The Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

C. Diseases of the Spinal Cord, Spinal Roots, and Limb Girdle Plexus

53 The Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease CAROLINE M. KLEIN AND ANNABEL K. WANG

Overview Anatomic Considerations Motor Syndromes Classification Lower Motor Neuron Disease Combined Upper and Lower Motor Neuron Disease: ALS

Sensory Syndromes Cobalamin Deficiency Sjögren’s Syndrome Combined Motor and Sensory Syndromes Cervical Spondylotic Myelopathy

Clinical assessment of peripheral neuropathy usually involves evaluation of motor, sensory, or autonomic symptoms and their distribution, typically as these symptoms affect the distal extremities. Clinicians are faced with the task of determining whether or not the patient’s symptoms are due to disease of peripheral nerve as well as the type and anatomic distribution of the nerve fibers involved in the disease process. As part of this evaluation, it is important for the clinician to realize that peripheral neuropathy may represent disease of any portion of the peripheral nerve, including not only the peripheral process innervating target tissue (muscle, sensory receptors, visceral organs, etc.) but also dorsal and ventral nerve roots and dorsal root and autonomic ganglia, as the most proximal anatomic components of peripheral nerve. All of these structures are part of peripheral nerve, which, by definition, includes all proximal and distal portions of neurons that are located outside of the central nervous system (CNS) and are associated with Schwann cells and not oligodendrocytes. Dorsal root ganglion neurons are associated

AIDS-Related Vacuolar Myelopathy Neurosyphilis Bulbospinal Muscular Atrophy (Kennedy’s Disease) Meningeal Disease

with satellite cells, but their distal processes innervating target organs and their centrally directed axons to the point of entry into the dorsal horn reside in the peripheral nervous system (PNS), and therefore are susceptible to disease processes affecting peripheral nervous tissue. Likewise, although the cell bodies of lower motor neurons reside within the spinal cord or brainstem, once their axons exit from the CNS, they are associated with Schwann cells within the ventral root and are therefore peripheral nervous tissue. There are disease processes, such as amyotrophic lateral sclerosis (ALS), that lead primarily to degeneration of the entire motor neuron (partly in the CNS and partly in the PNS), but an early change may be an accumulation of neurofilaments in axons (a change typical of some neuropathies). Proximal involvement may be expressed as distal clinical manifestations. Preganglionic autonomic nerve fibers arising from neurons within the CNS have axons lying within both the CNS and PNS. They exit the spinal cord to synapse on the postganglionic component, which is entirely PNS. 1295

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In considering the anatomic-pathologic locus of disorders with peripheral nerve manifestations, it is important to consider not only distal but also proximal levels of the neurons involved, that is, dorsal and ventral roots, dorsal root ganglion neurons, autonomic neurons, spinal nerves, plexuses, and finally the individual nerve trunks traveling to innervate target tissues in the limbs. Broadening the definition of peripheral neuropathy yields greater diagnostic possibilities in terms of consideration of many anatomicopathologic patterns such as neuronopathy, ganglionopathy, radiculoneuropathy, plexopathy, and distal polyneuropathy, among others. Ultimately, as clinicians evaluate patients presenting with distal muscle weakness or sensory or autonomic symptoms, recognition that these symptoms may be due to disease of either proximal or distal (or both) components of the neurons involved will result in better characterization of the underlying pathologic process as well as clinically better defined disease. Once the patient’s symptoms are defined anatomically in terms of level of involvement, correlation with known disease processes that affect certain levels of the neuron will result in greater diagnostic certainty and may result in more specific therapies. The objective of this chapter is to provide clinicians with an overview of pathologic processes affecting proximal portions of peripheral nerve, namely the neuronal cell bodies, roots, and proximal nerve fibers. Descriptions of these diseases are meant to provide clinicians with examples of situations in which they may need to consider what portion of the peripheral nerve is primarily involved and how to confirm that level of involvement with specific approaches or testing techniques, such as magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examination, somatosensory evoked potentials, and so on. The diseases selected for presentation in this chapter are meant to be representative but not inclusive of such considerations. Several diseases are discussed in greater detail in other chapters, to which the reader is referred for additional specific information as needed.

OVERVIEW Pathologic processes affecting peripheral nerves may be restricted to involvement of motor or sensory nerve cell bodies or their proximal or central axonal processes. Peripheral motor axons arise from the anterior horn cell located within the spinal cord or the brainstem motor nuclei, with the proximal axon found in the ventral root. Likewise, dorsal root ganglion cells, or primary sensory neurons, give rise to centrally directed and peripherally directed axonal processes. These anatomic sites of origin for peripheral nerve axons are important to consider in the pathogenesis of peripheral nerve disease, because these sites may be the location of the primary pathology

for a given condition or disease process. Determination of the site of the primary pathologic process producing neurologic symptoms in any given patient may have important clinical implications. For example, being able as a clinician to distinguish between ALS and pure motor neuropathy as a cause for progressive motor weakness in a patient is of vital importance in terms of prognosis and potentially available therapies. Likewise, primary neuronopathies may have pathologic implications for distal central or peripherally directed axons, which also need to be considered in terms of differential diagnosis and in regard to understanding the overall disease process and how it may manifest clinically and pathologically. Determination of which portions of the neuron are affected by the disease process and in what way is important to defining the stage and extent of the disease. With peripherally located, primarily distal disease of nerve processes, the chances for regeneration and repair are better than with those that are more centrally located, either in the soma, the roots, or centrally directed processes within the spinal cord. Many diseases damage the neuronal cell body as well as its central and peripheral processes in a global manner. In such situations, the clinician may not be able to limit consideration to the effects of the disease on peripherally located processes involved in isolation.188 Most disease processes that cause loss of the primary neuron, either motor or sensory, ultimately lead to secondary degeneration of the processes arising from that cell as a consequence. Whether that evolves in a proximalto-distal or distal-to-proximal sequence may depend on the underlying pathophysiology involved.179 Studies in neurotoxicology have provided useful methods to examine lesions affecting proximal versus distal neuronal processes and their implications. The reader is referred to the text by Spencer and Schaumburg180 for a detailed review of this subject. Methyl mercury and doxorubicin have selective toxicity involving dorsal root ganglion cells, but central and peripheral axons from these cells undergo degeneration as the cell bodies are lost. Distal axonopathies may involve peripherally or centrally directed distal axons. Isoniazid causes a “dying-back” toxic effect on distal peripheral sensory fibers, whereas clioquinol selectively damages the central afferent and efferent axons more than peripheral axons and results in deterioration of dorsal column and corticospinal tracts within the spinal cord preferentially. ␤,␤⬘-Iminodipropionitrile (IDPN) toxicity in animal models causes a proximal axonopathy affecting the proximal axons of anterior horn cells, with accumulation of neurofilaments and swelling thought to be due to a defect in slow axonal transport.68,188 In addition, with IDPN there is segmental demyelination and formation of onion bulbs in the distal peripheral nerve endings.74 There is progressive atrophy of the distal axon as a result of globally impaired axonal transport and secondary

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

demyelination (passive initially secondary to local edema, and later active demyelination) involving the proximal axon within the spinal cord ventral horn.68 In general, with dying-back neuropathies, whether central or peripheral, the length of the nerve fiber and its relative diameter are important factors in regard to selective vulnerability of particular parts of neurons in response to disease.188 The potential for central regenerative capacity in primary afferent nerve fibers has been studied in animal models of peripheral nerve injury. Woolf et al.199 demonstrated in a rat model of sural nerve transection in the leg that, within 1 week after injury, there was sprouting of retrogradely labeled afferent nerve fibers into lamina II of the dorsal horn of the spinal cord. Follow-up studies comparing transection versus crush injury of the sciatic nerve in the thigh, with prevention of peripheral nerve regeneration in the former and possible regeneration after injury in the latter, showed that there was sprouting of large myelinated axons into lamina II of the dorsal horn, which persisted for 6 months after injury and then disappeared by 9 months.200 These experiments suggested that, in response to peripheral nerve injury, there is A-fiber terminal reorganization in the dorsal horn by a mechanism of collateral sprouting conditioned by the injury to the peripheral sensory axon, because the sprouting centrally directed axon was not injured directly.199,200 Lamina II is normally where centrally directed unmyelinated or small myelinated afferent fibers terminate,34 so the sprouting of large myelinated fibers provides a novel input to this lamina. In these studies, the numbers of unmyelinated central afferent fibers did not differ from those of unoperated animals.200 Investigation of the differential response of centrally directed afferent fibers to different types of nerve injury has been accomplished with animal models of peripheral nerve injury. Chong et al.35 showed that sciatic nerve crush in rats resulted in an increase in growth-associated protein-43 (GAP-43) messenger RNA (mRNA) in dorsal root ganglion cells that occurred within 24 hours after injury and was maintained for 30 days postinjury. Ten days after sciatic nerve crush there was an increase in GAP-43 in the ventral horn motor neurons. However, dorsal rhizotomy produced no change in levels of GAP-43 in the dorsal root ganglion neurons or the dorsal horn of the spinal cord, even if the lesion was primed by peripheral sciatic nerve transection. Comparing dorsal rhizotomy in close proximity to the dorsal root ganglion versus a lesion made closer to the dorsal horn revealed a mild transient increase in GAP-43 in the dorsal root ganglion. GAP-43 is a marker for axonal growth in response to nerve injury.35 Thus the location of the axonal lesion in relation to the cell bodies of origin is crucial in regard to the response within the system to the injury. Coggeshall et al.39 compared sciatic nerve crush versus transection in the thigh of rats and quantified numbers of myelinated and unmyelinated axons in the L4 and L5 dorsal roots.

