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 K UMAR UMAR , MD, C HAIR Associate Professor, College of Medicine, Mayo Clinic, Rochester, Minnesota; Consultant, Consul tant, Depar Department tment of Neuro Neurology, logy, Mayo Clinic Clinic,, Roches Rochester, ter, Minnesota *† Dr Kumar has nothing to disclose.

JOSE´ ´ B B ILLER , MD, FACP, FAHA, FAAN Professor and Chairm Professor Chairman, an, Depart Department ment of Neuro Neurology, logy, Loyola Unive University rsity Chicago, Stritch School of Medicine, Chicago, Illinois *† Dr Biller has nothing to disclose.

T HOMAS HOMAS C OCHRANE, MD, MBA Instructor in Neuro Instructor Neurology, logy, Harvard Medic Medical al Schoo School, l, Bosto Boston, n, Massac Massachuset husetts ts *† Dr Cochrane has nothing to disclose.

JOHN K. FINK , MD MD Professor, University Professor, University of Michi Michigan, gan, Department of Neur Neurology ology and Geria Geriatric tric 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. L. FOGELSON, MD Neurosurgery Resident, Mayo Clinic, Rochester, Minnesota *† Dr Fogelson has nothing to disclose.

D AVID 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 G GRUENER , MD, MBA Professor Profe ssor of Neuro Neurology, logy, Associate Chairman, Associate Associate Dean of Educat Educational ional 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.

ILLIAM E. K RAUSS RAUSS, MD W ILLIAM MD

Associate Professor of Neurological Surgery, Mayo Medical School, Rochester, Minnesota * Dr Krauss has nothing to disclose. † Dr Krauss’s presentation includes figures of, but does not discuss, the unlabeled use of cervical pedicle screws.

K ERRY ERRY H. H. LEVIN, MD Chairman, Department of Neurology, Director, Neuromuscular Center, Cleveland Clinic; Professor of Neurology, Cleveland Clinic Lerner College of Medicine of Case Wester Western n Reser Reserve ve Unive University rsity,, Cleve Cleveland, land, Ohio *† Dr Levin has nothing to disclose.

DEVON I. R UBIN UBIN, MD MD Associate Professor of Neurology, Director, EMG Laboratory, Mayo Clinic, Jacksonville, Florida * Dr Rubin has received royalty payments for contributing to an EMG educational educa tional CD-ROM from AAN Enter Enterprises prises,, Inc., and the American Association Association of Neuromuscular and Electrodiagnostic Medicine. † Dr Rubin has nothing to disclose.

LUBDHA S SHAH, MD Assistant Professor, Radiology, University of Virginia Health System, Charlottesville, Virginia *† Dr Shah has nothing to disclose.

DEAN M. W INGERCHUK INGERCHUK , 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 ritux imab for preven prevention tion of relaps relapse e of certai certain n inflam inflammator matory y myeli myelitides tides..

MULTIPLE-CHOICE QUESTION WRITERS

R ONNIE ONNIE B ERGEN, MD Assistant Professor of Clinical Neurology, University of Arizona College of Medicine, Medici ne, Southern Arizo Arizona na VA Hospi Hospital, tal, Tucson Tucson,, Arizo Arizona na * 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 Neuro Professor Neurology, logy, University University of Michi Michigan, gan, Ann Arbo Arbor, r, Michig Michigan an * Dr Gelb has received personal compensation in an editorial capacity from Current Curr ent Opinion in Intern Internal al Medic Medicine. ine. † Dr Gelb has nothing to disclose.

*

Relationship Disclosure Unlabeled Use of Products/Investigational Use Disclosure

†

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

EDITOR’S EDIT OR’S PRE PREFAC FACE E This issue of Continuum 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 section’s eloquent discus dis cussio sion n of the int intric ricate ate org organi anizat zation ion of the spi spinal nal cor cord d by Drs Gre Gregor gory y Gruener Gruen er and Jose´ Biller helps us exerci exercise se that core princi principle ple of neuro neurologic logic 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 empha emphasizes sizes the excitem excitement ent surrounding surrounding neuromyelitis neuromyelitis optica (NMO) and the imp implic licati ations ons of the rece recentl ntly y dis discov covered ered NMO-Ig ant antibo ibody, dy, whi which ch is directed against aquaporin-4, the major water channel in the CNS. Although the previous issue of Continuum was 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 clinic cli nical al sce scenar narios ios.. Drs Dav David id Gel Geldma dmache cherr and Lub Lubdha dha Sha Shah h pre presen sentt a luc lucid id discus dis cussio sion n not onl only y of art arteria eriall syn syndro dromes mes but also of veno venous us dis disord orders ers 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 patient’s ability to walk. Unfortunately, spinal cord injury too often reminds us of the vulnerability of the human condition and will remain a

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‹ EDITOR’S 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. Don’t 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

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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 annu- lus 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.

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‹ 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 space, epidural space , which extends matter will separate caudal to the fo- the length of the spinal column ( Figramen magnum, forming an anatomic ure 1-3) . Within this space reside fatty

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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, dentic- ulate 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.

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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.


‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES KEY POINT: 

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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, Continuum: Lifelong Learning Neurol 2008;14(3)

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 column–medial 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)

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FIGURE 1-6

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FIGURE 1-7

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 Spinal cord laminae and cell groups (midthoracic level). an arousal system for the cerebral cortex (through the reticular activating Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and neuroscience. 5th system), and it helps to interpret the ed. London: Saunders, 2007:182. Copyright © 2007, Elsevier. nature of a stimulus (pleasurable or not). The spinocerebellar tracts provide dality of touch and pressure. The lat- nonconscious proprioception (Figure eral spinothalamic tract is lateral and 1-8). Fasciculus gracilis collaterals proposterior, somatotopically as well as vide 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 pro vide information about the state of Primary afferent neuron targets in the internuncial function in regard to spiposterior horn. nal cord reflexes and arise from the Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and neuroscience. 5th intermediate gray matter of the spinal ed. London: Saunders, 2007:183. Copyright © 2007, cord. (1) The anterior spinocerebellar Elsevier. tract arises from the lower spinal cord Continuum: Lifelong Learning Neurol 2008;14(3)

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 oli vary 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)

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‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES KEY POINTS:

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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 column–medial 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. Continuum: Lifelong Learning Neurol 2008;14(3)

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 ( Fig ure 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 inner vates 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.

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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.


‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES 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.

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FIGURE 1-11 Descending pathways (upper cervical level). Reprinted with permission from Fitzgerald MJ, Gruener G, Mtui E. Clinical neuroanatomy and neuroscience. 5th ed. London: Saunders, 2007:198. Copyright © 2007, 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 (Fig ure 1-13). The centripetal system is formed from radial arteries directed in ward 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 Continuum: Lifelong Learning Neurol 2008;14(3)



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. DeJong’s: 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):9–15. 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 cord’s 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 canal’s 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.


‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES 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

BrownSe´ quard 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 HTLV-I



Intramedullary tumors Cervical spondylosis

human T-cell leukemia virus I; HAM



human T-cell lymphotropic virus–associated 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

‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES 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-Se´quard syndrome). Reprinted with permission from Souayah N, Khella S. Neurology examination & board review. New York: McGraw Hill, 2005:46.

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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 Continuum: Lifelong Learning Neurol 2008;14(3)

Brown-Se´ quard 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 de veloped, 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 cer vical 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. Reprinted with permission from Souayah N, Khella S. Neurology examination & board review. New York: McGraw Hill, 2005:46.

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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

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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-Se´quard 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. Continuum: Lifelong Learning Neurol 2008;14(3)

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 patient’s 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. Continuum: Lifelong Learning Neurol 2008;14(3)

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‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES 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 theirsensory modalities. Thelamination 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 ( sus- pended sensory level ), can be demonstrated (Cases 1-1 and 1-2).

FIGURE 1-22 Syringomyelia (modalities involved). Reprinted with permission from Souayah N, Khella S. Neurology examination & board review. New York: McGraw Hill, 2005:45.

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 B 12 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 de velop 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. Reprinted with permission from Souayah N, Khella S. Neurology examination & board review. New York: McGraw Hill, 2005:44.


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‹ SPINAL CORD ANATOMY, LOCALIZATION, SYNDROMES 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 cell–pyramidal syndrome. Reprinted with permission from Souayah N, Khella S. Neurology examination & board review. New York: McGraw Hill, 2005:44.

ing) in character, and the deficit can be cell bodies of the sympathetic neurons are more prominent in darkness or with eye involved. closure as visual cues no longer can assist in maintaining balance. The affected limbs Combined Anterior Horn Cell– may become hypotonic but usually are Pyramidal Syndrome not weak. At times other spinal cord le- This syndrome is perhaps best exemplisions can produce a truncal ataxia but fied by ALS. These lesions produce a com without the associated proprioceptive dif- bination of flaccid and spastic paralysis. ficulties. In such cases, spinocerebellar Damage to the anterior horns or lower tract dysfunction, as a manifestation of spi- motor neurons will result in a flaccid panal cord compression, appears to be re- ralysis with atrophy and fasciculations, while a lesion of the lateral corticospinal sponsible for this clinical syndrome. With dysfunction of the posterior col- tract or upper motor neurons results in a umns in the cervical region, neck flexion spastic paralysis with associated hyperremay elicit an electric-like sensation that flexia and Babinski sign (Figure 1-24). radiates down the back or into the arms The degree of injury to either site can be (Lhermitte sign ). It is thought to represent highly variable and reflected in the clinical increased mechanosensitivity of the dorsal presentation. If one site is more or precolumns with neck flexion further activat- dominantly affected, an additional lesion ing those sensory pathways. The symp- in the other at the same level may not tom is most frequentlyassociated with spi- produce noticeable effects. nal cord involvement in multiple sclerosis. INTRAMEDULLARY VERSUS EXTRAMEDULLARY CORD Anterior Horn Cell Syndrome Damage to the motor anterior horn cells LESIONS leads to an ipsilateral flaccid paralysis ac- Neoplasms arising within the spinal companied by atrophy and fasciculations. canal tend to produce their symptoms Because larger muscles are supplied by and signs in a slow and progressive motor neurons from more than one seg- manner, although an acute presentament, damage to a single spinal cord seg- tion can occasionally be encountered. ment may lead only to muscular weak- When arising from lesions within the ness rather than complete paralysis of the spinal cord (intramedullary ) , sympaffected motor group (Figure 1-10). toms often begin within the vicinity of When the lateral horns are involved, a the central canal. Sensory symptoms decrease in sweating and vasomotor func- are initially less localizing and dissocitions may also be demonstrated, as the ation of sensory loss can occur. Early Continuum: Lifelong Learning Neurol 2008;14(3)

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. DeJong’s 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-Se´quard 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 motordysfunction 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. Continuum: Lifelong Learning Neurol 2008;14(3)

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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. DeJong’s 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):577–586. Bowen BC, Pattany PM. Vascular anatomy and disorders of the lumbar spine and spinal cord. Magn Reson Imaging Clin N Am 1999;7(3):555–571. 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, Le´ nelle 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):1377–1385. 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. DeJong’s 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):303–324. 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): 1113–1120. Souayah N, Khella S. Neurology: examination & board review. New York: McGraw Hill, 2005. Tattersall R, Turner B. Brown-Se´quard 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 to weeks requires urgent spinal cord Infectious and inflammatory diseases MRI (Transverse Myelitis Consortium can produce virtually any temporal Working Group, 2002). When imagpattern of myelopathy, including ing reveals an intramedullary spinal acute, subacute, or chronic presenta- cord lesion without evidence for extions. A comprehensive and consistent trinsic cord compression, the diagnoapproach to evaluating the patient sis of an inflammatory or infectious with an inflammatory myelopathy can myelitis be comes a primary considminimize the chance of missing a eration. Clinical features that suggest treatable condition and allow early ini- an infectious cause include fever tiation of therapy that impacts clinical and meningismus, encephalopathy, recovery and future prognosis. rash, lymphadenopathy, known systemic infection, immunocomproDIFFERENTIAL DIAGNOSIS OF mised status, or known exposure to ACUTE OR SUBACUTE an infectious agent. Lumbar puncINFLAMMATORY MYELOPATHY ture, to determine the presence of The clinical presentation of a my- inflammation, is the immediate next elopathy that developed over hours 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 1–associated 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 path ways (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):543–555. Copyright © 2005, Elsevier.


‹ INFECTIOUS AND INFLAMMATORY MYELOPATHIES 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 cytomegalo virus-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):1211–1215. 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 polio viruses, 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 un vaccinated 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 re veals 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 Continuum: Lifelong Learning Neurol 2008;14(3)

KEY POINT: 

Neurosyphilis should be considered in any patient with myelopathy and especially those with HIV risk factors.

41


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 de veloping 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 horn–predominant 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):287–295. 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, Blastomy- ces, 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 man- soni . Hydatid disease from infection with the larval form of the canine tape worm Echinococcus granulosa can in vade 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 tape worm 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 post vaccinial 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.

