chance because it is autosomal dominant
Greater than 50% chance because of anticipation
The correct answer is D. The clinical entity described is multifaceted, involving

initially corticospinal tracts, then cerebellar function, with eventual severe
involvement of peripheral nerves as well as motor neurons. Extrapyramidal disease
was present in mild form in this particular patient. The syndrome is inherited, with
the patients mother in this case being the proband. Because the patients mother
was affected, the condition is not X-linked. It is consistent with Machado-Joseph
disease (spinocerebellar ataxia type 3) with autosomal dominant transmission.
Although anticipation may occur in transmission of this disease, this would produce
earlier onset, not a higher probability of being affected.
37. A 41-year-old previously healthy woman began to notice a tendency to

stumble while walking. Over the next 2 months, her gait disturbance gradually
progressed to the point where it was obvious even when walking short
distances, and she developed urinary urgency and occasional incontinence.
Examination reveals spastic paraparesis, with a sensory level at T6. Spine MRI
225
PREFERRED RESPONSES
reveals an intramedullary enhancing lesion extending from T4 to T8, with
several enhancing pial nodules in the cervical and thoracic cord. Brain MRI is
normal except for meningeal enhancement around the brainstem. Spinal fluid is
notable for a protein level of 66 mg/dL and 24 white blood cells/L, all
mononuclear. Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Sarcoidosis
Syphilis
Vacuolar myelopathy
The correct answer is B. The MRI findings of subpial nodules in the spinal
cord and meningeal enhancement around the brainstem are characteristic of
sarcoidosis and would not be typical of neuromyelitis optica, syphilis,
vacuolar myelopathy, or varicella-zoster myelitis. Vacuolar myelopathy and
varicella-zoster myelitis would be unusual in a previously healthy 41 year old.
38. A 40-year-old man is referred for neurologic evaluation for difficulty

walking that began about 6 months ago and has progressively worsened.
One year ago, he underwent gastric bypass surgery for morbid obesity; he
has lost a total of 60 kg. He had been treated for type 2 diabetes, but after
weight loss his last hemoglobin A1C was 6.2. However, prior to surgery, he
had a history of paresthesias in the feet and a stocking loss to pinprick. He
has been faithful to his prescribed regimen of B vitamin replacement. For
the first 2 months after surgery, he had intermittent diarrhea, but that
stabilized shortly thereafter. On examination, he has increased tone in the
legs with mild bilateral footdrops. There is patellar clonus, but no ankle
jerks are elicited. Plantar signs are extensor. Profound vibratory loss as well
as impaired position sense is found in the legs. The previously described
stocking loss to pinprick is evident. He has mild low back pain, which has
been chronic. Serum methylmalonic acid level is normal. Which of the
following studies is most likely to lead to a diagnosis in this patient?
226
A.
B.
C.
D.
E.

Genetic testing for -tocopherol transfer protein gene mutation
MRI of the cervical spine
Serum copper level
The correct answer is E. This patient presents with a subacute syndrome of

pyramidal tract and dorsal column impairment, similar in phenotype to several
genetic syndromes but much more likely in this setting to be an acquired
disorder. -Tocopherol transfer protein gene mutation, a genetic defect found
in association with vitamin E deficiency, would present typically in childhood
with a much more gradual onset and would likely affect other organ systems
(eg, retina, heart). A complete blood count might be abnormal but is not
diagnostic. MRI of the spine might show increased T2 signal in the dorsal
columns in several acquired nutritional deficiencies but might be normal. Serum
vitamin B12 level would certainly be a leading consideration but is made less
likely by the normal methylmalonic acid level. Serum copper level is correct.
According to the author of the chapter Metabolic and Toxic Myelopathies,
vitamin B12 and copper deficiency can coexist and comprise similar
phenotypes. Particularly in an instance in which vitamin B12 deficiency has

been excluded or adequately treated, copper deficiency should be considered.
This has been reported in gastric surgery and zinc overdose.
39. A patient with a 3-month history of progressive myelopathy was found

to have an enhancing intradural-extramedullary lesion on MRI. There were
no bony abnormalities. Which of the following tumor types is most likely?
A. Astrocytoma
B. Ependymoma
C. Meningioma
D. Myeloma
E. Tuberculoma
The correct answer is C. The most common extramedullary intradural
tumors are nerve sheath tumors and meningiomas. Astrocytomas and
ependymomas are intramedullary. Myeloma and tuberculomas are
extradural and typically associated with bony abnormalities.
40. A 54-year-old man with a history of hypertension, diabetes, and prostate