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These investigators found that the number of unmyelinated axons was reduced by 50% in the dorsal roots by 4 to 8 months postoperatively, without a concomitant change in the numbers of myelinated axons, suggesting that, following peripheral axotomy, the amount of unmyelinated fiber input to the dorsal horn is reduced with a shift toward greater large fiber afferent input. Interestingly, the type of peripheral nerve lesion did not affect these results.39 By comparison, ligation of dorsal roots distal to the dorsal root ganglion in the rat causes a decrease in the number of dorsal root unmyelinated axons and loss of dorsal root ganglion cells within the first few weeks, with an associated increase in the number of small and thinly myelinated fibers. By 32 weeks after ligation, the total number of dorsal root axons has recovered, but the number of dorsal root ganglion cells is less than 50% of that seen in control animals without ligation. These findings imply that there is axonal sprouting in the dorsal root, with loss of dorsal root ganglion cells secondary to peripheral nerve lesion.111 Transection of the sciatic nerve in rats compared to dorsal rhizotomy leads to an upregulation of heat shock protein 27 mRNA, a known promoter of cell survival and axonal sprouting, within the dorsal horn and dorsal columns of the spinal cord.40 This upregulation persists in the spinal cord for several months after peripheral nerve injury.40

ANATOMIC CONSIDERATIONS An understanding of the basic anatomy of the spinal cord and the relationships between motor and sensory cell bodies of origin and their central and peripheral processes is crucial in regard to an appreciation of how they may influence various pathologic processes. Motor neurons or anterior horn cells are found in lamina IX of the ventral horn of the spinal cord. The initial component of the motor axon lies within the CNS, myelinated by oligodendrocytes rather than Schwann cells, and surrounded by glia. The neurons that reside within the ventral horn consist of “root cells,” which give rise to axons that form the ventral or motor root that forms the motor component of the spinal nerve peripherally, and the “column cells,” whose peripheral processes remain within the CNS. In addition, there are internuncial neurons that form propriospinal circuits.28 There is somatotopic organization of groups of cells within the anterior horn, in that the medial nuclear group (posteromedial and anteromedial) motor neurons innervate axial musculature and the lateral nuclear group, which is subdivided into smaller subgroups as the cervical and lumbar enlargements, innervate distal extremity muscles (lateral subgroups) and proximal extremity muscles (medial subgroups). Ventral roots are composed of myelinated axons from motor neurons, including large-diameter myelinated axons from alpha

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motor neurons destined to innervate extrafusal muscle fibers and small-diameter myelinated axons arising from gamma motor neurons to innervate intrafusal fibers within muscle spindles. There are autonomic preganglionic axons also within ventral roots, originating from specific segmental levels (T1-L2 sympathetic and S2-S4 parasympathetic general visceral efferent fibers), as well as a small number of unmyelinated primary afferent axons.28 Ventral roots combine with the dorsal root from the same segmental level to form the spinal nerve distal to the dorsal root ganglion within the intervertebral foramen. Schwann cells myelinate the axons within the dorsal and ventral roots as the proximal portions of the peripheral nerve. Dorsal root ganglia are the location of the primary sensory neurons, which are unique in their morphology as pseudounipolar neurons, with a peripherally directed axon that forms the spinal nerve in combination with the ventral root fibers and a centrally directed axon that terminates in the dorsal horn of the spinal cord. The initial process from the cell body is pseudounipolar in that the initial axon is unmyelinated and then bifurcates into the central and peripheral axons.68 The dorsal sensory roots contain both myelinated and unmyelinated axons that enter the spinal cord parenchyma, with large myelinated axons entering the spinal cord and traveling within the dorsal column white matter tracts or into deeper laminae of the dorsal horn. Small myelinated and unmyelinated axons from the dorsal root terminate within laminae I and II of the dorsal horn.28 The dorsal nucleus of Clarke is located within the spinal gray matter of the thoracic and upper lumbar segments and receives input as well from dorsal root afferent fibers, and is the origin of the posterior or dorsal spinocerebellar tracts.28 Because of the anatomic discrepancy between the length of the spinal cord and the surrounding bony spinal column, there is a longer distance between sensory ganglia and spinal cord in the lumbosacral region compared to the cervical or thoracic region.172 The blood-nerve barrier to the dorsal root ganglia is relatively deficient compared to that to the anterior horn cells, making the sensory neurons and axons more vulnerable to toxic and immune attacks.188 The lateral division of the dorsal root ganglion contains small-diameter neurons, which mediate nociceptive and temperature sensations, and the medial division contains large-diameter neurons that mediate proprioception, light touch, and mechanoreception.172 The primary sensory or motor neurons may respond morphologically to injury of the peripheral axon by central chromatolysis, with rounding of the soma, decreased staining of the Nissl substance with basophilic dyes resulting in a paler staining cytoplasm, and eccentric positioning of the nucleus.82,156 The nucleolus becomes enlarged with hypertrophy of the Golgi apparatus on a subcellular level.156 These changes typically precede pyknosis as the cell body degenerates and its nuclear material becomes condensed. A primary lesion of the cell body usually leads to secondary axonal and dendritic degeneration, which would evolve in a proximal-to-

distal gradient,179 as opposed to a dying-back process of distal axonopathy. The proximal axon, including the axon hillock and initial segment as well as the first few internodes of myelinated axons, is vulnerable to proximal neuropathic lesions and may also demonstrate early morphologic changes in response to injury.68 For motor neurons, the proximal axon lies at the transition zone between the CNS and PNS, and therefore may be a critically vulnerable location for processes affecting either peripheral or central nervous tissues.

MOTOR SYNDROMES Classification In patients who present with muscle weakness and in whom a diagnosis of peripheral neuropathy is being considered, careful investigation in order to optimally localize the portions of the motor neuron involved, either proximal or distal or both, is required for accurate diagnosis. Without associated sensory symptoms or findings, one cannot exclude a primary neurogenic process affecting the anterior horn cell or its proximal axon because such a process may appear clinically indistinct from a more distal motor axonopathy. Diseases that affect the lower motor neuron or its peripheral process range from inherited diseases such as spinal muscular atrophy to ALS, which also includes involvement of the upper motor neuron, to diseases that affect primarily the ventral root (radiculopathies) or selectively motor axons within peripheral limb nerves, such as multifocal motor neuropathy with conduction block (MMN-CB). Diagnostic confusion may arise from situations in which patients present with muscle weakness in a single extremity or nerve distribution, without or with minimal sensory symptoms, so that any of these diagnoses may be possible. Certain clinical features such as a positive family history or upper motor neuron findings on examination may help to narrow the diagnostic considerations, but in many cases either the progression of the disease process or specific tests are required in order to determine one of these diagnoses in an individual patient. Even in the situation in which upper motor neuron findings are present on examination, there is a need to differentiate between ALS and cervical spondylotic myelopathy, for example, which may present very similarly. In this section of the chapter, we discuss diseases of the anterior horn cell, the ventral root, and the peripheral motor nerve that may have similar clinical manifestations and be difficult to distinguish with certainty.

Lower Motor Neuron Disease In terms of diseases that affect primarily the lower motor neuron, the primary site of pathology may be the anterior horn cell in the spinal cord or motor nuclei of cranial nerves within the brainstem. The axon of the lower motor neuron may be affected in ventral root disease or pure motor

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

neuropathies. The reader is referred to an available review of lower motor neuron syndromes for details.192 Briefly, inherited disease of the lower motor neuron includes spinal muscular atrophy and spinobulbar muscular atrophy (Kennedy’s disease), which involve genetic defects leading to premature death of lower motor neurons. There are subtypes of familial ALS that have predominantly lower motor neuron findings, specifically the A4V mutation of the superoxide dismutase 1 gene.192 Other diseases, which have unclear genetic links, include progressive spinal muscular atrophy, distal spinal muscular atrophy, segmental spinal muscular atrophy (distal and proximal forms), and monomelic amyotrophy of the lower limb.192 Acquired lower motor neuron syndromes may include poliomyelitis and postpolio syndrome, postradiation lower motor neuron syndrome, paraneoplastic motor neuron syndromes, human immunodeficiency virus (HIV)–associated motor neuron disease, West Nile virus (WNV)–associated paralysis, spondylotic myelopathy, and MMN-CB. Some of these diseases variably involve upper motor neurons, which may lead to confusion in differentiating them from ALS, for example, or from each other. Distal spinal muscular atrophy, which may be sporadic or inherited, typically affects the lower extremities with muscle wasting, weakness, and fasciculations. However, demonstration on electrodiagnostic testing of normal motor nerve conduction velocities and normal sensory nerve conduction studies may help to differentiate this disease from hereditary motor and sensory neuropathy (HMSN) type I.46 Monomelic, focal or segmental spinal muscular atrophies are sporadic, typically involve a single upper extremity clinically in terms of distal muscle wasting and weakness, and predominantly affect young male patients.46 Van den Berg-Vos et al.193 recently published a cross-sectional study of 49 patients with sporadic, adultonset lower motor neuron disease with duration of more than 4 years and found that the typical patient was male, with onset of weakness in a single, distal upper extremity. Investigation revealed that four patients had focal spinal cord atrophy on MRI, two had elevated serum titers of anti-GM1 antibodies, and three patients had serum monoclonal proteins, suggesting more specific diagnoses or associated conditions. Based on the distribution of muscle weakness, these patients could be divided into groups including slowly progressive spinal muscular atrophy affecting the lower more than the upper extremities, symmetrical distal upper and lower extremity spinal muscular atrophy, and segmental (asymmetrical) distal or proximal spinal muscular atrophy.193 Overall, these patients did not develop upper motor neuron signs after a long period of observation and had a fairly good prognosis. Distal and segmental spinal muscular atrophy involving the upper extremities in young male patients was described initially by Hirayama and co-workers in 1963.75 Their patients presented with insidious onset of distal, asymmetrical muscle weakness in the upper extremities,

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with normal or reduced reflexes and little or no sensory symptoms and no sensory findings on examination. There was chronic denervation on needle electromyography, including muscles examined in the contralateral and asymptomatic upper extremity in a subset of patients.75 Sobue et al.178 later reviewed 71 similar cases and included a potential inherited case involving an affected father and son. In this series, 47 of 71 patients had a single upper extremity affected and 24 of 71 patients had both upper extremities involved. These patients had normal nerve conduction studies and CSF protein levels, with neurogenic changes on electromyography, including neurogenic changes in the contralateral limb in a majority of patients64 and mild neurogenic changes in the lower extremities in a “small percentage.”178 These patients had more rapid progression of their lower motor neuron disease within the first 2 years after onset; then their clinical course became slowly progressive or static.178 A subset of these patients has been found to have cervical spinal cord focal atrophy or abnormal signal intensities on MRI, which has led to some controversy as to whether the pathology is based on flexion-induced cervical myelopathy with secondary ischemia.64 This disease may be differentiated from ALS by the typical young age of onset, the characteristic progression, and absence of deep tendon reflexes.64 Another group of patients who present with upper extremity muscle weakness and atrophy are those with brachial amyotrophic diplegia and those with “flail arm” syndrome. Hu et al.79 described a subset of patients diagnosed with ALS who had symmetrical, severe weakness of the upper extremities bilaterally, proximally and distally, with a male predominance. Compared to the larger group of ALS patients, these patients showed a trend toward longer survival, but most eventually did develop bulbar signs and lower extremity spasticity, suggesting that they do represent a variant of ALS.79 A more benign form of lower motor neuron disease affecting the upper extremities, without significant progression after more than 18 months of follow-up since onset, is brachial amyotrophic diplegia as described by Katz et al. in 1999.93 These patients were a small percentage of patients seen for motor neuron disease. They had normal or mildly reduced compound muscle action potential amplitudes in the upper extremities, with preserved motor conduction velocities, F-wave latencies, and no evidence of conduction block with acute or chronic denervation with needle electromyography in the upper extremities. Their weakness was proximally more than distally distributed, and 9 of 10 patients had no upper motor neuron signs, implying limited lesion of the cervical anterior horn cells.93 In comparing patients with brachial amyotrophic diplegia to those classified as having “flail arm” syndrome by Hu et al., Katz et al.93 noted that the latter group probably contained a mixture of patients with classic ALS (with upper motor neuron signs and muscle weakness in other segments in addition to the arms as their disease progressed) and patients with brachial amyotrophic diplegia.