KEY POINTS: 

“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 trans verse 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 Continuum: Lifelong Learning Neurol 2008;14(3)



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

‹ INFECTIOUS AND INFLAMMATORY MYELOPATHIES

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



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

50  106 /L WBCs; lymphocytes

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):343–350.


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 patient’s 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-Se´quard 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 known with greater certainty than with in the “Infectious Myelopathies” sec- postinfectious myelitis; however, the tion; in many instances, evidence for wide spectrum of vaccines and infecrecent viral infection is limited to rec- tions that appear to trigger myelitis ollection of a nonspecific febrile ill- suggests that multiple or nonspecific ness, and a specific virus is neither immune activation may trigger the isolated nor confirmed with acute and event in a susceptible individual. convalescent serologic tests. The vac- Pathophysiologic mechanisms might cines associated with myelitis include include molecular mimicry (portions smallpox, hepatitis B, influenza, ru- of the vaccine or virus resemble selfbella, and rabies vaccines, among oth- antigens, prompting an autoimmune ers. The type and timing of exposure response) or stimulation by superantito an immunologic challenge is gens. The diagnosis of postinfectious Continuum: Lifelong Learning Neurol 2008;14(3)

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




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.





48

Infections and immunizations may be associated with relapse of any of the demyelinating diseases.

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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 ( Fig ure 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 Devic’s neuromyelitis optica. Brain 2002;125(pt 7):1450–1461. Reprinted by permission of Oxford University Press.







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 optica–immunoglobulin 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 Sjo¨gren 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 longitudinally extensive myelitis associated with systemic autoimmune disease ‹ Optic neuritis or myelitis associated with neuromyelitis optica–typical brain lesions (hypothalamic, corpus callosal, periventricular, brainstem) 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 Asian optico-spinal MS (which makes an optico-spinal presentation of MS up more than half of MS cases in Jaand is one of the three supportive cri- pan) (Kira, 2003) and in patients with teria for NMO diagnosis. Aquaporin-4 “limited” forms of NMO, including reis the most common of the aquaporin current LETM and recurrent ON with water transport proteins in the CNS normal brain MRI. (Amiry-Moghaddam and Ottersen, 2003), where it is found on astrocyte Treatment of Myelitis and Its foot processes and the abluminal sur- Associated Diseases face of blood vessels, the same regions Treatment recommendations are based where NMO pathology (immunoglob- largely on anecdotal experience. Acute ulin and complement deposition) is myelitis attacks are typically treated with located. Whereas loss of aquaporin-4 IV corticosteroids such as methylpredis dependent on the stage of demyeli- nisolone (1000 mg/d for 5 consecutive nation in MS lesions, NMO lesions are days). Some severe attacks of LETM fail characterized by severe aquaporin-4 to respond to corticosteroids. In this setloss regardless of the stage of demy- ting, evidence from a randomized, conelinating activity or extent of tissue ne- trolled trial (Weinshenker et al, 1999) crosis (Roemer et al, 2007). Further- supports use of rescue plasmapheresis more, foci of aquaporin-4 loss in NMO (administered every other day for seven coincided with sites of vasculocentric exchanges). In that crossover trial for immune complex deposition. These patients with idiopathic CNS demyelidata suggest that a complement acti- nating disease (MS, transverse myelitis, vating aquaporin-4-specific autoanti- NMO, ADEM) and severe deficits (eg, body is the primary initiator of the paraplegia or coma), meaningful clinical NMO lesion. improvement occurred in significantly NMO-IgG has broadened the more plasmapheresis patients (42%) NMO spectrum of disorders ( Table than sham exchange patients (6%). Ob2-6). In addition to the patients with servational experience also supports use coexisting autoimmune/connective- of plasmapheresis for treatment-refractissue diseases and serologic tests, tory myelitis attacks in NMO and for NMO-IgG is found in patients with severe, corticosteroid-refractory ON Continuum: Lifelong Learning Neurol 2008;14(3)

51

‹ INFECTIOUS AND INFLAMMATORY MYELOPATHIES 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 de veloping 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 non–stepwise 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]), Sjo¨gren syndrome (sicca syndrome), Behçet 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


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, re vealing multiple enhancing lesions with a nodular appearance and subpial location. Serum or CSF laboratory abnormalities occur, including ele vated 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.

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 Neoplastic and Paraneoplastic been associated with ovarian and Myelopathies non–small cell lung cancer as well as Most primary tumors of the spinal cord with glutamic acid decarboxylase 65 do not usually cause acute myelitis autoantibodies causing a stiff man–like

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 erythematosus–related 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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Weinshenker BG, O’Brien 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 following 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):957– 963. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6(9):810–815. Wingerchuk DM, Lennon VA, Pittock SJ, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66(10):1485–1489. Wingerchuk DM, Lucchinetti CF. Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis. Curr Opin Neurol 2007;20(3):343–350. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol 2005;7(3):173–182.

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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.

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 ocFOUR INHERITED MYELOPATHY curs in an intron (frataxin intron 1) and SYNDROMES does not alter the frataxin coding sequence. Nonetheless, this intronic muSpinocerebellar Degeneration Spinocerebellar degeneration (eg, tation leads to reduced frataxin mesFriedreich ataxia, Machado-Joseph senger RNA (possibly through locally disease [MJD] [spinocerebellar ataxia increased DNA methylation leading to type 3 (SCA3)], Bassen-Kornzweig reduced transcription) (Greene et al, syndrome, and vitamin E deficiency 2007), iron accumulation in mitochon[occasionally familial]) are recog- dria, and an apparent increased vulnized by a combination of progres- nerability to oxidative stress.

INTRODUCTION AND SYNDROMIC CLASSIFICATION Hereditary myelopathies are diverse inherited disorders in which major clinical and pathologic features in volve 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).

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

CNS predominant, Hereditary spastic paraplegia 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

Sjo ¨ gren-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 Leber’s 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 Rimoin’s principles and practice of medical genetics. 5th ed. Philadelphia: Churchill Livingstone, 2007a:2771–2801. 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 themajor CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002;125(pt 3):551–561. 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 Neurol2007;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/spinocerebellarataxia type 3. Semin Neurol 2007;27(2):133–142. 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. Continuum: Lifelong Learning Neurol 2008;14(3)



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 patient’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 child’s 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.

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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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 patient’s 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

‹ HEREDITARY MYELOPATHIES KEY POINTS: 

SPG3A/ atlastin

gene mutation is the most common cause of childhoodonset, autosomal dominant hereditary spastic paraplegia. 



66

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 proband’s 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

‹ 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 “pri vate,” 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 / Continuum: Lifelong Learning Neurol 2008;14(3)

mutations are the most common cause of dominantly inherited hereditary spastic paraplegia.

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‹ HEREDITARY MYELOPATHIES 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):967–971. Copyright © 2003, Elsevier.

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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 patient’s maternal grandmother and two sons of unaffected sisters of the patient’s 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


REFERENCES Bruyn GW, Went LN. A sex-linked heredo-degenerative neurological disorder, associated with Leber’s 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 Rimoin’s principles and practice of medical genetics. 5th ed. Philadelphia: Churchill Livingstone, 2007a:2771–2801. 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):551–561. Greene E, Mahishi L, Entezam A, et al. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res 2007;35(10):3383–3390. 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):133–142. 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):967–971. Rainier S, Sher C, Reish O, et al. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol 2006;63(3):445–447.

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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. Yang Y, Hentati A, Deng HX et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 2001;29(2):160–165.


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.

particularly pertinent for clinical or imINTRODUCTION Spinal vascular diseases can be grouped aging decision making will therefore into three main categories: (1) ischemic, be reviewed ( Figure 4-1). The semi(2) hemorrhagic, and (3) developmental. nal paper by Gillilan (1958) can proDevelopmental lesions are typically mal- vide additional detail. formations and can lead to neurologic signs and symptoms through either of the Extramedullary Arteries other two mechanisms or via mass effect. In the human embryo, arterial supply Each of these categories will be addressed to the spinal cord is provided by radicseparately in this chapter. Many other ular vessels that enter at each spinal causes of spinal cord dysfunction, such as level and divide to follow the dorsal tumor or traumatic compression, also op- and ventral roots. A single midline anteerate through the vascular mechanism of rior spinal artery arises from the anastomicrocirculatory compromise (Tator and moses of these ventral branches. During Koyanagi, 1997). Those illnesses will be development, five to eight anterior raaddressed elsewhere in this issue. dicular arteries become dominant and provide most of the flow to the anteVASCULAR ANATOMY OF THE rior two-thirds of spinal cord through a SPINAL CORD midline anterior spinal artery. These An understanding of the peculiarities feeding vessels are variably known as of spinal vascular anatomy is neces- radicular, medullary, or radiculomedsary for approaching patients with po- ullary arteries, terms that may be used tential cord dysfunction of vascular or- interchangeably in the literature. In igin. Elements of the vascular anatomy 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;3:92–95. 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 out ward 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 features—particularly 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; Continuum: Lifelong Learning Neurol 2008;14(3)

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. Diffusion weighted 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):1113–1120. Copyright © 2006, American Medical Association. All rights reserved.


cases (Masson et al, 2004) and nearly most common causes of cord ischemia three-fourths of a carefully assessed ret- (Cheshire et al, 1996), but more modrospective sample (Novy et al, 2006). ern endovascular approaches also carry significant risk. Prolonged Prognosis clamping of the aorta above the renal In one prospectively collected series, arteries (eg, for more than 20 to 30 approximately half of patients re- minutes) places the cord at risk for gained the ability to walk with no ischemia and infarction. Open thoramore than one assistive device and did coabdominal aortic aneurysm repairs not require urinary catheterization are therefore associated with a 5% to (Masson et al, 2004). Likelihood of re- 20% risk of significant neurologic deficovery is higher when the maximum cits. Operative ligation of lower thoracic deficits are less severe. In another or lumbar segmental vessels further instudy, more than 90% of patients creases risk. Although endovascular an whose acute deficits were classified at eurysmal repair techniques appear the mildest level were able to walk safer than open surgery, they do not independently or with an assistive de- eliminate risks for spinal cord isch vice within 4 years; among those with emia. Other evidence suggests that inmore severe acute dysfunction, nearly traoperative interventions, such as disone-third required a wheelchair tal aortic perfusion and CSF drainage, (Nedeltchev et al, 2004). Poor out- may lower complication rates for aorcome is predicted when propriocep- tic surgery (Estrera et al, 2001). Intraoptive loss, gait impairment, or urinary erative monitoring of somatosensory dysfunction is present at the time of evoked potentials also may reduce risk presentation. The duration of motor for permanent injury (Cheung et al, dysfunction is useful in determining 2005). See Case 4-1. 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

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


‹ VASCULAR MYELOPATHIES 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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


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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.

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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. Continuum: Lifelong Learning Neurol 2008;14(3)

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.

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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

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FIGURE 4-5

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.


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 (Bo¨rm 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 cer vical 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

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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


‹ VASCULAR MYELOPATHIES 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

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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):145–156.


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 Ta ble 4-3 (Figure 4-9). Spinal vascular malformations not included in this radiologic–pathologic 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

Type IV

Intradural, extramedullary (perimedullary)

●

More extensive than a glomus-type AVM

●

Frequently possesses extramedullary component

●

Sometimes an extradural component.

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, 1993:175–191.

onset and increase to affect 50% by 3 with a cutaneous angioma in the cor years. In less aggressive cases, the in- responding dermatome. terval between symptom onset and accurate diagnosis may be years. See Differential Diagnosis Case 4-2. Examination. Upper motor neu- Venous congestion and mass effect ron weakness, lower motor neuron complicate clinical diagnosis because weakness, or both may be present. A they contribute to deficits in multiple spinal bruit is a highly specific, al- arterial territories. The sometimes conthough uncommon, finding that is di- fusing and widely varied presentation agnostic of a spinal AVM. Vascular of spinal vascular malformations remalformations may coexist in the skin sults in a large differential diagnosis, or paraspinal muscles. In cutaneome- which includes neoplasm, herniated ningospinal angiomatosis (Cobb syn- discs, multiple sclerosis, intracranial drome), dural angioma may coexist SAH, subacute combined degeneraContinuum: Lifelong Learning Neurol 2008;14(3)

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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

●

Type B: Intermediate X

●

Extraduralintradural AVM

Juvenile or metameric AVM

Mixed

Single feeder

Often one large and several small feeders

Type C: Giant X

Multi-pediculated fistulae

X

Massive engorged veins

Follows somite level ●

Multiple tissues affected, (eg, bone, muscle, skin, spinal cord, nerve roots)

●

Known as Cobb syndrome when severe

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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.

Reprintedwith permission from KimLJ, Spetzler RF.Classification andsurgical management of spinalarteriovenous lesions: arteriovenous fistulae and arteriovenous malformations. Neurosurgery 2006;59(5 suppl 3):195–201.


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 Continuum: Lifelong Learning Neurol 2008;14(3)

Spinal dural arteriovenous fistula is the most common type of spinal vascular malformation; it occurs much more frequently in men.

85

VASCUL CULAR AR MYE MYELOP LOPATH ATHIES IES ‹ VAS

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.