cancer developed severe pain and weakness in his left thigh, which became
progressively more severe over the course of a week, to the point where he
could walk only with a walker. Over the next 2 weeks, his left lower
extremity symptoms stabilize while he develops similar (but milder)
symptoms in his right lower extremity. He also reports that he has no
appetite, and he has lost 9 kg. Motor examination is notable for marked
weakness and atrophy of the left knee extensors, moderate weakness of the
left hip adductors, mild weakness of left ankle dorsiflexion, left ankle
plantar flexion, and left knee flexion, and mild weakness of right knee
extension. He has a reduced right patellar reflex, and absent reflexes at the
left knee and both ankles. Electrodiagnostic testing reveals abnormal motor
and sensory nerve conductions and both acute and chronic denervation in a
patchy distribution in both lower extremities, worse on the left; there are
fibrillation potentials in the lumbar paraspinal muscles. MRI of the
lumbosacral spine is normal, as is an MRI of the left lumbosacral plexus.
Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Diabetic lumbosacral radiculo-plexus neuropathy

Metastatic spine disease
Neoplastic lumbosacral plexopathy
Spinal epidural abscess
The correct answer is A. Diabetic lumbosacral radiculo-plexus neuropathy

typically presents with subacute pain and weakness in one lower extremity
and often progresses to bilateral involvement. Profound weight loss and
anorexia are common. Electrodiagnostic studies reveal patchy changes
consistent with involvement of individual nerves, segments of the plexus,
and nerve roots (including paraspinal muscle denervation). The abnormal
sensory nerve conductions and the normal spine MRI in this case make
metastatic spine disease and epidural abscess less likely. The bilateral
involvement and the normal MRI of the plexus make retroperitoneal
hematoma and neoplastic plexopathy less likely.
227

Quintessentials is designed to help practicing neurologists identify and make changes to
their practices to improve patient care. Composed of two case-based questionnaires and
preferred responses, the program is intended to stimulate thought and help you assess your
practice behavior against expert opinion. The comments, references, and links to
should assist you in this process.
information provided in this issue of
This program consists of three parts:
Part 1Baseline
1. Go to www.aan.com/go/elibrary/continuum/quintessentials to complete Part 1
Baseline Questionnaire. Alternatively, you may cut out and complete Part
1Baseline Questionnaire on the following pages and then mail or fax your
completed forms to the AAN.
2. Review the preferred responses to the Baseline Questionnaire either online or in
this Quintessentials section. The preferred responses direct you to pertinent
issue and should help stimulate possible changes in
discussion in the
your practice of patients with spinal cord, root, and plexus disorders.
Part 2Follow-up
Approximately 1 month after receipt of your Part 1Baseline Questionnaire, the AAN will
send you an email reminding you to complete Part 2Follow-up Questionnaire. If you
completed Part 1 on paper, the AAN will mail the Part 2 questionnaire to you. This casebased questionnaire will reexamine your knowledge and behaviors related to your practice
of patients with spinal cord, root, and plexus disorders.
1. Complete Part 2Follow-up Questionnaire at www.aan.com/go/elibrary/continuum/
quintessentials, or mail or fax your completed forms to the AAN.
2. Review the preferred responses to the Follow-up Questionnaire. Like the preferred
responses to the Baseline Questionnaire, they will direct you to pertinent discussion
issue and should help stimulate possible changes in your
in the
practice.
Part 3Feedback and Evaluation
Upon receipt of your Part 2Follow-up Questionnaire, you will immediately receive an
electronic comparison report of your responses to Part 1Baseline Questionnaire and Part
2Follow-up Questionnaire and a program evaluation form. These forms will be sent by
mail to participants who have submitted Parts 1 and 2 on paper. The comparison report is
intended to help you identify any changes you made in your practice as a result of the
program.
1. Complete the evaluation form at www.aan.com/go/elibrary/continuum/
quintessentials or mail or fax the evaluation form to the AAN in order to be granted
CME for participation in the program.
231
2. A transcript of credits earned in Quintessentials Spinal Cord, Root, and Plexus