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Similar syndromes of lower motor neuron–type muscle weakness and atrophy isolated to the lower extremities have also been described in the literature. Prabhakar et al.155 reported on 40 patients in India with unilateral, nonprogressive, mild leg weakness and atrophy without a history of polio or affected family members. Electromyography of the affected limb was abnormal, with normal nerve conduction studies and neurogenic changes found on muscle biopsy, all of which implies isolated involvement of the lower motor neuron within the spinal cord.155 Rosenfeld et al.161 noted seven patients with onset of unilateral leg weakness that eventually involved the contralateral leg who were followed clinically for up to 8 years and did not develop upper extremity, bulbar, or respiratory weakness. Whether this also represents a limited form of progressive muscular atrophy or a limited lower motor neuron disease syndrome is speculative. Distal lower extremity weakness may also be due to inherited pathologic processes involving the lower motor neuron, such as distal hereditary spinal muscular atrophy, which may appear clinically similar to HMSN types I and II, which involve the peripheral nerve. Distal spinal muscular atrophy has relative preservation of most deep tendon reflexes, limited upper extremity involvement, normal clinical sensory examination, and normal sensory nerve action potentials and motor nerve conduction velocities, all of which are in contrast to the typical findings in HMSN type I or II. However, as in HMSN, these patients may manifest foot deformities and onset in young adulthood.69 The fact that the motor nerve conduction velocities are usually normal indicates that this is a process of primary neuronal involvement, compared to a distal axonopathy, which would result in slowed conduction velocities as a result of secondary demyelination or a primary demyelinative process.69 Poliomyelitis Poliomyelitis represents an infectious etiology for selective damage to anterior horn cells, which presents as acute muscle weakness in the setting of a febrile illness.133 Poliovirus is one member of the Picornaviridae family of RNA viruses, genus Enterovirus, which causes acute myelitis and destruction of anterior horn cells.118,125 Poliovirus type 1 is the most frequent cause of epidemic paralytic illness, which is transmitted person to person. The incubation period has been estimated to be from 4 to 14 days.64,78,125 Various estimates have been published, but between 1 in 1000 and 1 in 100 patients infected with the virus develop paralytic or symptomatic disease,125 representing approximately 0.02% of those infected according to recent literature.64 Children present with diphasic illness, with an episode of nonspecific viral illness followed by acute onset of paralysis, whereas adult patients typically have a more indolent onset of paralysis in the setting of severe myalgias.64,78,125,133 Early in the course of the paralytic illness, there is nuchal rigidity and

spastic painful muscles, particularly of the paraspinal and hamstring muscle groups.23,64,118,133 Patients may have brisk deep tendon reflexes initially, with some patients having Babinski signs, but as the paralysis proceeds, deep tendon reflexes are lost.23,64,133 The early spasticity may be due to early loss of internuncial neurons affecting intraspinal circuitry before the effects of anterior horn cell loss become apparent.23 Proximal more than distal limb muscles become weakened in an asymmetrical or segmental distribution, with sparing of sensory function clinically.125 Buchthal23 proposed that the reason for proximal muscle involvement was the larger diameter motor axons innervating these muscles compared to those innervating smaller distal limb muscles. Deep tendon reflexes are lost within 12 to 24 hours after the onset of muscle weakness.78 Mortality rates have been estimated to be between 5% and 8%78 in early literature, but more recently mortality rates are 2% to 5% for children and between 15% and 30% for adult patients.64 Early in the course of the illness, CSF demonstrates increased polymorphonuclear lymphocytes and later lymphocytes and monocytes, which clear from the CSF after the first week of the illness.78,125,133 CSF protein gradually increases during the first 3 weeks after the onset of weakness.125,133 Therefore, at a certain point during the illness the CSF cell count may be relatively low in the setting of rising protein levels, leading to potential diagnostic confusion with acute or chronic inflammatory demyelinating polyradiculoneuropathies.78 Some discriminating clinical features between acute poliomyelitis and Guillain-Barré syndrome (GBS) include symmetrical muscle weakness, sensory loss, and less prominent muscle pain and stiffness in GBS.78 Electrophysiologically, sensory nerve conduction studies are normal in poliomyelitis, with reduced compound muscle action potential amplitudes and relative preservation of conduction velocities.64 The reader is referred to an available review of the electromyographic findings in patients with poliomyelitis for additional details.64 Pathologically, poliovirus enters the human body via an oral route, with shedding of virus in lymphatic tissue associated with the alimentary tract, leading to viremia with entrance of the virus across the blood-brain barrier into the CNS with subsequent infection and replication in lower motor neurons.118,140 The neurotropism of the virus is based on binding to specific neuronal receptors. Once inside the neuron, the virus replicates and releases its RNA into the cytoplasm, which leads to neuronal degeneration.118 Ohka and Nomoto,140 using a transgenic mouse animal model, provided evidence for an additional mode of entrance of the virus via fast retrograde axonal transport from muscle tissue via the human poliovirus receptor. In 1949, Bodian18 published a review of findings in 24 human autopsy cases of poliomyelitis as well as results of an experimental monkey model for the infection. In the infected

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

monkeys, the earliest changes in the ventral horn after infection with polio are central chromatolysis and localized inflammatory reaction, which later becomes more diffuse. The inflammatory response only develops where neurons are still present, and the severity of the inflammation correlates with the amount of anterior horn cell degeneration.18 Subclinical involvement of the motor precentral cortex and subcortical motor areas has been noted.18,23,118 Because in most patients there is some degree of return of motor function subacutely, it is postulated that there is reversible injury in a subset of anterior horn cells, which may recover morphologically within 1 month after infection.18 In limbs with complete paralysis and no or little recovery, less than 10% of the anterior horn cells survived in the corresponding spinal cord segment.18 Bodian18 also noted that in the autopsy specimens there were some pathologic abnormalities in the dorsal root ganglia and posterior columns at levels of the spinal cord, with the most severe damage to the ventral horn, which may explain why patients complain of localized limb pain prior to the onset of paralysis. Other investigators have noted mild inflammatory changes in the dorsal root ganglia in patients with polio.23,82 Chronically, besides loss of anterior horn cells and fibrosis of the ventral roots, there may be mild perivascular lymphocytic infiltrates and gliosis of the anterior horn.89,118 Pathology studies of spinal cords from patients with a history of poliomyelitis have shown differences between patients with stable neuromuscular symptoms and those with new, slowly progressive muscle weakness, diagnosed with postpolio progressive muscular atrophy, or “postpolio syndrome.” In both groups of patients, there was loss or atrophy of lower motor neurons in the cervical and lumbar cord enlargements in anteromedial and anterolateral cell groups, with severe reactive gliosis, but in the postpolio syndrome patients there was an additional finding of axonal spheroids and occasional chromatolytic changes,130,153 consistent with more recent neuronal deterioration, suggesting that in these patients some of the surviving motor neurons become unable to maintain cellular function over time.153 The scattered axonal spheroids are immunoreactive for neurofilament protein, as noted in a recent case report of a patient who developed newly progressive muscle weakness 30 years after his initial attack of polio.130 The surviving lower motor neurons demonstrated atrophy, lipofuscin accumulation, and decreased amounts of Nissl substance.153 The amount of chronic perivascular and parenchymal inflammation was similar in both groups.130,153 By some estimates, approximately 25% to 30% of patients will develop symptoms consistent with postpolio syndrome 20 to 30 years after their initial paralytic illness.64 West Nile Virus The first North America outbreak of WNV was recognized in 1999, when two cases of encephalitis associated

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with muscle weakness were reported to the New York City Department of Health. Ten percent of the patients in the New York outbreak had complete flaccid paralysis, and half of the hospitalized patients were reported to have severe muscle weakness.135 Initially, the patients were thought to have GBS, or acute inflammatory demyelinating polyradiculoneuropathy. Findings of lymphocytic pleocytosis (30 to 100 cells/␮L; range, 0 to 1800 cells/␮L) with normal glucose and high protein (80 to 105 mg/dL, up to 1900 mg) in the CSF and predominant axonal rather than demyelinative changes found on electrophysiologic studies made the early diagnoses of GBS unlikely.5,11,25,135 Later cases were recognized to have electrophysiologic studies consistent with a disorder of the anterior horn cells and/or their axons (i.e., a poliomyelitis-like disorder): decreased compound muscle action potential amplitudes without evidence of demyelination (normal distal latencies and conduction velocities), normal sensory nerve action potential amplitudes, and needle electromyographic findings of denervation without evidence of myopathy. Weakness was asymmetrical, often proximal, with areflexia and no or minimal sensory abnormalities.29,62,110,113,142 The pattern of weakness was often severe, leading to respiratory failure requiring mechanical ventilation, but transient weakness and severe fatigue were also reported in some cases.25,109 WNV, first identified in Uganda, is indigenous to Africa, Asia, Australia, and Europe.25 An early report of a “polio syndrome” or anterior myelitis suggested the selective involvement of motor neurons in the brainstem and spinal cord by WNV. A 22-year-old man developed a high fever with pain in his neck, back, and left leg. He developed mild left facial weakness with fasciculations and flaccid paralysis of the left lower extremity, but had preserved sensation. WNV was diagnosed by the progressive increase of complement fixation antibodies. Eighteen months later, the patient still had diminished strength and reflexes of the left leg with mild atrophy.60 Infection by WNV, a single-stranded RNA virus of the Flaviviridae family, genus Flavivirus, has been reviewed extensively.25,76,149,150,160,163 The virus is primarily transmitted to humans by mosquitoes (Culex species) from the blood of infected birds, but can also be transmitted by blood transfusion, organ donation, breast-feeding, and percutaneous inoculation in the laboratory.8,30–33,59,84,146 The incubation period ranges from 2 to 14 days. Approximately 1 in 5 infected persons will develop a mild febrile illness after infection, whereas 1 in 150, more commonly older patients, will develop neurologic symptoms including meningitis, encephalitis, meningoencephalitis, or flaccid paralysis.149 Rare cases of associated brachial plexopathy,7 rhomboencephalitis,136 areflexic quadriplegia with absent brainstem reflexes,48 rhabdomyolosis,48,85 and movement disorders (parkinsonism, tremor, and myoclonus)173 have also been reported.