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more likely to be diagnosed with AVM (Type II or III vascular malformation) ( Table 4-3). Investigations MRII is th MR the e di diag agno nost stic ic pr proc oced edur ure e of choice in the initial evaluation of suspected spinal vascular malformations (Figu can n di discr scrim imin inat ate e ex ex-Figure re 4-1 4-10 0). It ca tramed tra medulla ullary ry fro from m int intram ramedu edullar llary y lesion si onss an and d de demo mons nstr trat ate e sp spin inal al co cord rd pathology (edema, hemorrhage) attributable to the effects of the vascular malformation. forma tion. Newer magnetic resona resonance nce (MR) techniq techniques ues includ include e three three-dimen -dimen-sion si onal al gad gadol olin iniu ium-e m-enh nhan ance ced d MR an an-Figure ure 4-1 4-11 1). Th giograp gio graphy hy (Fig The e spa spati tial al and temporal resolution available with Continuum: Lifelong Learning Neurol 2008;14(3)

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 neurointer ventio ven tional nal treatme treatment nt as to the location location of the feeding artery or fistula. These MR approaches also can track the success of therapeutic therap eutic interv intervention entionss by confir confirming ming effect eff ective ive thr thromb ombosi osiss of the mal malfor formamation 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 th the e T2 T2-w -wei eigh ghte ted d se sequ quen ence cess be be-cause cau se of hem hemorr orrhag hagic ic pro produc ducts ts sur sur-rounded 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 coron coronal al venou venouss plex plexus. us. The mos mostt con consis sisten tently tly obs observ erved ed abnorm abn ormali ality ty for dur dural al AVF is cen centra trall cord cor d hyp hyperi erinte ntensi nsity ty on T2T2-wei weight ghted ed images, which may extend over several levels. Other MR abnormalities are variable and include cord enlargement,, hypoi ment hypointen ntensity sity on T1-we T1-weighte ighted d images, a scalloped appearance of the cord cor d bou bounda ndarie riess on sag sagitt ittal al ima images ges,, and enhancement of the cord on postcontrast T1-weighted images. In general, era l, the these se fin findin dings gs are non nonspe specif cific ic and can mimic those of other elements of the cli clinic nical al dif diffe feren rentia tiall dia diagno gnosis sis,, such as cord neoplasm, infection, or ischemia. A finding of blood flow-related signal abnormalities in the subarachn ara chnoid oid spa space ce the theref refore ore be becom comes es the key diagnostic feature for identifying in g du dura rall AV AVF. F. Co Cont ntra rast st-e -enh nhan ance ced d three-dimensional spinal MR angiography allows direct visualization of the abno ab norm rmal al in intr trad adur ural al ve vein inss an and d ca can n 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 tie nt bo both th iod iodina inate ted d con contra trast st loa load d and radiation exposure from fluoroscopy. Ther Th ere e is li littl ttle e re rema main inin ing g ro role le fo forr plain plai n rad radiogr iograph aphy y or mye myelogr lograph aphy y for diagnosis of AVM, except in patients for whom who m MRI is tec techni hnical cally ly impo impossib ssible. le. 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 myelo gram is due to a spinal cord arteriovenous malformation.


VASCUL CULAR AR MYE MYELOP LOPATH ATHIES IES ‹ VAS

Angiography. Selective catheterizat catheterization ion FIGURE 4-14 Angiography. angiogram of type IVA spinal cord arteriovenouss malformation arteriovenou malformation.. The catheter angiogram demonstrates an intradural extramedu extramedullary llary arteriovenous fistula on the surface of the cord that results from a direct communication between the anterior spinal arter art eryy an and d a sp spina inall ve vein in wit witho hout ut an in inte terpo rposed sed va vasc scula ularr ne netwo twork rk..

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 dur al ves vessels sels,, but this is proc procedu edurall rally y challenging (Figure 4-13). Selective Select ive 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 angiog gi ogra raph phy y ty typi pica call lly y re requ quir ires es th that at each segm segmenta entall ar arte tery ry in th the e re regio gion n being bei ng exa examin mined ed be inj inject ected. ed. Thi Thiss is obvi ob viou ousl sly y co cost stly ly,, ti time me-c -con onsu sumi ming ng,, and—when overly prolonged—places the patient at considerable risk for anesthesia esth esia-rel -related ated comp complicat lications ions.. Despite spi te the ris risk, k, sel select ective ive spi spinal nal angiog gi ogra raph phy y re rema main inss th the e cr crit iter erio ion n standard for identifying the characteristic teri sticss of vasc vascular ular malf malforma ormation tionss 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 mal malfor format mation ionss is sur surgica gicall res resect ection ion and/or angiographically directed embolization of the malformation. Therapeuticc em ti embo boliz lizati ation on is us used ed to pr prom omot ote e thromb thr ombosis osis and dec decrea rease se blo blood od flo flow. w. 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.


REFERENCES 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, 1993:175–191. Bo¨rm W, Mohr K, Hassepass U, et al. Spinal hematoma unrelated to previous surgery: analysis of 15 consecutive cases treated in a single institution within a 10-year period. Spine 2004:29:555–561. Cheshire WP, Santos CC, Massey EW, Howard JF Jr. Spinal cord infarction: etiology and outcome. Neurology 1996;47:321–330. Cheung AT, Pochettino A, McGarvey ML, et al. Strategies to manage paraplegia risk after endovascular stent repair of descending thoracic aortic aneurysms. Ann Thorac Surg 2005;80:1280–1288. Duggal N, Lach B. Selective vulnerability of the lumbosacral spinal cord after cardiac arrest and hypotension. Stroke 2002;33:116–121. Estrera AL, Miller CC 3rd, Huynh TT, et al. Neurologic outcome after thoracic and thoracoabdominal aortic aneurysm repair. Ann Thorac Surg 2001;72:1225–1230. Gillilan LA. The arterial supply of the human spinal cord. J Comp Neurol 1958;110:75– 103. Ishizawa K, Komori T, Shimada T, et al. Hemodynamic infarction of the spinal cord: involvement of the gray matter plus the border-zone between the central and peripheral arteries. Spinal Cord 2005;43:306–310. Kauppila LI, Karhunen PJ, Lahdenrant U. Intermittent medullary claudication: postmortem spinal angiographic findings in two cases and in six controls. J Spinal Disord 1994;7:242–247. Kim LJ, Spetzler RF. Classification and surgical management of spinal arteriovenous lesions: arteriovenous fistulae and arteriovenous malformations. Neurosurgery 2006; 59(5 suppl 3):195–201. Kreppel D, Antoniadis G, Seeling W. Spinal hematoma: a literature survey with metaanalysis of 613 patients. Neurosurg Rev 2003;26:1–49. Lamin S, Bhattacharya JJ. Vascular anatomy of the spinal cord and cord ischaemia. ischaemia. Pract Neurol 2003;3:92–95. Masson C, Pruvo JP, Meder JF, et al. Spinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome. J Neurol Neurosurg Psychiatry 2004;75:1431–1435. Nedeltchev K, Loher TJ, Stepper F, et al. Long-term outcome of acute spinal cord ischemia syndrome. Stroke 2004;35:560–565. Nojiria J, Matsumotoa K, Kato A, et al. The Adamkiewicz artery: demonstration by intraarterial computed tomographic angiography. Eur J Cardiothorac Surg 2007;31:249–255. Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006;63:1113–1120. Pearce JM. The craniospinal venous system. Eur Neurol 2006;56:136–138. Pelser H, van Gijn J. Spinal infarction. A follow-up study. Stroke 1993;24:896–898.


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Rovira A, Pedraza S, Comabella M, et al. Magnetic resonance imaging of acute infarction of the anterior spinal cord. J Neurol Neurosurg Psychiatry 1998;64:279–281. Sandson TA, Friedman JH. Spinal cord infarction. Report of 8 cases and review of the literature. Medicine (Baltimore) 1989;68:282–292. Spetzler RF, Detwiler PW, Riina HA, Porter, RW. Modified classification of spinal cord vascular lesions. J Neurosurg 2002;96(2 suppl):145–156. Takase K, Sawamura Y, Igarashi K, et al. Demonstration of the artery of Adamkiewicz at multi-detector row helical CT. Radiology 2002;223:39–45. Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg 1997;86:483–492. Thurnher MM, Bammer R. Diffusion-weighted MR imaging (DWI) in spinal cord ischemia. Neuroradiology 2006;48:795–801. Toro G, Roman GC, Navarro-Roman L, et al. Natural history of spinal cord infarction caused by nucleus pulposus embolism. Spine 1994;19:360–366. Weidauer S, Nichtweiss M, Lanfermann H, et al. Spinal cord infarction: MR imaging and clinical features in 16 cases. Neuroradiology 2002;44:851–857.

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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. Note: Text referenced in the Quintessentials Preferred Responses, which appear later in this issue, is indicated in yellow shading throughout this chapter.

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.


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‹ 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):181–186.

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 Continuum: Lifelong Learning Neurol 2008;14(3)

93

‹ METABOLIC AND TOXIC MYELOPATHIES

and Hcy levels may be seen in other conditions ( Table 5-4). The sensitivity of the available metabolic tests has facilitated the de velopment 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 B 12 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 E–deficient 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 re verse 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 L methylmalonyl-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; CH 3 methyl group; CoA coenzyme A; SAM S-adenosylmethionine; THF tetrahydrofolate; THF1 and THF n 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):181–186.

tients with an absorption defect may respond to oral Cbl (Carmel, 2000). Long-term administration of 1000 g per day of oral vitamin B 12 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 N 2O 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 my- are HIV-infected, but the precise sigelopathy, neuropathy, myeloneuropa- nificance of this is unclear (Kieburtz et thy, and impaired cognition and mental al, 1991). The histopathology of AIDSstatus changes (Flippo and Holder, associated myelopathy resembles that 1993). MRI findings include hyperin- of subacute combined degeneration tense T2 signal in the dorsal and lateral seen in vitamin B12 deficiency. The columns, which may improve with treat- pathogenesis of many cases of AIDSment (Figure 5-3C) (Marie´ et al, 2000). associated myelopathy is possibly un A myeloneuropathy due to N 2O related to direct HIV infection of the should be considered when dealing spinal cord (Di Rocco et al, 2004). In with patients who develop neurologic AIDS-associated myelopathy, the Cblsymptoms after surgical or dental proce- and folate-dependent transmethyladures. Patients with vitamin B12 defi- tion pathway is depressed and CSF ciency are prone to developing neuro- and serum levels of S-adenosylmethilogic deterioration after N 2O anesthesia onine (SAM) are reduced. Possible (Kinsella and Green, 1995). It is prevent- benefit of administration of the SAM able by prophylactic vitamin B 12 given precursor L-methionine in AIDS-asso weeks before surgery in individuals with ciated myelopathy was suggested by a a borderline vitamin B 12 level who are pilot study but not confirmed in a subexpected to receive N2O anesthesia. IM sequent double-blind study (Di Rocco vitamin B12 should be given to patients et al, 2004). with acute N2O poisoning. AIDS-Associated Myelopathy and Cobalamin Deficiency Increased prevalence of vitamin B 12 deficiency has been recognized in patients with neurologic symptoms who

KEY POINT: 

N2O produces irreversible oxidation of the cobalt core of cobalamin and renders methylcobalamin inactive. Subacute combined degeneration due to N 2O toxicity may result from chronic exposure or after a single exposure in individuals with unsuspected cobalamin deficiency.

Folate Deficiency Methionine synthase requires folate as a cosubstrate. Despite this, for unclear reasons, neurologic complications due to folate deficiency are rare and con-

99

MRI in a patient with vitamin B 12-deficiency–related myelopathy. Sagittal ( A) and axial (B) T2-weighted cervical MRI from a patient with a myelopathy due to vitamin B 12 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.





100

A myeloneuropathy due to N 2O 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 co- folate deficiency include a myelopathy exists with other nutrient deficiencies. that resembles the syndrome of subReported neurologic manifestations of acute combined degeneration of the Continuum: Lifelong Learning Neurol 2008;14(3)

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 copper’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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

‹ METABOLIC AND TOXIC MYELOPATHIES 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 kidney disease, malignancy, smoking, common (Juhasz-Pocsine et al, 2007). diabetes, myocardial infarction, and Laboratory indicators of copper various inflammatory and infections deficiency include low serum copper diseases. Copper deficiency could or ceruloplasmin and low urinary cop- therefore be masked under these conper excretion, but these parameters ditions. Wilson disease, a disease of may not be sensitive to marginal cop- copper toxicity, also is associated with per status. Ceruloplasmin is an acute- a low serum copper. In Wilson disphase reactant, and the rise in cerulo- ease, urinary copper excretion and plasmin is probably responsible for copper content in the liver and brain the increase in serum copper seen in a are elevated. A low serum copper variety of conditions such as preg- level also can be seen in some carriers nancy, oral contraceptive use, liver or 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 M metallothionein; SOD superoxide dismutase; Zn zinc. 











copper; cyt c ox



cytochrome c oxidase;



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.


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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):1371–1384. Reprinted with permission from Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209–255. Copyright © 2007, Elsevier.

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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.


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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 in volved. 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.