Disorders will be available to you electronically in 2 business days. If you
completed the module on paper, you will be sent your transcript within 2 months
of receipt of your evaluation form.
Faculty
NEERAJ KUMAR, MD
Associate Professor, Mayo Clinic College of Medicine, Rochester, Minnesota; Consultant,
Department of Neurology, Mayo Clinic, Rochester, Minnesota
Relationship Disclosure: Dr Kumar has nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kumar has nothing to disclose.
Learning Objectives
Upon completion of Quintessentials Spinal Cord, Root, and Plexus Disorders, the
participant will be able to:
Recognize the various conditions that can cause subacute combined degeneration of
the cord
Develop a practical approach to the workup of patients with an inflammatory
myelopathy
Manage patients with radiculopathy and cord compression due to degenerative disc
disease
Core Competencies
Quintessentials Spinal Cord, Root, and Plexus Disorders covers the following core
competencies: Patient Care, Medical Knowledge, Practice-Based Learning and Improvement,
and Systems-Based Practice.
Estimated Time to Complete
The estimated time to complete Parts 1 and 2 is 3 hours.
232
Accreditation
The American Academy of Neurology (AAN) is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians. The
AAN designates this educational activity (Quintessentials Spinal Cord, Root, and Plexus
Disorders) for a maximum of 3 hours of AMA PRA Category 1 Credits. Physicians should
only claim credit commensurate with the extent of their participation in the activity.
The American Board of Psychiatry and Neurology has reviewed Quintessentials and has
approved this product as a part of a comprehensive lifelong learning and self-assessment
program, which is mandated by the ABMS as a necessary component of maintenance of
certification.

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L I F E L O N G L E A R N I N G I N N E U R O L O G Y

SPINAL CORD, ROOT, AND PLEXUS

NEERAJ KUMAR, MD, CHAIR

JOSE BILLER, MD, FACP, FAHA, FAAN

THOMAS COCHRANE, MD, MBA

Dr Fink has nothing to disclose.

Dr Geldmacher has nothing to disclose.

GREGORY GRUENER, MD, MBA

Dr Gruener has nothing to disclose.

Dr Rubin has nothing to disclose.

DEAN M. WINGERCHUK, MD, MSc, FRCP(C), FAAN

Dr Wingerchuk discusses the unlabeled use of methylprednisolone,

MULTIPLE-CHOICE QUESTION WRITERS

Dr Bergen has nothing to disclose.

DOUGLAS J. GELB, MD, PhD, FAAN

Dr Gelb has nothing to disclose.

SPINAL CORD, ROOT, AND PLEXUS DISORDERS

SPINAL CORD ANATOMY,

ANATOMY OF THE SPINAL

A notch in the inferior aspect of the

Copyright 2008, American Academy of Neurology. All rights reserved.

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

Functions of the constituent parts of a vertebra.

nium and meningeal layer of the dura

space, epidural space, which extends

Lateral view of a lumbar (second) vertebra.

Continuum: Lifelong Learning Neurol 2008;14(3)

tissue and the vertebral venous plexus.

tively numbered vertebrae (C2

Spaces associated with the spinal meninges.

Continuum: Lifelong Learning Neurol 2008;14(3)

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

The first pair of

Relationships of the sixth cervical spinal nerve.

(or horn), a lateral column, and an

laminae I through V, more clearly

specific and will give rise to the major

Vertebral column, spinal cord, and nerve

pathway is the anterolateral spinothalamic tract (Figure 1-9). This tract

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

Spinal cord laminae and cell groups

Primary afferent neuron targets in the

Continuum: Lifelong Learning Neurol 2008;14(3)

and will initially cross, ascend to the

Ascending pathways (upper cervical level).

GF gracile fasciculus; CF cuneate

those effects are abolished by a cord

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

The dorsal root

Spinothalamic pathways (sensory modalities, upper cervical level).

zation is alpha neurons innervating extensor muscles lying ventral or anterior

The majority of fibers that give rise

lateral corticospinal tract) or the majority adjacent to the anterior median

The reticulospinal tracts, through

Continuum: Lifelong Learning Neurol 2008;14(3)

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

and have inhibitory effects on sensory

FIGURE 1-11 Descending pathways (upper cervical level).

Continuum: Lifelong Learning Neurol 2008;14(3)

The anterior spinal artery arises

FIGURE 1-12 Arterial supply of the spinal cord.

SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES

FIGURE 1-13 Arterial supply of a spinal cord segment.