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The diagnosis of WNV in patients with neurologic symptoms requires one of the following160: 1. WNV immunoglobulin M (IgM) antibody in CSF detected by enzyme-linked immunosorbent assay 2. WNV RNA in CSF 3. Fourfold increase in immunoglobulin G (IgG) antibodies between acute sera and convalescent sera obtained 4 weeks later 4. Isolation of the virus from brain or spinal cord Positive IgM and IgG antibody titers by enzyme-linked immunosorbent assay should be confirmed with more specific plaque-reduction neutralization assay in cell culture because false-positive serologic results occur as a result of the cross-reactivity between other flaviviruses, such as St. Louis encephalitis virus.25 Results may not become positive for 8 days after symptom onset but can persist for up to 500 days.149,159 IgM does not cross the blood-brain barrier, so a positive CSF IgM is diagnostic for WNV.25 A positive test result has high predictive value in the months of July to December, particularly if there is additional evidence of WNV activity in the area. A large percentage of subclinical infections, however, do occur.81,159 MRI revealed nonacute abnormalities and bilateral focal lesions in the basal ganglia, thalamus, and pons on T2- and diffusion-weighted images.173 Abnormal signal in the anterior horns has been demonstrated in the lumbar spine on MRI.113 Leptomeningeal, periventricular, isolated nerve root, and cauda equina enhancement have also been reported.96,135,173 Treatment is mainly supportive. One patient in the New York outbreak received plasmapheresis, but it was unclear if recovery was related to treatment. Administration of intravenous immunoglobulin (IVIG) for cases of presumed WNV-associated GBS has not been found to be effective to date.11,57,113,173 A multicenter study has been initiated to study the effects of IVIG in patients with suspected WNVrelated meningoencephalitis and/or weakness.160 The risk of developing severe neurologic disease, longterm morbidity, and death is higher in patients over the age of 50.100,132,135,149 Case-fatality ratios range from 4% to 14%.25,113,135 Recovery of muscle weakness is generally poor and incomplete as a result of the amount of axonal damage and is dependent on collateral sprouting. Autopsy findings in patients with meningoencephalitis revealed microglial nodules, mononuclear infiltrates, perivascular inflammation, and leptomeningitis, as well as focal mononuclear inflammation in cranial nerve roots. Inflammatory destruction of brainstem motor nuclei and anterior horn of the spinal cord along with patchy gliosis have also been reported.4,48,57,62,85,96,97,110,113,165 Inflammatory infiltrates revealed CD3⫹ lymphocytes (slight CD8 over CD4 predominance), CD68⫹ macrophages, and rare CD20⫹ B lymphocytes.97 The pathologic changes in the CNS are due to viral proliferation, cytotoxic immune

response, diffuse perivascular inflammation, and microglial nodule formation.25 Infiltrates in the dorsal roots have not been reported.48 The pathologic changes are focal and mild compared to eastern and western equine encephalitides. Vasculitis has not been demonstrated pathologically. The brainstem is frequently involved.164 Limited muscle pathology in one case of rhabdomyolysis revealed only mild focal inflammation. There was no evidence of WNV or necrosis in the muscle.48 The pathogenesis of WNV-associated weakness is not yet understood. Intracerebral inoculation of WNV in monkeys led to the development of excitement, slowness of movements, clumsiness, and ataxia. Paralysis was only seen in 5 of 15 monkeys. Lesions consisting of degenerative neuronal changes, perivascular infiltrates, changes of glia, and cell nodules were found predominantly in the cerebellum, spinal cord, and medulla oblongata but were seen scattered also throughout the brain. Neuronal degeneration consisted of either dissolution of the Nissl substance, pyknosis of the nuclei, or chromatolysis; swelling of the cytoplasm; and peripheral apposition of the pyknotic nuclei. Focal and severe meningitis was seen over the cerebellum. No characteristic changes were seen in the peripheral sensory ganglia.123 A new animal model, using the golden hamster (Mesocricetus auratus),202 has been developed. Signs consistent with meningoencephalitis (lethargy and paralysis) were reported 7 days after intraperitoneal inoculation with WNV. Pathologic findings occurred in the following sequence: infection of neurons, then inflammatory infiltrate (perivascular inflammation and microgliosis), followed by the presence of well-formed microglial nodules with degenerating neurons, consistent with apoptosis. The findings suggest that the main mechanism of neuronal damage is direct infection with WNV. The viral load determines the severity of the infection, that is, whether cells undergo necrosis or apoptosis.37 Two other studies also suggest that WNV induces cell death by apoptosis. WNV-induced apoptosis was shown to be associated with upregulation of bax gene expression.143 The WNV capsid, a pathogenic protein, was also demonstrated in vitro to induce apoptosis via the mitochondrial/caspase-9 pathway. Capsid gene injected into the striatum of mouse brain and muscle led to inflammation and cell death in tissue culture.204 Paraneoplastic Lower Motor Neuron Syndrome Lower motor neuron syndromes may manifest in patients with occult malignancy, serum monoclonal proteins, and other lymphoproliferative diseases. Presumably, in the case in which a known paraneoplastic antineuronal antibody is present, the lower motor neuron dysfunction is related to selective vulnerability of these neurons to it. Verma and co-workers194 reported a case with autopsy findings of a 51-year-old man with progressive upper more

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

than lower extremity weakness, small cell lung cancer, and high titers of anti-Hu antibodies. Nerve conduction studies were normal, but there were denervation abnormalities on needle examination,194 which implies disease of the motor neuron with relatively sparing of the peripheral motor axons.15 The patient’s CSF protein was mildly increased but cytology was negative for malignant cells. Autopsy findings included decreased numbers of cerebellar Purkinje cells, loss of large anterior horn cells, and lack of inflammation. Corticospinal and corticobulbar tracts were normal pathologically.194 Additional case reports, in patients with breast cancer, have demonstrated reversible lower motor neuron syndromes. Ferracci et al.56 reported a patient who had weakness progressing to areflexic quadriparesis in 2 months’ time, with preserved sensation and absent upper motor neuron findings. Cervical spine MRI reportedly showed T2-weighted signal hyperintensities in the gray matter. Initial electrodiagnostic testing showed normal motor and sensory nerve conduction studies, with neurogenic changes on electromyography. The patient had mild improvement after cancer treatment but no improvement with additional immunosuppressive therapy.56 The authors postulated that a partially reversible lesion of the axon initial segment or nodes of Ranvier secondary to autoimmune attack by an antineuronal antibody was present.56 A more recent case of a patient with breast cancer and lower motor neuron syndrome confirmed the presence of serum autoantibodies to isoforms of beta-IV spectrin and an unspecified surface antigen localized to axonal initial segments and nodes of Ranvier.14 In this particular patient, clinical improvement in muscle strength occurred following treatment of breast cancer with reduction of autoantibody titers.14 A similar association between lymphoma and motor neuron diseases (including MMNCB, lower motor neuron syndrome, and ALS) has been proposed by some.117,205 Parry and co-workers145 reported a patient who developed flaccid quadriplegia over a period of 4 months. After initial acral paresthesias, the patient had no significant sensory symptoms or signs. Electrophysiologically the motor nerve conduction studies showed low amplitudes, but were otherwise normal. However, acute and chronic neurogenic changes were present in all limbs on electromyography. The patient had an IgM gammopathy, with elevated CSF protein. Although he improved clinically with immunosuppressive therapy, he later died as a result of a pulmonary embolus. Postmortem examination revealed central chromatolysis in anterior horn cells with occasional axonal swellings, loss of axons in the ventral roots with focal swellings, and endoneurial lymphocytic perivascular infiltrates. Dorsal horn and roots were spared.145 This case demonstrates proximal motor axonopathy associated with monoclonal gammopathy that mimicked a lower motor neuron disease. A similar case of a patient with a progressive lower motor neuron syndrome and serum monoclonal IgM

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protein was also reported with autopsy findings demonstrating normal numbers of anterior horn cells in the lumbar cord, although some central chromatolysis was noted. The ventral roots were severely affected, with loss of nerve fibers and evidence of demyelination, which extended to a lesser degree into the proximal peripheral nerves. A primary motor radiculopathy with retrograde changes in the ventral horn was postulated in this patient.162 Postirradiation Lower Motor Neuron Syndrome A lower motor syndrome that may mimic motor neuron disease may be seen in patients who have received radiation therapy for pelvic cancer, typically testicular cancer.20,46,64 The syndrome presents as slowly progressive weakness and atrophy in distal leg muscles with reduced to absent reflexes and minimal, if any, sensory symptoms or findings, which, if present, are very distally distributed.20,64 In some patients, there may be sphincter dysfunction.20 These symptoms may develop up to 25 years after the radiation is administered.20,64 Bowen et al.20 described six patients with this presentation, and they noted that, in two of three patients who were examined with MRI of the lumbosacral spine, there was linear and focal enhancement of the cauda equina. Electromyography demonstrated denervation in L5-S1 myotomes, with normal sural sensory conduction studies. At autopsy of one of these patients, the cauda equina roots were found to be irregularly thickened with focal areas of hemorrhage, fibrosis associated with loss of axons, and changes consistent with a radiation-induced vasculopathy affecting selectively and primarily the lumbosacral nerve roots.20 HIV Infection and Motor Neuron Disease There have been isolated case reports of patients who are infected with HIV who develop motor neuron disease. Many of these cases presented with lower motor neuron syndromes, with progressive bulbar and limb weakness, preserved sensation, normal or minimally abnormal nerve conduction studies, and neurogenic changes on electromyography. 61,80,137,147,169 In some cases, treatment with antiviral medication resulted in improved motor function,137 but no improvement with treatment was reported in others.80 Description of limited postmortem examination of one of these cases demonstrated neuronal atrophy and occasional intracytoplasmic lipofuscin and central chromatolysis in brainstem motor nuclei.61 Verma et al.195 described a case of myeloradiculoneuropathy and myopathy as an initial clinical manifestation of HIV infection. Postmortem examination in that case showed preserved upper motor neurons, normal number and morphology of anterior horn cells, but capillary proliferation and hemorrhages in the anterior horn and ventral roots with depletion of ventral root axons with fibrosis.195

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Other Causes of Lower Motor Neuron Disease Amyloid neuropathy has rarely been reported to present with progressive symmetrical weakness with reduced reflexes, initially intact sensation, and normal nerve conduction studies and neurogenic changes on electromyography, all of which are suggestive of lower motor neuronopathy.158 Amyloidosis was diagnosed after fascicular nerve and muscle biopsies were performed. This patient only later developed the more common symptoms and findings of axonal sensorimotor peripheral and autonomic neuropathies.158 Lower motor neuron involvement may also appear as a prominent feature of prion disease.82,201 Worrall et al.201 reviewed 50 reported cases with various prion diseases, all of whom had amyotrophy and pathologic evidence of anterior horn cell degeneration at postmortem examination.