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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, Ku¨ hne D, Malin JP. Spinal MRI in progressive myeloneuropathy associated with vitamin E deficiency. Neuroradiology 1996;38(suppl 1):111–113. 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

AD



autosomal dominant; AR



autosomal recessive; apoB



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

Chylomicron Retention Disease

apolipoprotein B.


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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.

more than 50,000 persons and caused optic neuropathy, sensorineural deafness, dorsolateral myelopathy, dysautonomia, bulbar dysfunction, and axonal sensory neuropathy (Romań, 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-I–associated myelopathy in Japan. HTLV-I–associated myelopathy and tropical spastic paraparesis are now believed to be identical synTropical Myeloneuropathies dromes. HTLV-II also is recognized to (Including Cuban cause a chronic myelopathy that reMyeloneuropathy) sembles tropical spastic paraparesis. The term tropical myeloneuropathies The term tropical ataxic neuropathy has been used to describe a multifac- currently is used to describe a broad torial condition seen in several de- spectrum of neurologic conditions at veloping countries. Associations tributed to a toxic-nutritional cause. It have included malnutrition, cyanide initially was used to describe a specific intoxication due to cassava con- neurologic syndrome seen in Nigeria sumption, lathyrism, organophos- and attributed to cassava consumption. phate neurotoxicity, malabsorption, and vegetarian diets (Romań et al, METABOLIC MYELOPATHIES 1985). Often the precise cause of the DUE TO POSSIBLE TOXINS BUT syndrome is unknown but possibly WITHOUT A GEOGRAPHIC has been felt to be nutritional. Disor- PREDILECTION ders that probably fall into this category include 19th century descriptions Chemotherapy-Induced of Strachan Jamaican neuropathy and Myelopathy “burning feet,” and neurologic syn- Myelopathy has been reported after dromes such as “happy feet” and Stra- administration of certain chemotherachan syndrome seen in the Far East in peutic agents ( Table 5-1), particularly World War II prisoners. From 1991 to so with intrathecal administration. 1994, an epidemic in Cuba affected Paraparesis after intrathecal chemoSubacute 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).


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.

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.

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.

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 in volvement 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 reacHepatic Myelopathy Hepatic myelopathy (portosystemic my- tion. Hypersensitivity as a possible elopathy) 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 FIGURE 5-8 MRI in a patient with chemotherapy-related myelopathy. Sagittal MRI ( A) and axial (B) T1 with increased serum manganese and with contrast MRI showing an enhancing MRI evidence of manganese deposition intramedullary cervical cord lesion ( A) (arrows), which on axial sequences shows involvement of the lateral columns in the basal ganglia without extrapyra(B) (arrows). The patient developed delayed-onset midal manifestations or clinical eviprogressive paraplegia a few weeks after intrathecal dence of decompensated cirrhosis also administration of methotrexate and cytarabine. has been reported (Gospe et al, 2000). Modified with permission from McLean DR, Clink HM, Ernst P, et al. Myelopathy after intrathecal chemotherapy: a case report with unique There is symmetric demyelination of the magnetic resonance imaging changes. Cancer 1994;73(12):3037–3040. lateral corticospinal tract and, less comCopyright © 1994, John Wiley & Sons, Inc. monly, in the ventral pyramidal tracts, Continuum: Lifelong Learning Neurol 2008;14(3)

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

110

Acute or progressive myelopathies are well-recognized complications of heroin abuse.

mechanism is suggested by the fact that, not infrequently, the myelopathy occurs after a period of abstinence followed by single use.

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).

Superficial Siderosis-Related Myelopathy Rarely, a Superficial siderosis of the CNS remyelopathy may sults from hemosiderin deposition in be the presenting the subpial layers of the brain and manifestation of spinal cord. Patients present with superficial slowly progressive gait ataxia and siderosis. A history of prior sensorineural hearing impairment. intradural surgery Additional manifestations include or trauma is anosmia, cognitive decline, and mycommon. elopathy. Rarely, a myelopathy may Organophosphate Toxicity be the presenting manifestation of Triorthocresyl phosphate is an orsuperficial siderosis. A history of ganophosphate 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. ContamiMRI in heroin myelopathy. A and B, Cord nation likely occurred when the oil was FIGURE 5-9 MRI in a patient with acute heroin transported in containers previously myelopathy. A, Axial gradient-echo image used to store mineral oils. Sensory abshows a mildly expanded cord with abnormal normalities were minimal. A distal axhyperintensity. B, Sagittal T1-weighted cord MRI with contrast shows that abnormal enhancement involves a onopathy and pyramidal tract dysfunclong segment of midthoracic cord. C and D, MRI in a tion were present. Significant patient with progressive heroin myelopathy. C , Axial T2improvement was noted over a 3-year weighted MRI of the caudal pons showing bilateral hyperintense signals in the pyramidal tract ( arrows). D, period. Axial T2-weighted cord MRI at the craniovertebral junction The signs and symptoms of acute shows bilateral hyperintense signal in the dorsal column organophosphate toxicity are due to (arrows) and lateral columns (arrowhead ). acetylcholinesterase inhibition and reReprinted with permission from McCreary M, Emerman C, Hanna J, Simon sulting muscarinic and nicotinic dysJ. Acute myelopathy following intranasal insufflation of heroin: a case report. Neurology 2000;55(2):316–317. Copyright © 2000, AAN function. Pralidoxime, a reactivator of Enterprises, Inc. inhibited acetylcholinesterase, is the Reprinted from Nyffeler T, Stabba A, Sturzenegger M. Progressive myelopathy with selective involvement of the lateral and posterior columns specific antidote. It is used in conjuncafter inhalation of heroin vapor. J Neurol 2003;250(4):496– 498. With kind tion with atropine in the acute stages. permission of Springer Science and Business Media. In some patients, after resolution of Continuum: Lifelong Learning Neurol 2008;14(3)

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. Continuum: Lifelong Learning Neurol 2008;14(3)

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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-

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FIGURE 5–11 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):323–328. Copyright © 2004, John Wiley & Sons, Inc.


sory evoked potential studies may plastic myelopathy, or myelopathy show central conduction delay. as a delayed effect of radiation need to be considered. Hereditary spastic DIFFERENTIAL DIAGNOSIS paraparesis can mimic adrenomyelo A compressive etiology should be ag- neuropathy and other leukodystrogressively sought in patients present- phies. A progressive myelopathy ing with a myelopathy. Dural arterio- also can be seen in some mitochon venous fistulas can present as a drial disorders. Vitamin E deficiency progressive myelopathy. Intramedul- can mimic hereditary ataxias such as lary tumors, progressive multiple scle- Friedreich ataxia and spinocerebellar rosis, and, rarely, transverse myelitis degeneration. The clinical presentaare included in the differential diagno- tion of the chronic form of hexsis of a metabolic myelopathy. When osaminidase A deficiency may suggest dealing with a myelopathy in the set- a possible diagnosis of spinocerebellar ting of malignancy, the possibilities of degeneration, Friedreich ataxia, or compressive myelopathy, paraneo- ALS.

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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;250:496– 498. Osuntokun BO. An ataxic neuropathy in Nigeria: a clinical, biochemical and electrophysiological study. Brain 1968;91:215–248. Parry TE. Folate responsive neuropathy. Presse Med 1994;23:131–137. Perkin GD, Murray-Lyon I. Neurology and the gastrointestinal system. J Neurol Neurosurg Psychiatry 1998;65:291–300. 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;174:863–865. Reynolds EH, Rothfeld P, Pincus JH. Neurological disease associated with folate deficiency. Br Med J 1973;2(5863):398–400. Robitaille Y, Carpenter S, Karpati G, et al. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain 1980;103:315–336. Romań GC. An epidemic in Cuba of optic neuropathy, sensorineural deafness, peripheral sensory neuropathy and dorsolateral myeloneuropathy. J Neurol Sci 1994;127:11–28. Romań GC, Spencer PS, Schoenberg BS. Tropical myeloneuropathies: the hidden endemias. Neurology 1985;35:1158–1170. Rosenblum JL, Keating JP, Prensky AL, et al. A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 1981;304:503–508. Senanayake N, Jeyaratnam J. Toxic polyneuropathy due to gingili oil contaminated with tri-cresyl phosphate affecting adolescent girls in Sri Lanka. Lancet 1981;1(8211):88–89. Senanayake N, Karalliedde L. Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome. N Engl J Med 1987;316:761–763. Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289–1298. Sokol RJ. Vitamin E deficiency and neurologic disease. Annu Rev Nutr 1988;8:351–373. Sokol RJ, Heubi JE, Iannaccone ST, et al. Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis. N Engl J Med 1984;310:1209–1212. Spencer PS, Schaumburg HH. Central-peripheral distal axonopathy. The pathology of dying-back polyneuropathies. Prog Neuropathol 1976;3:253–295. Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clin Proc 1994; 69(2):181–186. Vorgerd M, Tegenthoff M, Ku¨hne D, Malin JP. Spinal MRI in progressive myeloneuropathy associated with vitamin E deficiency. Neuroradiology 1996;38(suppl 1):111–113. Weihl CC, Lopate G. Motor neuron disease associated with copper deficiency. Muscle Nerve 2006;34:789–793.


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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. Note: Text referenced in the Quintessentials Preferred Responses, which appear later in this issue, is indicated by yellow shading throughout this chapter.

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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.

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 suTraumatic pine. Frequently, the compression will Whereas most compressive myelopa- be located in the general region of the thies occur as a result of relatively slow axial spine pain. processes, trauma is an explosive event that results in cord compression Examination within seconds. In some cases, the Before the neurologic examination, it compression will last only for a few is important that the clinician perform seconds or less. In other cases, dis- a direct examination of the spine. The placed bone fragments will continue vertebral column should be inspected, to compress the cord. palpated, and percussed over its entire extent. Special attention should be given to any spine region implicated History by the patient’s history. During inspec A complete and thorough history is tion, the clinician should check for inessential. The purpose of the history is terspinous widening, skin ulceration twofold: (1) It will help determine over the spine, or obvious deformities whether compression exists and, if so, of spinal alignment, which are all very its possible sources. (2) It will guide common in trauma. Gentle palpation the physical examination. In cases of may find point tenderness, indicating trauma, the patient or onlookers will an underlying tumor. Percussion is be able to provide details that should mainly an extension of palpation and make the cause obvious. In cases of may also disclose point tenderness. neoplastic compression, the patient The physical examination should may have a known history of cancer. encompass a complete neurologic exCases due to non-neoplastic causes amination with special attention to its present a bigger challenge. Trauma is motor, sensory, and reflex compotypically seen in young males. Older nents. Localization is based on sensory patients frequently have neoplastic or and motor findings. Sensory levels are non-neoplastic causes. quite common in traumatic and neoThe rate of progression is impor- plastic causes, and identification of tant. As a rule, the sudden, abrupt on- them is extremely useful in ordering set of myelopathy is uncommon in appropriate imaging studies. Some paneoplastic and non-neoplastic causes. tients will have diffuse sensory If the onset is acute, compressive eti- changes that are difficult to ascribe to a ologies other than trauma are unlikely. specific spinal level. The clinician Many patients will complain of the in- should attempt to differentiate motor sidious onset of gait problems. If the findings into upper and lower motor lesion is located in the cervical spine, neuron types. Findings consistent with CLINICAL APPROACH


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.

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‹ 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 T2 weighted 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 ob vious 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 Go´mez, 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 se vere 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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.

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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).

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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.


‹ COMPRESSIVE AND TRAUMATIC MYELOPATHIES

Case 6-2

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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 patient’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 cer vical 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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TABLE 6-1

Primary Primar y Tumors Tumors of the the Spine 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.