Combined Upper and Lower Motor Neuron Disease: ALS Patients with progressive muscular atrophy, which denotes lower motor neuron degeneration without upper motor neuron involvement, overlap clinically with patients who have ALS but who, in the early stages before upper motor neuron symptoms and signs develop, may have muscle weakness, atrophy, and fasciculations limited to a single extremity. One of the earliest pathologic studies of patients with ALS and progressive spinal muscular atrophy, by Lawyer and Netsky in 1953,107 confirmed that in the latter group of patients there was loss of anterior horn cells without degeneration of the corticospinal or pyramidal tracts within the spinal cord. Interestingly, these authors reported a single patient in their series who had a 35-year history of weakness and atrophy without upper motor neuron findings but did develop them prior to his death, with consequent pathologic evidence of demyelination of the corticospinal tracts, suggesting a form of progressive spinal muscular atrophy that may transition into ALS very late in its course, clinically and pathologically.107 In the spinal cord preparations from their patients, they also noted small perivascular lymphocytic infiltrates “in some cases” localized primarily to the gray matter of the cord, which they ascribed to a reaction to the primary change in the motor neurons in the spinal cord, which showed decreased amounts of chromatin, pyknosis, shrinkage, and axonal changes.107 Other investigators have noted lymphocytic infiltrates in the ventral horns and pyramidal tracts of the spinal cords in a percentage of patients with ALS.189 More recently, Ince et al.83 reviewed autopsies from patients with premorbid diagnoses of progressive muscular atrophy (10 patients) and ALS (63 patients), and 6 patients who seemed to have evolved clinically from the former to the latter, in addition to control patients without a history of neurologic disease. Of note, the progressive muscular atrophy patients had rapid clinical progression to death in less

than 2 years, presenting with upper extremity or bulbar weakness eventually also involving the lower extremities. Approximately 50% of the progressive muscular atrophy patients demonstrated pathologic changes in the corticospinal tracts, with more than a third with moderate or severe pathologic changes.83 More than 95% of patients in the study had ubiquitinated cytoplasmic inclusions within the lower motor neurons.83 Almost 90% of the patients clinically diagnosed with ALS had moderate to severe pathologic changes in the corticospinal tracts. With progressive upper extremity weakness without upper motor neuron signs, these patients may look very similar to patients with multifocal motor neuropathy, when, in fact, they are really a subgroup of progressive muscular atrophy that overlaps with ALS.83 Interestingly, in terms of the differences reported regarding pathologic correlates in the transitional form of progressive muscular atrophy, one finding was that 30% of those patients had pathologic abnormalities in the dorsal columns of the spinal cord (in addition to the ventral horn pathology), whereas only 8% of the progressive muscular atrophy and almost 50% of the ALS patients had abnormalities in the dorsal columns.83 Troost et al.189 examined the spinal cords of 48 ALS patients and reported that there were pathologic abnormalities in 85%. Brownell et al.22 examined pathologically the spinal cords of 36 classic ALS patients and 8 patients with possible progressive muscular atrophy and found that there was loss of lower motor neurons in the anterior horns and cranial motor nuclei without changes in the posterior columns or spinocerebellar tracts, with sparing of Clarke’s column. In the ALS patients, the degeneration of the corticospinal tracts was more severe at lower cord levels and was difficult to detect proximal to the level of the brainstem unless there was severe motor neuronal degeneration in the spinal cord.22 More extensive pathologic involvement of the central motor pathways, such as the thalamus, mammillary bodies, basal ganglia, substantia nigra, and subthalamic nucleus, was noted in a patient with ALS, although this patient also had supranuclear ophthalmoplegia as a result of astrocytosis in the superior colliculi and periaqueductal gray matter, raising the question of an alternative disease process.186 Even within the diagnostic realm of ALS, there are groups of patients who have primarily lower motor neuron involvement both clinically and pathologically. Familial ALS patients with the A4V mutation in superoxide dismutase 1, the most common mutation, have short disease durations but predominantly lower motor neuron findings.41 Cudkowicz et al.41 performed postmortem examinations of patients with this condition and compared their results to those in patients with sporadic ALS. Both groups of patients demonstrated severe loss of anterior horn cells with gliosis and intracytoplasmic inclusions in remaining anterior horn cells. However, the sporadic cases had severe abnormalities in the corticospinal tracts, in contrast to the familial cases. In this study, demyelination and gliosis in

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

the posterior columns, Clarke’s column, and the dorsal spinocerebellar tracts was more common in familial ALS but was noted in patients from both groups.41 Details of the typical pathologic findings in ALS and related motor neuron syndromes may provide important clues as to the features of the neurons that provide a substrate for these various disease processes. Hirano73 provided an early review of these features, which include spheroids, or focal accumulation of filaments with resulting focal enlargement of the neuronal process, and Bunina bodies, which are small, eosinophilic inclusions of dense granular material of unknown significance (Fig. 53–1). In comparing findings of ALS in human spinal cord with those of animals exposed to IDPN, they both have accumulations of filaments within axons, but the anterior horn cells in the animals do not demonstrate chromatolysis, nor do the animals have clinical weakness.73 The central chromatolysis that is seen in postmortem tissue in ALS patients resembles postaxotomy changes but differs in the presence of spheroids, argentophilic soma, and accumulations of filaments within the cytoplasm of the cell body, suggesting significant disruption of axonal flow within the neuron.73,122 Based on this comparison with the animal model, there is a pathologic process beyond axonal transport dysfunction that leads to the characteristic changes within the neurons in ALS. Extensive pathologic examinations of CNS tissue affected by ALS have shown that abnormalities in the process of phosphorylation of neurofilaments may lead to greater accumulation of the filaments within the cell bodies and proximal axons of lower motor neurons in ALS patients compared to age-matched controls.122 Spheroids have been found to be immunoreactive for monoclonal antibodies for phosphorylated neurofilaments.122,176 In ALS patients there is an absence of nonphosphorylated neurofilaments in the ventral roots as compared to control

FIGURE 53–1 Chromatolytic anterior horn cells and axonal spheroids in a case of amyotrophic lateral sclerosis. (Bielschowsky stain; ⫻550.) (From Hirano, A.: Aspects of the ultrastructure of amyotrophic lateral sclerosis. Adv. Neurol. 36:75, 1982, with permission.)

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roots, with an equivalent amount of phosphorylated neurofilaments in both groups.122 More recently, investigators have co-localized superoxide dismutase-1 and nitric oxide synthase to the accumulated neurofilaments in surviving upper and lower motor neurons in patients with ALS.36 It may be that peroxynitrite formation at the neurofilament light chain may lead to inhibition of phosphorylation of neurofilaments and eventually alter axonal transport, resulting in proximal accumulation of neurofilaments and ultimately motor neuron cell death.36 Additional pathologic findings in the anterior horn cells of patients with motor neuron disease include descriptions of Lewy body–like, eosinophilic cytoplasmic inclusions reported in patients with lower motor neuron syndromes,91,92 which were found in addition to spheroids, Bunina bodies, chromatolysis, and gliosis in the anterior horns. These Lewy body–like inclusions are immunoreactive for ubiquitin but do not contain neurofilaments.92 There is one report of similar findings in a patient with ALS.103 Other investigators have examined the synaptic alterations that occur in ALS. Sasaki and Maruyama168 found no difference in the amount and distribution of immunostaining for synaptophysin, a presynaptic vesicle membrane protein, in the ventral horns of patients with ALS compared to those with lower motor neuron disease only. With mild loss of anterior horn cells in either disease, there was decreased staining in the lateral or ventrolateral anterior horn neuropil. Synaptophysin immunostaining was preserved in the proximal dendrites and around the cell bodies of normalappearing anterior horn cells and reduced around the cell bodies and distal portion of proximal dendrites of degenerating or atrophic neurons.168 This decreased staining, presumably reflecting loss of synaptic inputs, was similar in both diseases, indicating that those inputs are not originating from upper motor neurons, which are only involved by definition in ALS.168 Matsumoto et al.126 confirmed these findings and also noted that, in the ventral horns of four patients with pyramidal tract transection resulting from focal spinal cord lesions, the neuropil synaptophysin immunoreactivity was not different from controls, also indicating that the lack of upper motor neuron input is not the cause for the altered staining in motor neuron disease patients. A subsequent ultrastructural analysis of the axon hillocks and initial segments of axons of normal-appearing anterior horn cells in patients with ALS, patients with lower motor neuron disease, and age-matched controls showed that in both disease states the mean number of synapses and mean length of synaptic contacts at the axon hillock are reduced. The mean cell body area was also reduced in ALS and lower motor neuron disease compared to controls.167 Morphometric analysis of the distribution of cell loss in the anterior horn in ALS has revealed that the amount of cell loss at a particular segment of the spinal cord is variable, with the anterolateral quadrants of the ventral horn being most affected. Variation in severity and distribution of cell

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loss may occur between the two sides of the spinal cord at the same level.184 Based on serial section analysis of the lower cervical cord in patients with ALS, there appear to be zones of focal neuronal loss within the spinal cord, including subgroups of the ventral horn and Clarke’s column.184 Various hypotheses regarding the possible pathogenesis of ALS have been proposed based on the available pathologic data. Karpati et al.90 proposed that the vulnerable neurons contained bundles of neurofilaments in their dendrites that become progressively depleted, with associated dendritic atrophy and loss of afferent input into the soma leading to atrophy. Based on this theory, the neurofilaments accumulate in the soma and axon as a result of impaired transport of those neurofilaments into the dendrites. These authors proposed further that the early clinical manifestations of fasciculations and cramping were secondary to dendritic atrophy, which altered the balance of synaptic inputs to the motor neuron and motor unit.90 Others proposed that in ALS the earliest lesion was not in the lower motor neuron but resulted from loss of the upper motor neurons located in the precentral gyrus, which leads to secondary degeneration of the anterior horn cell in an anterograde fashion.53 This theory would eliminate an etiologic connection between ALS and progressive spinal muscular atrophy, despite their close similarities pathologically. The reader is referred to a recent review of potential mechanisms for cell death in motor neuron disease by Martin et al.124 Involvement of components of the nervous system beyond the upper and lower motor neurons in ALS has also been described in the literature. Wakabayashi et al.198 published a case report of a 57-year-old Japanese man who initially complained of patchy sensory symptoms but who progressed to have motor weakness and elevated CSF protein, who did not improve despite immunosuppressive therapies. Autopsy findings revealed loss of Betz cells in the motor cortex, degeneration of corticospinal and spinocerebellar tracts, severe loss of anterior horn cells with gliosis with surviving neurons containing Bunina bodies and bundles of ubiquitin-positive filaments, loss of neurons in Clarke’s column, and severe degeneration of posterior columns and dorsal root ganglion cells.198 Morphometric analysis of motor neurons, ventral root axons, dorsal root ganglion cells, and dorsal root axons in ALS patients compared to controls demonstrated loss of large motor and sensory neurons and their axons.94 Serial sensory studies have shown mild but progressive abnormalities in ALS patients compared to control patients, suggesting a more generalized neurodegenerative process.66 This may also include autonomic fibers, demonstrated by abnormalities in sympathetic skin responses in ALS patients44 and pathologic cell loss in the intermediolateral cell column.198 These studies raise the question of more widespread pathologic involvement in some patients with ALS, although the abnormalities may

be subclinical, and the possibility that the underlying pathophysiology is one of multiple system neurodegeneration within the CNS. Peripheral Motor Neuron Disease: MMN-CB Pure motor neuropathy, presenting with muscle atrophy, weakness, fasciculations, and reduced or absent deep tendon reflexes, is an important diagnosis to differentiate clinically from an inherited or sporadic segmental spinal muscular atrophy or early lower motor neuron variants of ALS or progressive muscular atrophy.46 Without sensory abnormalities, however, it can be difficult to determine if the pathology resides at the level of the lower motor neuron, the ventral root, or the peripheral motor nerve.205 MMN-CB is one type of peripheral motor neuropathy that is immune mediated and may respond to certain immunemodulating therapies.13,102,148 One study described clinical evaluations of 74 patients who presented with asymmetrical weakness, without sensory, upper motor neuron, or bulbar symptoms or findings. Twenty-five of these patients had multifocal conduction block on nerve conduction studies; the remaining patients had primarily diffuse axonal changes, with only a small number with slowed conduction velocities only.148 Of the patients with conduction block, those with distal more than proximal muscle weakness were more likely to have high serum titers of anti-GM1 antibodies, compared to those patients with proximal-predominant weakness, who were more likely to have serum antibodies to nonsialated carbohydrate epitopes of the neuronal glycolipids.148 Patients with MMN-CB are typically adult males with asymmetrical distal upper extremity weakness with minimal fasciculations clinically.46 Electrodiagnostic studies in patients with MMN-CB typically demonstrate proximal conduction block of compound muscle action potentials with associated slowing of the segmental conduction velocity across the region of block, and sparing of the sensory nerve action potential along this segment of the nerve.19,87,102,144,187 Conduction block should be demonstrated outside of sites of common compression if possible.19,87 Prolonged distal motor and F-wave latencies may also be present.46,102,191 One clinical clue to the possible presence of conduction block is weakness in a muscle with normal bulk.102 Electrodiagnostic abnormalities are more often found in nerves innervating weak muscles, but in one study, a third of the abnormal findings involved nerves innervating clinically normal muscles.191 Electromyography may demonstrate minimal fibrillation potentials but high-amplitude, polyphasic motor unit potentials with reduced recruitment in affected muscles.19,144 Compared to more centralized lower motor neuron lesions, this disorder is a peripheral nerve disease restricted to the peripheral motor axons and their myelin in particular. In evaluation of patients with lower motor neuron–type weakness, those with electrophysiologic abnormalities consistent

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

with motor axonal changes are more difficult to distinguish from those with ALS as pure motor axonal neuropathies, because both diseases may appear very similar in terms of the lower motor neuron involvement. In such patients, especially those without bulbar or signs of upper motor neuron involvement clinically, motor nerve fascicular biopsy or a therapeutic trial of immune-modulating therapy may be indicated to provide improved diagnostic accuracy.102 Early in ALS, motor nerve conduction studies may be relatively normal, although commonly there are abnormalities on needle examination in clinically normal muscles.19 Kornberg and Pestronk102 suggested that anti-GM1 antibody titers (IgM) greater than 1:6000 have the greatest specificity for MMN-CB, although such titers only occur in a third or less of patients with this disease.46 Anti-GM1 antibody titers (IgG) greater than 1:1000 are more likely seen in chronic, asymmetrical distal axonal motor neuropathies.102 Within the diagnostic possibilities in patients with MMN-CB is chronic inflammatory demyelinating polyradiculoneuropathy, which may also demonstrate conduction block and slowed conduction velocities; however, abnormal sensory nerve conduction studies, elevated CSF protein, and typically symmetrical motor weakness should aid in distinguishing these diseases in any given patient.102,144 Pathophysiologically, conduction block is believed to be due to focal demyelination or blockage of sodium channels in the axonal membrane. Persistent conduction block, as may occur in MMN-CB, has been postulated to be due to inhibition of remyelination of the affected nerve segment or of redistribution of sodium channels, thereby preventing restoration of the conduction of action potentials across the involved segment.86 Theoretically this is in part due to the presence of antiglycolipid antibodies, such as anti-GM1. There is also some evidence based on MRI evaluation of affected peripheral nerves that shows focal nerve enlargement and contrast dye enhancement at the site of the conduction block, implying a disruption of the bloodnerve barrier at this site, which may allow for exposure of the nerve to these serum antibodies.86 Neuropathologic examination of peripheral nerve at sites of conduction block demonstrated demyelination, poor remyelination, and onion bulb formation in the study by Kaji et al.,87 which examined a single nerve biopsy done distal to an area of focal enlargement from a single patient with MMN-CB. In contrast, a more recent study by Taylor et al.187 of fascicular biopsies done at the site of intraoperatively determined conduction block in seven patients with chronic disease showed multifocal loss of myelinated fibers, degenerating axons, altered size distribution, and rarely small perivascular lymphocytic infiltrates without evidence of significant demyelination or onion bulb formation. These findings imply that there is some degree of axonal involvement, possibly resulting from an immunemediated attack at the axolemma at the node of Ranvier,

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especially in areas of persistent conduction block.187 The fact that sensory nerve fibers are relatively spared from conduction block in these patients may be related to differences in ceramide composition between sensory and motor nerve fibers.138

SENSORY SYNDROMES Sensory loss, paresthesias, or pain in the hands and feet, along with symptoms of ataxia, are all suggestive for peripheral neuropathy but can also be seen in posterior column dysfunction associated with cobalamin deficiency and Sjögren’s syndrome.

Cobalamin Deficiency The most common neurologic symptoms are tingling and numbness.58,71 Other symptoms include generalized weakness, stiffness, deadness, tightness, feelings of cold or heat, formication, and shooting pains. Symptoms generally are symmetrical and begin in the lower extremities and progress proximally in all four limbs. Less common symptoms include vague aches and pains, girdle sensations, calf cramping, bowel or bladder disturbances, orthostatic hypotension, and changes in smell, vision, or taste or a roaring sensation in the ears. Depression, psychosis, and dementia can also occur.16,71,128,196 Symptoms progress to development of unsteady gait and awkwardness of limbs, leading to ataxic paraplegia with spasticity and contracture. Severe pseudoathetosis of the limbs has also been reported as a presenting symptom.17 Examination may reveal distal symmetrical sensory loss and absent tendon reflexes, consistent with peripheral dysfunction, or may reveal spasticity, extensor plantar responses, hyperreflexia, and segmental sensory loss, consistent with central dysfunction or myelopathy.71,82,196 Peripheral neuropathy and myelopathy can occur alone or concomitantly. Isolated hand involvement is suggestive of myelopathy.71,166,196 Examination can be normal or suggestive of small fiber dysfunction.71,166 Centrocecal scotomas have also been demonstrated in some patients.196 The peripheral neuropathy associated with cobalamin, or vitamin B12, is extensively reviewed in Chapter 89. Cobalamin deficiency is most commonly caused by pernicious anemia but can be caused by gastrointestinal malabsorption, nitrous oxide exposure, or inborn errors of metabolism.58,65,129,174,183 The lack of cobalamin leads to the accumulation of homocysteine and methylmalonic acid, with the development of megaloblastic anemia as a result of the decreased production of purines and pyrimidine and/or abnormal myelination of nerve fibers of the CNS and PNS. Neurologic symptoms can occur in the absence of any hematologic changes.26,27,82 The inability to absorb cobalamin leads to a subacute degeneration of the posterior