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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 oste os teop ophy hyti ticc ba bars rs.. In th the e is isch chem emic ic model, mode l, veno venous us conge congestion stion,, compr compresession of large vessels such as the anterior spinal artery, and reduced flow in the th e pi pial al pl plex exus uses es ma may y be pr pres esen entt (Baron and Young, 2007). Clinical features. Symptoms generally develop insidiously and include neck stiffness, neck and shoulder pain, clumsi clu msines nesss of the han hands, ds, num numbne bness ss and tingling in the hands, and weakness ne ss or st stif iffn fnes esss in th the e le legs gs ( Table Pati tien ents ts ma may y re repo port rt di diff ffic icul ulty ty 6-2). Pa Continuum: Lifelong Learning Neurol 2008;14(3)

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. Hype Hy perr rref efle lexi xiaa is co comm mmon on,, an and d Babins Bab inski ki sig sign, n, Hof Hoffma fmann nn sig sign, n, Lhe Lherrmitt mi tte e si sign gn,, or an ankl kle e cl clon onus us ma may y be present. Some patients may have signs and symptoms of myeloradiculopathy (mye (m yelo lopa path thic ic an and d ra radi dicu cula larr sy symp mp-toms to ms). ). Fo Forr ex exam ampl ple, e, a pa pati tien entt wi with th spondylosis at the C5-6 interspace may have absent biceps and supinator reflexes fle xes due to rad radicu icular lar com compro promis mise e and hyperactive triceps reflex due to myelop mye lopath athy. y. Wea Weakne kness ss and atr atroph ophy y also als o may be pre presen sent. t. Typ Typica ically lly,, 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 [published erratum appears in Am Fam Physician 2001;63(10):1916]. Am Fam Physician 2000;62(5):1064–1070, 2000;62(5):1064–1070, 1073. Copyright © 2000, American Academy of Family Physicians. All rights reserved.

tients pre tients presen sentt wit with h wea weakne kness ss in the intrinsic muscles of the hand, triceps, iliopsoas, and quadriceps (Chiles et al, 1999) ( Case 6-3). studie diess hav have e Management. Few stu analyzed the natural history of cervical spondy spo ndylot lotic ic mye myelop lopath athy. y. Som Some e 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 men ts in ne neuro urolog logic ic fun functi ction. on. Mor More e than 71% of patie patients nts 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 corre correlate late with multi multiple ple 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 spondyl spon dylotic otic mye myelopa lopathy thy has not bee been n shown sho wn to alte alterr the dise disease ase.. Pri Primar marily, ily, anti-inflammatories and other medicines can be used to treat the pain syndromes that may be significant in cervical spondylo dy loti ticc my myel elop opat athy hy (M (Maz azan anec ec et al al,, 2007). Some authors claim that cervical tract tr actio ion n ca can n im impro prove ve th the e ra radic dicul ular ar sy sympmptoms and axial neck pain that may be associated with myelopathy. In patients with modest modest complain complaints, ts, symptom symptomss that appear to be stable, no evidence of spinal instability, and no T2-signal change within with in the cor cord, d, non nonope operat rative ive man manageagement me nt ma may y be of offe fere red d wit with h se seri rial al fo folllow-u lo w-up p an and d sy symp mpto toma matic tic tre treat atme ment nt (Matz et al, 2007). Patients with more advanced signs and symptoms or those who hav have e dem demons onstrat trated ed pro progres gressio sion n over ov er tim time e ar are e of offe fere red d spi spina nall co cord rd de de-compre com pressio ssion. n. In pati patient entss who cho choose ose surgical treatment, anterior, posterior, or comb co mbin ined ed app appro roach aches es ma may y be us used ed.. 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 zat ion and and/or /or cor correc rection tion of ins instab tabilit ility, y, and/or correction correction of defor deformity” mity” (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 cer vical vic al lor lordos dosis, is, cer cervic vical al ins instab tabilit ility y req requiruiring fusion, and spondylolisthesis (Matz et al, 2007). Continuum: Lifelong Learning Neurol 2008;14(3)

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Case 6-3

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A 68-year-old 68-year-old woman was referred to the neurology clinic for progre progressive ssive hand weakness. Upon questioning, questio ning, she report reported ed 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 mi midl dline ine at the C3 to C7 levels. B , Intraoperative photograph after multilevel incision inci sion is cervical laminectomies. extended down do wn to th the e dors do rsal al sp spin inou ouss pr proce ocess sses es,, an and d th the e mu muscl scles es ar are e re refl flec ecte ted d la late tera rally lly to ex expo pose se th the e la lami mina nae. e. Th The e la lami mina nae e ar are e remo re move ved d us using ing dr drill ills, s, ro rong ngeu eurs rs,, an and d cu cure rett ttes es.. At th the e en end d of th the e de deco comp mpre ress ssion ion,, th the e ce cerv rvic ical al du dura ra sh shou ould ld ha have ve a pu puls lsat atil ile e mo moti tion on in co conc ncer ertt wi with th th the e he hear artb tbea eat, t, wh whic ich h us usua uall lly y co conf nfir irms ms th the e fl flow ow of CS CSF F ar arou ound nd th the e sp spin inal al Figur gure e 6-3 6-3B B). Th cord co rd (Fi This is pa pati tien entt st stay ayed ed tw two o ni nigh ghts ts in th the e ho hosp spit ital al an and d we went nt ho home me wi with th a fr fron ontt-wh whee eele led d walk wa lker er.. At 33-mo mont nth h fo follo lloww-up up,, he herr ba bala lanc nce e ha had d im impr prov oved ed to in inde depe pend nden entt am ambu bula latio tion, n, an and d fi fing nger er coor co ordin dinat atio ion n ha had d re reso solv lved ed to th the e po poin intt th that at sh she e co coul uld d dr dres esss he hers rsel elf. f.

Spinal Epidural Abscess the e pa past, st, spi spina nall Pathophysiology. In th epidural abscess accounted for approximately 1 in 20,000 hospital admissions; howe ho weve ver, r, th the e in incid ciden ence ce ha hass do doub uble led d over the past several decades for multiple rea reason sons. s. An agin aging g popu populati lation, on, increasi cre asing ng fre freque quency ncy of spin spinal al sur surgery gery,, more vascular access devices, and injection-drug use are all contributors to the Continuum: Lifelong Learning Neurol 2008;14(3)

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 ju ry,, re rena nall di dise seas ase, e, mu multi ltiple ple me medi dical cal problems, and history of spine surgery are predisposing predisposing factor factors. s. The most common mo n or orga gani nism sm is Staphylococcu Staphylococcuss aureus, followed followed by coagul coagulase-ne ase-negative gative

staphylococcus, and then gram-negative organi org anisms. sms. Tub Tuberc erculo ulosis sis is also com common mon in certain parts of the world (Pereira and Lync Ly nch, h, 20 2005 05;; Ri Riga gamo mont ntii et al al,, 19 1999 99;; Soehle and Wallenfang, 2002). Clinical features and investigations. A typical triad of symptoms on presentation is back pain, progressive neurologic deficit, and fever. Laboratory tor y ana analys lysis is rev reveal ealss a leu leukoc kocyto ytosis sis 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 myelog el ogra raph phy y is ju just st as se sens nsit itiv ive e wh when en MRI is not obtainable. Caution is ad vised, however, as the subdural and subara sub arachn chnoid oid spa space ce can be see seeded ded with org organi anisms. sms. MRI is pre prefer ferred red because it is less invasive and because the soft tissues surrounding the spinal canal also can be assessed. If a diagnosis of spinal spin al epid epidura urall absc abscess ess is ent entert ertain ained, ed, 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). The st stan anda dard rd of Management. The care ca re is ea earl rly y di diag agno nosi siss fo foll llow owed ed by emergent surgical decompression, debridement, and IV antibiotics. The diagnosis can be confirmed only by obtaining a spe peccimen for culture. Nono No nope pera rati tive ve ma mana nage geme ment nt ca can n be cons co nsid ider ered ed wh when en mi mini nima mall de defi fici cits ts,, small sma ll abs absces cesses ses,, ext exten ensiv sive e spi spinal nal in volvement, or comorbidities precluding surgery are present (Curry et al, 2005). 200 5). In mos mostt ser series ies,, pat patien ients ts wit with h comple com plete te par paraly alysis sis tha thatt alr alread eady y has been present for 24 to 48 hours have shown poor neurologic outcomes, and this may be an indication indication towar toward d nonsurgical management. If medical management is chosen, the pathogen may be det determ ermine ined d fro from m sys system temic ic blo blood od

cultures in 60% of cases. Occasionally, CT-guided needle biopsy is necessary. Evacuation of the abscess percutaneously has been reported, but this procedu ce dure re is us used ed on only ly in ra rare re ci circ rcum um-stan st ance cess (L (Lyu yu et al al,, 20 2002 02;; Ru Rust st et al 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. press ed. Magne Magnetic tic reso resonance nance– – guide guided d 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, 200 2006). 6). We pre predict dict that MRIMRI-guid guided ed 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. Traumat Traumatic ic spi spine ne injury with resultant myelopathy is the most common cause of severe disability after trauma. Spinal cord injury affects fec ts app approx roxima imatel tely y 10, 10,00 000 0 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, interrupti ru ption on of no norm rmal al sp spina inall co cord rd blo blood od 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 patient pati entss hav have e a spin spinal al col column umn and and/or /or spinal cord injury. Trauma patients must unde un dergo rgo sp spina inall im immo mobi biliz lizati ation on un until til spine injuries have been ruled out. Furtherr dis the displac placeme ement nt of spin spinal al ele elemen ments ts can exacerbate injuries and worsen outcome co mes. s. Th This is aw awar aren enes esss st star arts ts in th the e “field,” where extrication and transport are completed using spinal precautions. Continuum: Lifelong Learning Neurol 2008;14(3)

KEY POINTS: 

Improvement after surgery for cervical spondylotic myelopathy is not typical. The primary goal of surgery surge ry 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 remainss a key remain goal in public health education.

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‹ COMPRESSIVE AND TRAUMATIC MYELOPATHIES 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 ap- airway, breathing, circulation, disability plied before extrication. Then the pa- (neurologic status), and exposure/envitient is placed supine, and complete ronment. Studies have demonstrated spine precautions are instituted. Patients that the initial management of patients are rolled with maintenance of spinal with spinal cord injury is critical in optialignment and transported on flat mizing outcome. Poor oxygenation, boards. After extrication, the next step is anemia, and ischemia all correlate with to attend to the “ABCDE’s” of trauma: poorer outcomes (Case 6-4).

Case 6-4

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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 contro versial. 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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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

1

Lateral angulation 15°

1

Burst

1

B. Translational/rotational

3

C. Distraction

4

(2) Posterior ligamentous complex disrupted in tension, rotation, or translation

Description

130

Qualifier

Points

A. Intact

0

B. Suspected/indeterminate

2

C. Injured

3

(3) Neurologic status

Description

Qualifier

Nerve root involvement Cord, conus medullaris involvement

Cauda equina involvement

Points 2

Incomplete

3

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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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. Note: Text referenced in the Quintessentials Preferred Responses, which appear later in this issue, is indicated in yellow shading throughout this chapter.

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 in volve 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 C2–3 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 net work, 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)

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‹ 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 Patient history. Obtaining a hisgroup. Of these cases, 46% involved tory consistent with radiculopathy rethe C7 root, 17.6% involved the C6 quires exploring the major symptoms root, and less than 10% involved each of arm and leg pain, paresthesia, of the other levels. The cause of radic- numbness, and weakness. Pain is ulopathy was disc protrusion in 22% present in virtually all patients with and spondylosis, disc, or both in 68%. acute radiculopathy, but it is seldom of Of those, 26% subsequently under- localizing value. The diagnosis of cer went surgical treatment, but at last fol- vical radiculopathy is supported by the low-up 90% of all patients were presence of a history of radicular pain asymptomatic or only mildly affected emanating from the neck or shoulder, by their radiculopathy. with extension into the arm (sometimes in a specific dermatomal distriClinical Localization of bution). The diagnosis of lumbosacral Radiculopathy radiculopathy is supported by radicuClinicians use reference charts to cor- lar pain that begins in the back or relate specific distributions of weak- buttock with radiation into the leg or ness with the likely anatomic level of foot. The diagnosis is further supnerve root involvement. Significant ported when the symptoms are exac variation exists among the published erbated by Valsalva maneuvers reference charts. The lack of agree- (cough, sneeze, or strain), indicating ment from one myotomal chart to an- stretching of the dura at an intraspinal other relates to anatomic variations in point of compression. Radicular symphumans and differences in the nature toms in the arm may also be reported of the research material used in the with neck/head movement. Patients collection process. Anatomic charts with lumbosacral radiculopathy may have been derived by tracing root and report the presence of a self-induced peripheral nerve innervations of mus- straight-leg raising sign: radicular cles from cadaver studies. Clinical symptoms in the leg occurring when charts have been derived by correlat- sitting up straight with the legs exing the distribution of clinical muscle tended, or even when lying supine if weakness in patients with specific the symptoms are severe. In the latter traumatic lesions. EMG charts have case, relief may be reported when the been derived from patterns of muscle knees are flexed. denervation in patients with focal Paresthesia and numbness are nerve root lesions. Figures 7-2 and present less often than pain. They are 7-3 show electromyographically de- usually nonspecific and therefore of rived myotomal charts for the main little localizing value. However, these cervical and lumbar root levels (Levin symptoms are seldom present with et al, 1996; Tsao et al, 2003). nonradicular causes of neck and back pain. The Clinical Diagnosis of The presence of Lhermitte sympRadiculopathy toms (spinal or radicular tingling, The initial diagnosis of radiculopathy shocklike paresthesia with neck flexrests upon the clinical assessment, ion), supports dysfunction of the posbased on the history and physical ex- terior columns of the spinal cord, posamination. The anatomic localization sibly due to spondylotic cord can be inferred in some cases by the compression, but also potentially due neurologic examination, but the pre- to intraspinal mass lesions or incise structural cause can only be deter- tramedullary processes such as multimined by neuroimaging procedures. ple sclerosis. The presence of bowel Continuum: Lifelong Learning Neurol 2008;14(3)

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.