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columns followed by the lateral columns of the spinal cord, hence the name “subacute combined degeneration.”2,82 It is estimated that 80% of patients with pernicious anemia have neurologic symptoms,196 and 8% of patients with polyneuropathy are estimated to have cobalamin deficiency.166 Subclinical cobalamin deficiency is thought to be 10 times more common than clinically evident cobalamin deficiency.27 Diagnosis of cobalamin deficiency as the cause of polyneuropathy can be difficult because, despite normal cobalamin levels, patients can still present with peripheral neuropathy.128 In one study, 12 of 27 patients (44%) with polyneuropathy had normal cobalamin but elevated serum metabolic levels.166 Asymptomatic patients have been found to have electrophysiologic abnormalities; a small proportion of these patients eventually will develop overt clinical manifestations.27 Nerve conduction studies have been reported to be mixed (axonal and demyelinating)71 or primarily axonal.128,166 Somatosensory evoked potentials can be abnormal, consistent with lesions in the spinal cord.166 In peripheral nerves, myelin loss without axonal loss has been described.196 Sural nerve biopsies have revealed axonal degeneration, with reduction of both large and small myelinated as well as unmyelinated fibers. No intrinsic abnormalities of myelin or Schwann cells have been reported.128 Focal spinal cord lesions have been found in cobalamin deficiency, although normal cervical and thoracic MRIs have also been described.12,58,116,157 Hyperintense signal seen in the posterior columns of the spinal cord in T2weighted MRI sequences are thought to be secondary to demyelination, wallerian degeneration, and gliosis. If resolution of these hyperintense signals occurs after treatment, demyelination is thought to be the underlying process. Abnormalities have also been seen with normal cobalamin levels.116 The significance of enhancement with gadolinium is unclear but possibly related to differences in vascularity or an increase in the permeability of the blood–spinal cord barrier.12 Mild spinal cord swellings on fluid-attenuated inversion recovery MRI sequences have also been described.157 Atrophy is a late change. Spinal cord pathology has revealed spongy degeneration primarily in the dorsal and lateral columns of the cervical and thoracic spinal cord. Swelling and ballooning of myelin sheaths, formation of intramyelinic vacuoles, and separation of myelin lamellae have been reported with degenerative changes of axis cylinder and myelin sheaths. Phagocytosis by macrophages, reactive astrocytosis, and fibrosis are also reported. Spinothalamic tracts and corticospinal tracts may be involved.12,65,196 Animal models do not replicate human disease, but lesions indistinguishable from subacute combined degeneration have been noted in the absence of hematologic changes in the monkey, fruit bat, and pig.26,65,129,174 Nutritional cobalamin deprivation of monkeys leads to spastic paralysis of hind limbs with separation and vacuolation

of myelin lamellae, with complete destruction of myelin sheaths in 33 to 45 months. Repeated exposure to nitrous oxide leads to neuropathy by 9 to 12 weeks and ataxia by 15 weeks. Spinal cord pathology reveals degeneration of myelin sheaths and axis cylinders in posterior columns with accumulation of lipid-laden macrophages. Nine months of cobalamin deprivation in fruit bats leads to the inability to fly, ataxia, spastic paresis, and death. With additional exposure to nitrous oxide, neuropathy occurs within 9 weeks. In the pig, repeated exposure to nitrous oxide leads to neuropathy in 9 weeks. Studies also suggest that a defect in the methylcobalamin-dependent methionine synthetase reaction is important in neurologic complications because administration of methionine can delay the onset of neuropathy in experimental cobalamin deficiency. Neuropathy has not been induced in the rabbit, mouse, or rat.

Sjögren’s Syndrome Inflammatory sensory polyganglionopathy67,105,106,121,131,177 (also reviewed in Chapter 103), such as may occur with Sjögren’s syndrome, can be mistaken for sensory axonal polyneuropathy when the initial symptoms are distal sensory loss.105 Thorough neurologic examination, however, should reveal asymmetrical or multifocal sensory loss, with or without loss of sensation over the trunk or face, which would suggest proximal sensory impairment, as with a sensory ganglionopathy.105,106 Symptoms such as light-headedness and Raynaud’s phenomenon can also be elicited. Abnormal pupillary responses, pseudoathetosis, ataxic hands and gait, loss of vibration and joint position sense, and positive Romberg’s sign may also be demonstrated on examination. Early ataxia is thought to be due to loss of afferent signals from proximal muscle spindles and joints.106 Kinesthesia and proprioceptive sensation seem to be relatively more affected than pain and temperature sensations.67 Reflexes are absent or diminished but strength is usually normal.106 A small percentage of patients have been reported to present with pain, paresthesias, and clumsiness of a single hand,106 which would seem to represent a mononeuropathy or radiculopathy clinically. Both the peripheral and central afferent axons may be damaged as a result of primary degeneration of dorsal root ganglion neurons,105 which is reflected by absent or reduced sensory responses with preserved sensory nerve conduction velocities in a non–length-dependent pattern of peripheral axonal degeneration on electrophysiologic testing,106 and by absent or abnormal somatosensory evoked potentials, reflecting pathology of the centrally directed afferent processes.105 Griffin et al.67 reported one patient who initially had normal sensory nerve action potentials 3 days after the abrupt onset of ataxia, but 6 weeks later with repeat examination all of his sensory responses were unobtainable.

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

A percentage of patients with sensory ganglionopathy caused by Sjögren’s syndrome have autonomic dysfunction.67,105,106 Cardiovascular autonomic failure, as well as abnormalities in heart rate and Valsalva maneuver, have been demonstrated with laboratory testing.67 Neurologic symptoms in Sjögren’s syndrome are typically thought to be due to sensory and autonomic neuronopathies. There is a range in the severity of large fiber myelinated fiber loss seen on nerve biopsies, although a relative preservation of unmyelinated fibers is seen. Collections of perivascular inflammatory infiltrates can be present.67,177 Involvement of short axons in the face and trunk, along with generally poor recovery, were all considered to be consistent with involvement of the sensory ganglia.177 Lymphocytic infiltration (T cell) of the dorsal root ganglia, with neuronal degeneration and loss of fibers in the dorsal roots, has previously been found on pathologic examination67,121 (Fig. 53–2). These findings are consistent with a

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length-independent sensory neuropathy with pathologic involvement of the primary sensory neuron. Satake and co-workers170 noted that incubation of the serum and CSF from a patient with Sjögren’s syndrome and sensory ganglionopathy with rat dorsal root ganglia revealed positive immunoreactivity in small neuronal cell bodies, which seemed to be specific because peripheral nerve and cerebellum did not react. These findings are suggestive of an autoimmune ganglionitis in Sjögren’s syndrome with an “anti–dorsal root ganglion neuron antibody.”170 Dorsal column abnormalities seen on cervical spine MRIs correlated with sensory symptoms in 14 patients with primary Sjögren’s syndrome and sensory neuronopathy.131 Twelve presented with paresthesias of the hands (nine patients) and feet (three patients), initially unilateral, before the diagnosis of Sjögren’s syndrome was made. Two presented with numbness in the face. Sensory nerve conduction studies revealed axonal loss, and abnormal median

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FIGURE 53–2 Thoracic dorsal root ganglia in Sjögren’s syndrome. A, Loss of neurons and clusters of mononuclear cells. (Cryostat section stained with hematoxylin-eosin; ⫻330 before 2% reduction.) B, Subsequent section from the same biopsy as A, immunostained for T cells and photographed in dark field; immunostained cells appear white, often with a dark spot in the center representing the cell nucleus (examples identified by arrows). Two neurons are labeled N1 and N2. Note the cluster of T cells and scattered individual T cells (arrowheads). Note also the degenerating neuronal cell body on the left (N1). (⫻330 before 2% reduction.) C, Numerous clusters of mononuclear cells and reduced number of neurons. (Paraffin section stained with hematoxylin-eosin; ⫻110 before 2% reduction.) D, Neuron (N) surrounded by intense mononuclear infiltrates. (Paraffin section stained with hematoxylin-eosin; ⫻210 before 2% reduction.) (From Griffin, J. W., Cornblath, D. R., Alexander, E., et al.: Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjogren’s syndrome. Ann. Neurol. 27:304, 1990, with permission.)

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somatosensory potentials suggested central pathology. High-intensity areas in T2-weighted images seen in the posterior columns of cervical MRIs, which represented degeneration of central sensory projections secondary to dorsal root ganglion damage, have been reported to occur in these patients105,106,131 (Fig. 53–3). Involvement of both cuneatus and gracilis fasciculi was seen in patients with extensive sensory deficits in the face, trunk, and upper and lower extremities. Sensory ataxia was severe, and a high frequency of autonomic abnormalities was present: pupillary dysfunction, vomiting, orthostatic hypotension, and

decreased uptake on 123I-meta-iodobenzylguanidine cardiac accumulation. High signal seen only in the gracilis fasciculus correlated with only partial sensory deficits in upper and lower limbs and mild to moderate sensory ataxia. Mild sensory deficits only were present in patients who did not have abnormal signal on their MRIs.

COMBINED MOTOR AND SENSORY SYNDROMES Cervical spondylotic myelopathy and acquired immunodeficiency syndrome (AIDS)–related vacuolar myelopathy can affect both motor and sensory pathways; however, the symptoms can be mistaken for peripheral neuropathy, and the findings of upper motor neuron dysfunction can be masked by superimposed disease such as peripheral neuropathy. Syphilis, “the great imitator,” can present with purely motor, sensory, or mixed features. Bulbospinal muscular atrophy, although primarily considered a lower motor neuron syndrome, is characterized by significant pathologic involvement of the sensory nerves.

Cervical Spondylotic Myelopathy

FIGURE 53–3 Axial T2-weighted gradient echo magnetic resonance imaging scans (repetition time, 500 ms; echo time, 9 ms; flip angle, 20 degrees) of cervical spinal cord (C4 level) in Sjögren’s syndrome. A, Normal appearance of posterior column white matter and anterior and posterior horns. B, Arrowhead shows diffuse highintensity signal in the posterior column in a patient with idiopathic sensory ganglionopathy. (From Lauria, G., Pareyson, D., Grisoli, M., and Sghirlanzoni, A.: Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies. Ann. Neurol. 47:104, 2000, with permission.)