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‹ DISEASES OF THE NERVE ROOTS 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):1022–1025. 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 maneu vers 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 patient’s 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 examiner’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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‹ DISEASES OF THE NERVE ROOTS

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

L2–3-4

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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 in volvement. 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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

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 recumManagement of Radiculopathy bence in bed more painful, preferring Approaches to the management of ra- to be up and around, even performing diculopathy vary depending on the light work duties. acuity of illness and the degree of neuPatients with the sensory/painful rologic deficit. In general, the likeli- radicular pattern have no neurologic hood for spontaneous recovery is deficits, aside from a segmental pathigh, except in situations with severe tern of sensory dysfunction, so the neurologic impairment. For acute ra- likelihood that neuroimaging will lead diculopathy, treatment recommenda- to a consideration for surgery is very tions can be specified for the sensory/ low. painful radicular pattern, the mild For patients with acute sensory motor deficit pattern, and the marked cervical radiculopathy, treatment with motor/progressive pattern of illness. cervical traction and spinal manipulaTreatment strategies are summarized tion is not recommended in the presin Tables 7-2 to 7-4 . ence of spinal cord compression or Acute sensory/painful radicu- large disc protrusion, and should not lar pattern. The management of the be considered unless the intraspinal sensory/painful radicular pattern is not anatomy has already been defined by significantly different from the ap- neuroimaging. In the patient with proach to acute mechanical back pain, acute cervical radiculopathy due to since the likelihood of spontaneous neural foraminal stenosis from facet or resolution of all symptoms is very uncovertebral osteophytes, cervical high. Treatment includes rest for sev- traction may provide temporary relief eral days and avoidance of lifting and by modestly increasing the separation activities that increase the pain. Radic- between vertebral bodies. This therulopathy is often extremely painful. apy can be self-administered with a Continuum: Lifelong Learning Neurol 2008;14(3)

TABLE 7-2

Treatment Approaches for Acute Lumbosacral Radiculopathy (Less Than 4 Weeks)

‹ Painful/Sensory Pattern Nonsteroidal anti-inflammatory drugs 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 Nonsteroidal anti-inflammatory drugs Consideration of gabapentin, pregabalin and/or duloxetine, and tricyclics for neuropathic pain Active physical therapy Education


143

‹ DISEASES OF THE NERVE ROOTS 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 ini- chis and Strohm, 1966). With 7 sectial counterweight should not exceed onds of 30 pounds of applied traction 5 to 7 pounds but can be increased as alternating with 5 seconds of rest, tolerated to 15 or more pounds. Fif- maximal separation occurred at 25 teen- to 20-minute episodes of traction minutes, but the effect was lost within should be repeated throughout the 20 minutes of the last applied traction. day as needed. Reports indicate that, Although the efficacy of cervical tracduring cervical traction and for some tion has not been proven, it is a stanminutes after, some anterior cervical dard therapy, and many patients claim vertebral separation does occur. In benefit. If traction induces increased one study, greater separation ap- symptoms or pain, it should be disconpeared with 50 pounds than with 30 tinued. A systematic review of the litpounds of traction, but traction ap- erature could not support firm concluplied for more than 7 seconds at a time sions on the efficacy of cervical provided no further separation (Cola- traction because of methodologic inContinuum: Lifelong Learning Neurol 2008;14(3)

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 inter vention. 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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

‹ DISEASES OF THE NERVE ROOTS 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 fa voring 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 diff di ffer eren ence ce in pa pain in or de defi fici cits ts wh when en compared with placebo at 12 weeks (Cuckl (Cu ckler er et al, 198 1985). 5). A ran random domize ized d 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 evi eviden dence ce of dis discc her hernia niatio tion n (Carette et al, 1997). Six weeks after three epidural injections of either corticostero ticos teroid id or salin saline, e, patie patients nts havi having ng received corticosteroid had somewhat more improvement in leg pain, but at 3 months there was no significant differe fe renc nce e be betw twee een n th the e tw two o gr grou oups ps.. Twen Tw enty ty-f -fiv ive e pe perc rcen entt of pa pati tien ents ts in both bo th gr grou oups ps ev even entu tual ally ly we went nt on to lumbar spine surgery. With the interlaminar approach it has been shown that only 70% of cases have epidural deli de live very ry of st ster eroi oid d wi with thou outt fl fluo uoro ro-scopic guidance (Karasek, 2001). Transforaminal epidural injections have been promoted as a more selective ti ve,, an and d th ther eref efor ore e mo more re ef effe fect ctiv ive, e, treatment technique. The likelihood of ster st eroi oid d de deli live very ry at th the e ro root ot le leve vell 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 fora fo rame men. n. On One e pl plac aceb eboo-co cont ntro roll lled ed 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-t ceb o-trea reated ted pat patien ients ts ult ultima imatel tely y received surgery. Concerns raised with thiss stu thi study dy inc includ luded ed a non non-ho -homog mogeeneous patient population (disc herniation and foraminal stenosis), atypical pain scale assessment tools, and multiple surgeons makin making g opera operative tive decisions (Joelson, 2001). Epidural Epidu ral corti corticoste costeroid roid injec injections tions 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 nott be no been en we well ll co cont ntro roll lled ed an and d ha have ve lacked lac ked hom homoge ogeneo neous us stu study dy pop popula ula-tions. One study involving injections perf pe rfor orme med d at th the e C5 C5-6 -6 an and d C6 C6-7 -7 in in-terspa ter spaces ces pro produc duced ed pai pain n rel relief ief for 1 mont mo nth h or lo long nger er in 38 38% % of pa pati tien ents ts (Shulman, 1986). A retrospective study of 100 patients attempted to identify a patient profile that predicted response to cer vical epidural injection of a combination tio n of cor cortic ticost ostero eroid id and ane anesth stheti eticc (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 rad radicu icular lar pai pain n pre predic dicted ted a bet better ter outc ou tcom ome e fr from om ep epid idur ural al in inje ject ctio ion. n. Other measured predictors, including age, abno abnormal rmal senso sensory ry exami examinatio nation, n, change in muscle stretch reflexes, motor changes on examination, and abnormal EMG findings, were not found to be significant. Predictors of a poor outcome outco me inclu included ded norm normal al radio radiologic logic 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 poores poo restt pro probab babili ility ty was see seen n in patients with radicular symptoms without structural changes and in patients with nonspecific axial pain symptoms. One stu study dy des descri cribed bed a 76 76% % suc succes cesss rate for parav paraverteb ertebral ral trans transfora foraminal minal Continuum: Lifelong Learning Neurol 2008;14(3)

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

‹ DISEASES OF THE NERVE ROOTS 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). Pote Po tent ntia iall co comp mpli lica cati tion onss of ep epiidural steroid injections include spinal headache, epidural or intrathecal hematoma, transient worsening of radiculopathy, and steroid effects. While report po rted ed co comp mpli lica cati tion onss of ce cerv rvic ical al injections are rare, they can be severe, includ inc luding ing spin spinal al cor cord d and bra brains instem tem infarctio infa rction n (Rath (Rathmell mell et al, 2004 2004). ). nummSurgical managem management. ent. A nu ber 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 cei ve eit either her con conser servat vative ive tre treatm atment ent (with or without eventual surgery) or early minimal unilateral transflaval surgery ger y wit with h mag magnif nifica icatio tion n (Pe (Peul ul 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 reco re cove very ry we were re fa fast ster er fo forr th thos ose e as as-sign si gned ed to ea earl rly y su surg rger ery. y. In an anot othe herr stud st udy, y, pa pati tien ents ts wi with th lu lumb mbar ar sp spon on-dylol dy lolist isthes hesis, is, lum lumbar bar can canal al ste stenos nosis, is, and neurogenic claudication with neurologic signs were randomly assigned to conse conservati rvative ve treat treatment ment or decom decom-pressi pre ssive ve sur surger gery y wit with h spi spinal nal fus fusion ion (Wei (W eins nste tein in et al al,, 20 2007 07). ). Th This is st stud udy y demonstrated significantly greater impro pr ovem emen entt in pa pain in an and d fu func ncttio ion n 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 nerv e root– root–relat related ed sympt symptoms oms (Dey (Deyo, o, 2007). The factors that increase the likelihood that surgery will be performed Continuum: Lifelong Learning Neurol 2008;14(3)

for ce for cerv rvic ical al ra radi dicu culo lopa path thy y in incl clud ude e identi ide ntific ficati ation on of an ana anatom tomic ic les lesion ion that corresponds with the clinical picture in the presence of one or more of the following: obvious neurologic deficit ic it,, pr prog ogre ress ssio ion n of th the e de defi fici citt ov over er time, unresolved pain, and spinal cord compression on neuroimaging in the presen pre sence ce of ass associ ociate ated d mye myelop lopath athic ic neurologi neur ologicc defic deficits its (Care (Carette tte 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 patien ti ents ts wi with th ce cerv rvica icall ra radi dicu culo lopa path thy y 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, patie nts, respectively. 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 distributi distr ibutions. ons. Infec Infection tionss may invol involve ve single or multiple nerve roots. In particular, ticul ar, herpe herpess zoste zosterr infec infection tion 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, erall y, and somet sometimes imes diffusely. diffusely. The caus ca uses es ar are e di dive vers rse e an and d at ti time mess un un-clear. In general, this process affects the lum lumbos bosacr acral al seg segmen ments, ts, wit with h the cervical segments involved later or not at all all.. In som some e ne neuro urolog logic ic dis disord orders ers,,

TABLE 7-5

Differential Diagnosis of Polyradiculopathies

Polyra Pol yradic dicul ulopa opathy thy

Polyne Pol yneuro uropat pathy hy

Myelop Mye lopath athy y

Disorders with true root involvement

Arachnoiditis



Inflammatory polyneuropathy





Diabetes





HNPP





Adrenal insufficiency





Procainamide polyradiculoneurop polyradiculoneuropathy athya





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)







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 simplex virus; EBV  Epstein Barr virus.



herpes zoster virus; CMV



cytomegalovirus; cytomegalov irus; HSV

149



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. a

polyradic polyra diculo ulopat pathy hy coe coexis xists ts wit with h lesions sio ns in dis distal tal per periph iphera erall ner nerves ves,, lesions in the CNS, or both. Table 7-5

lists some causes of polyradiculopathy and disorders that fall into the differential diagnosis. Continuum: Lifelong Learning Neurol 2008;14(3)


150

Compressive Compressi ve polyr polyradicu adiculopa lopa-thies. Spondylosis of the spine is often multifocal, and multiple roots may suffer suf fer com compre pressi ssive ve dam damage age con concur cur-rent re ntly ly.. Th This is is es espe peci cial ally ly tr true ue at th the e lumbosacral level, where spondylosis causes lumbar canal stenosis and multilevel tilev el neur neurofor oforamina aminall steno stenosis. sis. With lesions from L1 to the sacrum, a large discc her dis hernia niation tion or mar marked ked con concen centri tricc 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 dif diffus fuse e spo spondy ndylos losis, is, per perhap hapss associated with congenital narrowing of the intraspinal canal or hypertrophy of the ligamentum flavum. This condition is often associated with cervical myelopath myel opathy. y. Occasi Occasionall onally y the occur occur-rence 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 infarc inf arctio tion n of lon long g tra tracts cts and ant anteri erior or 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). Othe Ot herr ca caus uses es of po poly lyra radi dicu cu-lopathy. The polyradiculopathy associated with diabetes can be among the most disabling of all the neuropathic compli com plicat cation ionss of tha thatt con condit dition ion.. 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 Shi Shield elds, s, 198 1984). 4). Dia Diabet betic ic pol polyra yra-diculopathy is usually associated with underlyin unde rlying g diabe diabetic tic polyn polyneuro europathy pathy Continuum: Lifelong Learning Neurol 2008;14(3)

(so-called diabe (so-called diabetic tic polyr polyradicu adiculone loneuuropathy), 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 conditi di tion on as di diab abet etic ic lu lumb mbar ar ra radi dicu culo lo-plexon ple xoneur europa opathy thy (Dy (Dyck ck et al, 199 1999) 9) (Case 7-2). Any process that can infiltrate or compress nerve roots or their sheaths can lead to polyradiculopathy. Infectious tio us cau causes ses inc includ lude e Lym Lyme e dis diseas ease, e, tuberculo tube rculosis, sis, syphi syphilis, lis, and funga fungall infections. Cytomegalovirus polyradiculopath lop athy y ass associ ociate ated d wit with h und underl erlyin ying g HIV inf infect ection ion pre presen sents ts as a pai painfu nful, l, rapidly rapid ly progre progressive ssive parapa paraparesis resis with urinary and rectal sphincter dysfunction ti on (E (Eid idel elbe berg rg et al al,, 19 1986 86). ). Ma Mali liggnancy produces polyradiculopathy by compression and invasion. Malignancies with a predilection for bone (myelom el oma, a, me meta tast stat atic ic br brea east st,, pro prost stat ate, e, lung lun g can cancer cer)) are esp especi eciall ally y lik likely ely to cause polyradiculopathy, myelopathy, or both, because of their tendency to spread into contiguous regions. Malignant cells may also gain entry into the intras int raspin pinal al can canal al by hem hemato atogen genous ous spread. Polyradiculoneuropathies The Th e di diag agno nosi siss of po poly lyra radi dicu culo lone neuuropathy indicates the presence of coexisting features of polyradiculopathy and periph peripheral eral polyn polyneuro europathy pathy.. The clinical clini cal prese presentati ntation on inclu includes des 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. Electr Ele ctrodi odiagn agnost ostica ically lly,, the pict picture ure is charac cha racter terize ized d by los losss of sen sensor sory y response spo nses, s, com combin bined ed wit with h fe featu atures res of moto mo torr ax axon on lo loss ss,, or de demy myel elin inat atin ing g conduction block in multiple root distributions, or both. The leading causes include inclu de acute infla inflammato mmatory ry demy demyelieli-

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 A 1c 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. Differential Diagnosis 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.

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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 patient’s 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 4–5 (U) Flexor pollicis longus (M)

SSc suprascapular nerve; MC nerve. 



musculocutaneous nerve; M

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).



median nerve; R



radial nerve; Ax



axillary nerve; U

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 di vide 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)



ulnar

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 in volving 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 di vided 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 plexuses—the 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 ( Ta ble 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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‹ DISEASES OF THE PLEXUS

TABLE 8-3 Cord

Terminal Nerve

Commonly Innervated Muscles

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 (4–5), 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 Continuum: Lifelong Learning Neurol 2008;14(3)

Sensory Distribution

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 to ward 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 in volving 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 Continuum: Lifelong Learning Neurol 2008;14(3)

161


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 in volved. 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). Continuum: Lifelong Learning Neurol 2008;14(3)

163


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 cies or radiation to the lung, chest, or Other clinical features may also help shoulder region; and recent surgical to provide a clue to disorders involv- procedures. A careful family history to ing the brachial or lumbosacral plex- assess for similar episodes in other opathies. In lesions of the lower trunk family members, which may have of the brachial plexus or those involv- been diagnosed as radiculopathies or ing the T1 root, a Horner syndrome , mononeuropathies, may provide a with ipsilateral ptosis, miosis, and an- clue to a hereditary predisposition to hidrosis may be present. This classi- plexopathies. The neuromuscular excally occurs with Pancoast tumors in amination should be comprehensive the apex of the lung, but can occur in and consist of a careful motor examiany disorder involving the lower trunk nation, noting the distribution of of the plexus. In suspected lumbosa- weakness and atrophy in limb and cral plexopathies, the presence of en- shoulder girdle muscles, any reduction larged inguinal lymph nodes or a pul- in reflexes, the distribution of sensory satile femoral mass may provide a clue loss, and the presence of other associto the etiology, such as neoplastic or ated features, such as a Horner synaneurysmal compression. drome. While a careful clinical assessment GENERAL EVALUATION OF and a high index of suspicion that the PLEXOPATHIES disease involves the plexus are often sufficient for localization, electrodiagClinical History and nostic testing is useful to confirm loExamination calization and exclude other disorders A thorough and comprehensive his- (Wilbourn, 1985). Furthermore, once a tory and neuromuscular examination plexopathy is confirmed, imaging and are important first steps in evaluating other studies are necessary to identify plexopathies. Important historical fea- the etiology. tures to be considered include the date of symptom onset; history of anteced- Electrodiagnostic Testing ent trauma, infections, or immuniza- Electrodiagnostic testing with nerve tions; history of underlying malignan- conduction studies (NCS) and needle

164

FIGURE 8-3

Sensory involvement in brachial plexopathies.


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. Continuum: Lifelong Learning Neurol 2008;14(3)

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

166



abductor pollicis brevis; ADM



abductor digiti minimi; FDI



first dorsal interosseus.

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.

(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, DISEASES OF THE BRACHIAL and individual components may be inAND LUMBOSACRAL PLEXUS volved in a nonuniform fashion. Fur A wide variety of diseases may injure thermore, in cases of severe trauma, the brachial and lumbosacral plexus simultaneous injury to the root, such Continuum: Lifelong Learning Neurol 2008;14(3)

KEY POINTS:

TABLE 8-7

Etiologies of Brachial Plexopathies

‹ Trauma Blunt, traction, penetrating “Burner” and “stinger” syndrome Rucksack palsy Postmedian sternotomy Shoulder dislocation Obstetric

‹ Ischemia Medial brachial fascial syndrome

TABLE 8-8

Etiologies of Lumbosacral Plexopathies

Thromboembolism Vasculitis

‹ Inflammatory Diabetic lumbosacral radiculoplexus neuropathy Nondiabetic lumbosacral radiculo-plexus neuropathy

‹ Neoplastic

Metastatic

‹ 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

Vasculitis

Hereditary neuralgic amyotrophy



Blunt, traction, penetrating

Primary

Idiopathic neuralgic amyotrophy

Blunt or penetrating trauma is a common cause of brachial plexus injury; concomitant injury to the roots is often present.

‹ Trauma

Thromboembolism

‹ Inflammatory



‹ Radiation ‹ Structural Retroperitoneal hematoma Aneurysm Abscess

Primary Metastatic

‹ Radiation ‹ Structural Neurogenic thoracic outlet syndrome Displaced clavicular fracture

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 as root avulsion, may occur in con- plexus that typically follows sudden, junction with injury to the plexus. Dis- forceful trauma to the shoulder, typitinguishing root avulsion from a pure cally during contact-sports activities. plexopathy can be difficult. Clinical The upper portion of the plexus is clues that point toward a suspected stretched from traction due to separaavulsion are severe weakness and sen- tion of the head and shoulder. Sympsory loss of the entire arm, bony injury toms include sudden onset of pain and to the cervical spine, evidence of spi- paresthesias in the upper and distal nal cord injury, or a Horner syndrome. arm, with a variable degree of weakOn electrodiagnostic testing, the spar- ness. The symptoms are transient, typing of the sensory nerve conduction ically lasting for several minutes, but responses in the context of severe sen- may be more prolonged. Continuum: Lifelong Learning Neurol 2008;14(3)

167


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 definite precipitating event is not iden-

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 de vices, 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 Continuum: Lifelong Learning Neurol 2008;14(3)

tified (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 aggra vated 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

some patients pain may persist for more than 6 weeks (Parsonage and TABLE 8-9 Disorders Associated With Turner, 1948). Neuralgic Muscle weakness and atrophy are Amyotrophy common and classically delayed in onset by days to weeks after the onset of ‹ Infectious Diseases pain. In most cases, weakness begins Influenza by 2 weeks after the onset of symptoms and characteristically worsens as Salmonella the pain subsides (Tsairis et al, 1972). Schistosomiasis The distribution of weakness is variMalaria able and depends on the portion of the plexus or individual nerves that are Typhus affected. Weakness is most commonly Tuberculosis in shoulder girdle muscles but may Hepatitis involve any distribution of the brachial plexus and may even be confined to a Poliomyelitis single nerve distribution in 6% to 41% Yersinia enterocolitis of patients (Tsairis et al, 1972). Isolated Parvovirus B19 involvement in the distribution of the Rheumatic fever radial, long thoracic, suprascapular, axillary, and anterior interosseus Escherichia coli sepsis branch of the median nerve has been Osteomyelitis described (Rubin, 2001). In addition, ‹ Connective-Tissue Diseases unilateral or bilateral diaphragm paral ysis due to phrenic nerve involvement Systemic lupus erythematosus may occur in isolation or in association Polyarteritis nodosa with other nerve involvement. Sensory Rheumatoid arthritis loss occurs in up to 66% of patients (Rubin, 2001; Tsairis et al, 1972). SenEhlers-Danlos syndrome sory symptoms are often overshad‹ Immunizations owed by the severe degree of pain and Tetanus toxoid weakness and may be identified only after close scrutiny during the sensory Swine flu vaccine examination. Botulinum toxin Symptomatic bilateral brachial Antiallergy injections plexus involvement occurs in up to 29% of patients and is usually asym‹ Hodgkin Disease metric (Tsairis et al, 1972). The interval ‹ Postoperative between symptoms on each side is ‹ Pregnancy usually less than 24 hours but may be ‹ Strenuous Exercise as long as several months. In some cases pain may be unilateral, with Adapted with permission from Rubin DI. Neuralgic amyotrophy: clinical fea weakness and atrophy developing bitures and diagnostic evaluation. Neulaterally, and vice versa. In addition, rologist 2001;7(6):350–356. involvement of the clinically unaffected side may be found more often on needle EMG than on clinical examdegree of pain. The pain usually per- ination. sists for several hours to several Evaluation. Electrodiagnostic test weeks before subsiding, although in ing 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

‹ DISEASES OF THE PLEXUS 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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 in volvement 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 in volvement, 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 workmen’s 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 25 year 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 in volved 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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

‹ DISEASES OF THE PLEXUS 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 se vere 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). Continuum: Lifelong Learning Neurol 2008;14(3)

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 in volvement 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). Continuum: Lifelong Learning Neurol 2008;14(3)

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 lum bosacral 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 radiculo- plexus 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.


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‹ DISEASES OF THE PLEXUS KEY POINTS:

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

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 in volved 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 in volvement, 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.

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REFERENCES Aho K, Sainio K. Late irradiation-induced lesions of the lumbosacral plexus. Neurology 1983;33(7):953–955. Dunn HG, Daube JR, Gomez MR. Heredofamilial brachial plexus neuropathy (hereditary neuralgic amyotrophy with brachial predilection) in childhood. Dev Med Child Neurol 1978;20(1):28–46. Dyck PJ, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculoplexus neuropathy: natural history, outcome and comparison with the diabetic variety. Brain 2001;124(pt 6):1197– 1207. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment. Muscle Nerve 2002; 25(4):477–491. Ferrante MA. Brachial plexopathies: classification, causes, and consequences. Muscle Nerve 2004;30(5):547–568. Franklin GM, Fulton-Kehoe D, Bradley C, Smith-Weller T. Outcome of surgery for thoracic outlet syndrome in Washington state workers’ compensation. Neurology 2000; 54(6):1252–1257. Gardiner MD, Mangwani J, Williams WW. Aneurysm of the common iliac artery presenting as a lumbosacral plexopathy. J Bone Joint Surg Br 2006;88(11):1524–1526. Gilliatt RW, Le Quesne PM, Logue V, Sumner AJ. Wasting of the hand associated with a cervical rib or band. J Neurol Neurosurg Psychiatry 1970;33(5):615–624. Harper CM Jr, Thomas JE, Cascino TL, Litchy WJ. Distinction between neoplastic and radiation-induced brachial plexopathy, with emphasis on the role of EMG. Neurology 1989;39(4):502–506. Jaeckle KA, Young DF, Foley KM. The natural history of lumbosacral plexopathy in cancer. Neurology 1985;35(1):8–15. Killer HE, Hess K. Natural history of radiation-induced brachial plexopathy compared with surgically treated patients. J Neurol 1990;237(4):247–250.

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Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology 1981;31(1):45–50. Levin KH, Wilbourn AJ, Maggiano HJ. Cervical rib and median sternotomy-related brachial plexopathies: a reassessment. Neurology 1998;50(5):1407–1413. Lumsden AB, Miller JM, Kosinski AS, et al. A prospective evaluation of surgically treated groin complications following percutaneous cardiac procedures. Am Surg 1994;60(2): 132–137. Luthra K, Shah S, Purandare N, et al. F-18 FDG PET-CT appearance of metastatic brachial plexopathy in a case of carcinoma of the breast. Clin Nucl Med 2006;31(7):432–434. Mondrup K, Olsen NK, Pfeiffer P, Rose C. Clinical and electrodiagnostic findings in breast cancer patients with radiation-induced brachial plexus neuropathy. Acta Neurol Scand 1990;81(2):153–158. Parsonage MJ, Turner JW. Neuralgic amyotrophy: the shoulder-girdle syndrome. Lancet 1948;1:973–978.


Pritchard J, Anand P, Broome J, et al. Double-blind randomized phase II study of hyperbaric oxygen in patients with radiation-induced brachial plexopathy. Radiother Oncol 2001;58(3):279–286. Rubin DI. Neuralgic amyotrophy: clinical features and diagnostic evaluation. Neurologist 2001;7(6):350–356. Seror P. Brachial plexus neoplastic lesions assessed by conduction study of medial antebrachial cutaneous nerve. Muscle Nerve 2001;24(8):1068–1070. Soto O. Radiation-induced conduction block: resolution following anticoagulant therapy. Muscle Nerve 2005;31(5):642–645. Spinner RJ, Kline DG. Surgery for peripheral nerve and brachial plexus injuries or other nerve lesions. Muscle Nerve 2000;23(5):680–695. Suarez GA, Gianninni C, Bosch EP, et al. Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis. Neurology 1996;46(2):559–561. Sunderland S. The anatomy and physiology of nerve injury. Muscle Nerve 1990;13(9): 771–784. Taylor BV, Kimmel DW, Krecke KN, Cascino TL. Magnetic resonance imaging in cancerrelated lumbosacral plexopathy. Mayo Clin Proc 1997;72(9):823–829. Tender GC, Thomas AJ, Thomas N, Kline DG. Gilliatt-Sumner hand revisited: a 25-year experience. Neurosurgery 2004;55(4):883–890. Thomas JE, Cascino TL, Earle JD. Differential diagnosis between radiation and tumor plexopathy of the pelvis. Neurology 1985;35(1):1–7. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idiopathic lumbosacral plexopathy with intravenous immunoglobulin. Muscle Nerve 1997;20(2):244–246. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus neuropathy. Report on 99 patients. Arch Neurol 1972;27(2):109–117. Tsao BE, Wilbourn AJ. The medial brachial fascial compartment syndrome following axillary arteriography. Neurology 2003;61(8):1037–1041. van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases. Brain 2006;129(pt 2):438– 450. Watts GD, O’Briant KC, Borreson TE, et al. Evidence for genetic heterogeneity in hereditary neuralgic amyotrophy. Neurology 2001;56(5):675–678. Wilbourn AJ. Electrodiagnosis of plexopathies. Neurol Clin 1985;3(3):511–529. Wouter van Es H, Engelen AM, Witkamp TD, et al. Radiation-induced brachial plexopathy: MR imaging. Skeletal Radiol 1997;26(5):284–288.


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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.

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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 patient’s husband and her parents. The neurosurgeon indicates that the patient’s 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 patient’s pain and to maximize the chances of some recovery. To the neurosurgeon’s surprise, the patient’s 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 patient’s 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 patient’s 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 we’re 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, she’d 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 surrogate’s 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 patient’s 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 patient’s 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 surrogate’s 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 patient’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

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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 patient’s 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. PROTECTING THE PATIENT FROM PSYCHOLOGICAL HARM

‹ This patient’s husband and her parents have argued that it is in the patient’s best

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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 patient’s 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 Continuum: Lifelong Learning Neurol 2008;14(3)

be able to understand the potential risks and benefits of the alternatives and be able to make a choice between the alternatives. Finally, the patient’s decision must not be coerced (Bernat, 2002). In the case described, the patient’s 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 patient’s 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 patient’s 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 patient’s life and health, but also as defending the patient’s right to make informed decisions about life-sustaining treatments for herself, which shows greater respect for her autonomy. Continuum: Lifelong Learning Neurol 2008;14(3)

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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):191–196. 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):175–176. 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.

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MULTIPLE-CHOICE QUESTIONS These items are an integral part of the issue. They are not intended as an examination but rather as a means of stimulating thought and helping you assess your general understanding of the course material. Some are designed to stimulate independent study; the comments and references provided with the preferred responses should assist in this process. For each item, select the single best response , marking it on the answer form provided inside the back cover of this issue and return your completed form to the AAN. No formal grade is assigned, as the goal is to encourage critical thinking and selfassessment. Your responses will be kept completely confidential. By returning the completed answer form to the AAN, you earn up to 10 AMA PRA Category 1 Credits™. A transcript of credits earned in will be sent to you within 2 months of receipt of your answer form. subscribers now have the option of completing the Multiple-Choice Questions online. Visit http://www.aan.com/go/elibrary/ continuum/cme to start the test for the current issue. TYPE A QUESTIONS (ONE BEST ANSWER) ‹ 1. A 50-year-old man is seen in consultation for acute low back and leg

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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 patient’s 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 column–medial lemniscal system, first-order neurons,

after bifurcating, ascend in laminated tracts, the medial fasciculus gracilis

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‹ MULTIPLE-CHOICE QUESTIONS 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 Somatosensory evoked potentials

‹ 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?

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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

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‹ MULTIPLE-CHOICE QUESTIONS ‹ 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 Nonsteroidal anti-inflammatory drugs 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

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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 mus Hand muscle cle atro atrophy phy Involvement Invol vement of spinoth spinothalamic alamic tracts Lower extrem extremity ity fascic fasciculation ulation Positi Pos itive ve Rom Romber berg g sign sign Sparing of two-poi two-point nt discri discriminati mination on

‹ 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 flu fluid id dra drainag inage e Distal Dis tal aort aortic ic perf perfusi usion on Endovascular Endovas cular techniq techniques ues Intraoperative Intraop erative somatos somatosensory ensory evoked potenti potentials als Open Op en su surge rgery ry

‹ 18. Which of the following is more common in neoplastic brachial

plexopathy than in radiation-induced brachial plexopathy? A. B. C. D. E.

Horner syn Horner syndro drome me Low sig signal nal on T2-we T2-weigh ighted ted MRI Muscle Mus cle atr atrophy ophy Myokym Myo kymic ic disc discharg harges es on on EMG Sensory nerve conduc conduction tion abnormal abnormalities ities

‹ 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 response Abnormal responsess Antece Ant ecedent dent inf infect ection ion Enhanci Enh ancing ng lesio lesions ns on brai brain n MRI Lesionss longer Lesion longer than three three vertebral vertebral segments segments on spine spine MRI Oligoc Oli goclona lonall bands bands in the spin spinal al fluid 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

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‹ MULTIPLE-CHOICE QUESTIONS is wide based and lurching. Which of the following abnormalities is likely to be found upon further investigation of this child’s problem? A. B. C. D. E.

Accumulation Accumulatio n of very very long long chain chain fatty fatty acids acids Multiv Mul tivitam itamin in ove overdos rdose e A mutati mutation on in in the frata frataxin xin gene Ragged Ragg ed red fibe fibers rs on musc muscle le biops biopsyy Undetec Und etectab table le serum serum vit vitami amin n E level levelss

‹ 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 equi Cauda equina na comp compres ressio sion n Compressive Compre ssive extram extramedullar edullaryy lesion lesion at L1 L1 Compressive Compre ssive extram extramedullar edullaryy lesion lesion at T7 Expansile Expansi le intrame intramedullary dullary lesion at C7 C7 Expansi Exp ansile le intra intramedu medulla llary ry lesi lesion on at T7

‹ 22. Which of the following treatments is associated with the best outcome

in most patients with spinal metastasis?

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A. B. C. D. E.

Radiation Radiati on ther therapy apy alo alone ne Radiation Radiati on therapy therapy alone alone or surgery alone (depend (depending ing on age) Radiation Radiati on therapy alone or surgery surgery alone alone (equivalent (equivalent results results)) Surgery Surg ery and and radia radiatio tion n therapy therapy Surge Sur gery ry al alon one e

‹ 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 Babins ki sig signs ns Losss of Los of sphi sphinct ncter er con control trol Lumbar Lum bar cana canall sten stenosi osiss Segmenta Segm entall sens sensory ory los losss Upper Upp er ext extrem remity ity wea weaknes knesss

‹ 24. A 40-year-old man comes to the emergency department (ED) 1 day after

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 an and d C4 C4 an and d C5 C5 an and d C6 C6 an and d 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 patient’s symptoms? A. B. C. D. E.

Flexed posi Flexed position tion of the lumb lumbar ar spine spine Inward Inw ard rotat rotation ion of of the knee knee with with the the hip flex flexed ed Outward rotatio rotation n of the the knee with the the hip flexed Revers Rev erse e straig straight-l ht-leg eg rais raise e Straight-leg Straigh t-leg raise (supin (supine e positi position) on)

‹ 26. Which of the following MRI findings is most specific for dural

arteriovenous fistulae of the spinal cord? A. B. C. D. E.

Blood flow–rela flow–related ted signal signal abnormalities abnormalities in subarachnoid subarachnoid space space Enhancement Enhance ment of the the cord cord on postco postcontrast ntrast T1 sequences sequences Hyperintensit Hyperi ntensityy in cord parenchy parenchyma ma on T2 sequences sequences Scalloped Scallo ped cord cord boundari boundaries es on sagitta sagittall images images Widen Wi dened ed co cord rd

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‹ MULTIPLE-CHOICE QUESTIONS ‹ 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 blo Aortic blood od flow Bony Bo ny ar artif tifac actt Intesti Int estinal nal gas patt patterns erns Patient Pati ent mov moveme ement nt Teratog Tera togeni enicc effe effects cts

‹ 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 Complet Com plete e blo blood od cou count nt Methylm Meth ylmalon alonic ic aci acid d level level Plasma Plas ma homo homocys cystei teine ne level level Serum Ser um fo fola late te lev level el

‹ 29. A 20-year-old college student comes to the physician because of

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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 Accumulatio n of long chain fatty acids Antibodies Antibo dies to aquapori aquaporin-4 n-4 water channe channell Antibo Ant ibodies dies to HIV Expanded Expande d trinucleoti trinucleotide de repeat repeat in frataxi frataxin n gene Presenc Pres ence e of of JC vir virus us in bra brain in

‹ 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.

Cervic Cerv ical al ri rib b Neoplas Neo plastic tic inf infilt iltrati ration on Obstetr Obs tetric ic trau trauma ma Open hear heartt sur surgery gery Radia Rad iati tion on in inju jury ry

‹ 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 year’s 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

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‹ MULTIPLE-CHOICE QUESTIONS ‹ 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 patient’s 25-year-old daughter is concerned about the possibility of inheriting her father’s condition; the patient’s 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.

Neuromyelitis optica Sarcoidosis Syphilis Vacuolar myelopathy Varicella-zoster virus

‹ 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.

Complete blood count Genetic testing for -tocopherol transfer protein gene mutation MRI of the cervical spine Serum vitamin B12 level 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 Retroperitoneal hematoma Spinal epidural abscess

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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.


‹ PATIENT MANAGEMENT PROBLEM

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 patient’s 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 optica–immunoglobulin G (NMO-IgG) serology F5. Visual evoked potentials F6. Spinal cord biopsy F7. Serum vitamin B 12 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). Continuum: Lifelong Learning Neurol 2008;14(3)

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.


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WEIGHTS AND COMMENTS EXPLANATION OF WEIGHTS 5 Unequivocally required for diagnosis or effective treatment, without which management ● would be negligent 3 Important for diagnosis and treatment but not immediately necessary ● 1 Potentially useful for diagnosis and treatment (routine studies fall into this category) ●

0 Neutral impact, neither clearly helpful nor harmful under given circumstances ● 1 Not harmful, but nonproductive, time-consuming, and not cost-effective ● 3 Nonproductive and potentially harmful ● 5 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.

5 ●

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.

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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 patient’s 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. Continuum: Lifelong Learning Neurol 2008;14(3)

5 ●

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 patient’s 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.

1 ●

5 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.

1 ●


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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). 5 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 2–7). 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. 1 F3. Paraneoplastic antibody panel ● Paraneoplastic myelopathy is rare but has been reported in conjunction with CRMP-5 and amphiphysin antibodies. 5 F4. Neuromyelitis optica–immunoglobulin 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. 3 F5. Visual evoked potentials ● Visual evoked potentials might detect subclinical anterior optic pathway lesions that support a diagnosis of NMO.

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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 B 12 levels are inexpensive and might be valuable in detecting coexisting disorders, including autoimmune pernicious anemia. 1 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. Devic’s 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, O’Brien 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):957–963. Wingerchuk DM, Lennon VA, Lucchinetti CF, et al. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6(9):805–815.

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PREFERRED RESPONSES Following are the preferred responses and critiques for the multiple-choice items in this issue. The questions and answer selections are repeated, and the 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 Roots”—a 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

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‹ 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 patient’s 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?

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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 column–medial 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.

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‹ 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 Somatosensory evoked potentials

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 patient’s 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?

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A. B. C. D. E.

Borrelia burgdorferi Taenia solium Treponema pallidum Varicella-zoster virus 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 vitamin B12 level 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 B 12 level is correct—a 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 patient’s 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

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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 Nonsteroidal anti-inflammatory drugs 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. ‹ 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

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

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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 basis—typically 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 child’s 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

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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 patient’s 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. ‹ 24. A 40-year-old man comes to the emergency department (ED) 1 day after

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

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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 patient’s 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 spine—L5 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 flow–related 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 flow–related 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 Complete blood count 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.

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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 patient’s 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):2245–2256. 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): 2257–2270.

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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 year’s 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?

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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 patient’s 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 patient’s 25-year-old daughter is concerned about the possibility of inheriting her father’s condition; the patient’s 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 patient’s mother in this case being the proband. Because the patient’s 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

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‹ 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.

Neuromyelitis optica Sarcoidosis Syphilis Vacuolar myelopathy Varicella-zoster virus

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?

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A. B. C. D. E.

Complete blood count Genetic testing for -tocopherol transfer protein gene mutation MRI of the cervical spine Serum vitamin B12 level 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 B 12 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 Retroperitoneal hematoma 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.

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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 information provided in this issue of should assist you in this process. This program consists of three parts:

Part 1—Baseline 1. Go to www.aan.com/go/elibrary/continuum/quintessentials to complete Part 1— Baseline Questionnaire. Alternatively, you may cut out and complete Part 1—Baseline 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 discussion in the issue and should help stimulate possible changes in your practice of patients with spinal cord, root, and plexus disorders. Part 2—Follow-up Approximately 1 month after receipt of your Part 1—Baseline Questionnaire, the AAN will send you an email reminding you to complete Part 2—Follow-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 2—Follow-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 in the issue and should help stimulate possible changes in your practice. Part 3—Feedback and Evaluation Upon receipt of your Part 2—Follow-up Questionnaire, you will immediately receive an electronic comparison report of your responses to Part 1—Baseline Questionnaire and Part 2—Follow-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. Copyright © 2008, American Academy of Neurology. All rights reserved.

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Spinal Cord, Root, And Plexus Disorders Comlete

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