Cervical spondylosis is often present but asymptomatic by the age of 60. If nerve roots or spinal cord are affected, symptoms of radiculopathy, cervical myelopathy, or a combination of the two may develop.21 Cervical spondylotic myelopathy refers to myelopathy associated with degenerative spine disease (e.g., cervical spondylosis), and the term often includes ossification of the posterior longitudinal ligament (OPLL). The progression of spondylosis to myelopathy is thought be uncommon and occurs in a slow and stepwise fashion.108,171 OPLL is rare among whites but is a significant cause of myelopathy in older Japanese adults. The onset of OPLL is usually insidious, beginning in the fifth decade. Patients are asymptomatic or develop symptoms similar to cervical spondylotic myelopathy.88 One of the earliest symptoms reported is difficulty walking in the dark, which occurs because compensatory visual cues are lost. Symptoms of paresthesia, dysesthesia, and sometimes pain in the toes, which can be mistaken for peripheral neuropathy, are predominant.50 Symptoms can evolve slowly with ascending sensory loss, followed by the development of a spastic paraparesis. The classic picture of cervical spondylotic myelopathy is that of a spastic tetraparesis, walking disturbance, loss of sensation, tingling in the hands, and difficulty performing fine manual tasks.82,139 Atrophy of intrinsic hand muscles may be present. Bladder, bowel, and sexual dysfunctions are late findings. Neck pain is usually not prominent unless superimposed radiculopathy is present. Other vague symptoms include headache, dizziness, and disturbances of equilibrium. Lhermitte’s sign has also been reported.50

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

Patients with atrophic upper extremity muscles and spastic and weak lower limbs have been mistakenly diagnosed with motor neuron disease.112 The increased reflexes and spasticity, however, can be masked by secondary disorders such as peripheral neuropathy, radiculopathy, and anterior horn cell disease. The degree of deep tendon reflex abnormalities depends on degree of anterior horn cell involvement. Other disorders that can be mistaken for cervical spondylotic myelopathy include multiple sclerosis (MS), ALS, polyradiculitis (GBS), Lyme disease (borreliosis), and syringomyelia.38,50 It has been suggested that up to 17% of cases attributed to cervical spondylotic myelopathy actually had another disease process such as ALS or MS.38 Spondylotic radiculopathy may be confused clinically with ALS because both may have prominent lower motor neuron signs, especially early in the course of ALS, before upper motor neuron or bulbar signs develop. Rarely, spondylotic radiculopathy may present with weakness, fasciculations, reduced reflexes, and absence of sensory changes, with improvement following decompressive cervical spine surgery.49 A subset of patients is thought to have a slightly different syndrome called “amyotrophic type of myelopathy hand.”52 They present with insidious wasting and weakness of intrinsic hand muscles, which can be unilateral or asymmetrical (Fig. 53–4). There is mild or no sensory disturbance, which is disproportionate to motor dysfunction. Posterior cervical, shoulder, or radicular pain is generally not reported by patients. Deep tendon reflexes may be normal or increased in the lower extremities, with down-going toes with plantar stimulation. There is typically no associated gait disturbance.52 These patients can be misdiagnosed with median

FIGURE 53–4 Typical amyotrophic type of myelopathy hand in cervical spondylotic myelopathy (CSM). (From Ebara, S., Yonenobu, K., Fujiwara, K., et al.: Myelopathy hand characterized by muscle wasting: a different type of myelopathy hand in patients with cervical spondylosis. Spine 13:785, 1988, with permission.)

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and ulnar entrapment neuropathies, ALS, or polyneuropathy. They generally have multisegmental spondylosis involving the C5-C6 and C6-C7 spinal segments, with narrowing of the anteroposterior diameter of the lower cervical spine to less than 13 mm, with improvement in their symptoms following cervical spine surgery.52 These patients can be differentiated from patients with ALS by absence of bulbar signs, no involvement of clinically normal muscles on electromyography, and correlation of spinal structural changes with their arm weakness.52 Cervical spondylosis may also simulate lower motor neuron disease or progressive spinal muscular atrophy with painless, progressive muscle weakness and fasciculations, normal to slightly brisk deep tendon reflexes, absence of sensory findings, and down-going toes.115 Dissociated motor and sensory symptoms in patients with cervical spondylosis may occur with selective compression of the ventral more than the dorsal nerve roots within the spinal canal.95 Chronic cervical myelopathy with age-related degenerative changes has previously been reviewed.21,38,50,112,171 By the fourth decade, 30% of asymptomatic individuals can have degenerative changes in the intervertebral discs. By the seventh decade, 90% have degenerative changes. The spinal cord diameter ranges between 8.5 and 11.5 mm, and the cervical spine canal ranges in diameter from 16 to 18 mm. The mechanism of cervical myelopathy is thought to be secondary to a slow progressive compression with minor but repetitive trauma and can be multifactorial in origin: disc degeneration with annulus bulging leads to osteophyte formation, which can lead to spinal cord and nerve root compression; and spondylotic transverse bars, hypertrophic facets, and hypertrophic ligamentum flavum can lead to spinal canal diameter narrowing (with and without movement), and differences in cord sensitivity to hypoxia. OPLL originates in the rostral cervical canal and extends caudally.50,171 A spinal canal anteroposterior diameter of less than 12 mm is associated with myelopathy, particularly in patients with congenital canal stenosis.139 Patients are symptomatic when the cross-sectional area of the cord is reduced by one third. Alteration of blood supply to the spinal cord may also be a factor. Intramedullary vessels may be more vulnerable than the larger extramedullary vessels to intermittent ischemia as a result of distortion and compression of the anterior spinal artery.82,115 Ischemic compression of the anterior spinal artery at upper and midcervical spinal levels with resulting ischemic changes in the lower cervical cord has been found in patients with midcervical spine subluxations associated with rheumatoid arthritis.127 Acute trauma exacerbates any of the above-mentioned conditions.21,139 Long-standing cord compression resulting from spondylosis has been found to result in wallerian degeneration of the posterior columns and lateral corticospinal tracts.139 Plain radiographs are helpful in revealing cervical stenosis. T2-weighted images reveal spinal cord abnormalities on MRI171,197 (Fig. 53–5). Electromyography may reveal

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FIGURE 53–5 T2-weighted magnetic resonance imaging in cervical spondylotic myelopathy. A, Sagittal image showing cord compression at the midvertebral body level as well as at the vertebral end plate level from C4 to C6. B–E, Transverse or axial images showing an isointense-signal hypertrophy of the posterior longitudinal ligament (wide arrow) as well as a low- to isointense-signal herniated intervertebral disc (small arrow) and osteophyte (large arrow) compressing the spinal cord, with a high-intensity signal in the anterior horns with left-side predominance (asterisk). (From Mizuno, J., Nakagawa, H., and Hashizume, Y.: Cervical amyotrophy caused by hypertrophy of the posterior longitudinal ligament. Spinal Cord 40:484, 2002, with permission.)

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

denervation and confirm the presence of radiculopathy but does not help in prognosis. Somatosensory evoked potentials can help differentiation between cervical myelopathy and anterior horn cell disease.50 In the early stages of myelopathy, changes of demyelination, rather than axonal damage and gray matter infarction, are seen.171 Spinal cords of patients with cervical myelopathy may be flattened and distorted with demyelination in the lateral columns and corticospinal tracts. In more severe cases, myelin destruction, axonal loss in white matter, and mild chromatolysis and neuronal loss in gray matter occur.203 Gliosis has been reported in areas of injury with damage in the posterior root entry zones.171 Sparing of anterior columns can occur because the proximal branches of the anterior spinal artery are shorter and subjected to less obliterative stress. Distal ramifications of the anterior spinal artery are thought to be most affected, and ischemia occurs as a result of the slow metabolic exchange.120 The underlying pathology of the amyotrophic type of myelopathy hand is attributed to segmental necrosis of the anterior horn cells resulting from the reduced transectional area of C7, C8, or T1.50,52,119 Autopsy cases revealed two patterns in OPLL: boomerang and triangular.88 The boomerang pattern (convex lateral surfaces and concave anterior surfaces) was restricted to gray matter, with relative preservation of white matter even with severe compression. In the triangular pattern (angular lateral surfaces and flat anterior surface), pathologic changes were seen in both white and gray matter but sparing the anterior columns. Pathologic changes were seen over more than one segment and in both descending degeneration of the lateral pyramidal tracts and ascending degeneration of the posterior columns, including the fasciculus gracilis. A triangleshaped spinal cord with transverse area of less than 60% of normal in more than one segment appears to be associated with severe and irreversible pathologic changes. The mechanisms of chronic mechanical compression have been described in an animal model of chronic cervical cord compression.203 The tiptoe-walking Yoshimura mouse develops spontaneous calcified deposits posterior to the C1-C2 vertebrae leading to compression and paresis by 4 to 8 months of age. Evaluation of 6-month-old mice revealed reduction of neurons in the gray matter, and degeneration of anterior, lateral, and posterior columns was observed; this was most severe at the level of compression. Apoptosis of both neurons and oligodendrocytes was identified using terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL) staining and immunostaining with caspase-3. Similar changes were identified in postmortem cervical cord from a patient with cervical myelopathy caused by OPLL. Apoptosis has been recognized to play an important role in the morbidity of cervical spondylotic myelopathy, and studies are underway to understand the molecular pathways governing apoptosis.99

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Diseases of the lumbar spine may also present with symptoms and signs of myelopathy. Kleopa et al.101 recently described four patients with progressive asymmetrical leg weakness with fasciculations, muscle cramps, and variable deep tendon reflexes, with only one of the four showing extensor plantar responses. Later in the course, these patients reported distal sensory symptoms of asymmetrical burning and tingling paresthesias in their feet. MRI of the spine revealed stenosis of the lower thoracic spine with compressive lumbar myelopathy with symptoms and findings restricted to the anterior horn cells, presumably resulting from spinal artery compression and anterior cord ischemia.101 There have also been rare reports of progressive lower motor neuron syndromes developing in the lower extremities years after an episode of lumbosacral transverse myelitis.134

AIDS-Related Vacuolar Myelopathy The prevalence of peripheral neuropathies in HIV infection (reviewed in Chapter 94) is estimated to be as high as 36%, despite the introduction of highly active antiretroviral therapy (HAART). In the pre-HAART era, autopsy studies estimated the prevalence of AIDS-associated vacuolar myelopathy to be between 22% and 55%.10,42,151 Myelopathic signs were not obvious in patients with pathologically mild disease or in patients with concurrent peripheral neuropathy, so the diagnosis in early reports was made post mortem. An early symptom may be erectile dysfunction, followed by a slowly progressive spastic paraparesis with loss of vibration and joint position sensations with urinary frequency and incontinence.45 AIDS-related vacuolar myelopathy has been reported to improve on a HAART regimen, especially when diagnosed early in the disease course.181 AIDS-related vacuolar myelopathy was first identified in an autopsy series in which 20 of 89 consecutive patients were found to have spongiform degeneration,151 usually of the middle and lower thoracic regions, with patchy or confluent vacuoles and intravacuolar macrophages. Cervical spinal cords were not evaluated in this initial study. These changes were later demonstrated in cervical regions but less frequently in the lumbar spine.10 HIV type 1 was isolated from macrophages in affected patients.10,151 Clinical symptoms and signs of myelopathy were noted in patients with marked pathologic changes, whereas patients with mild changes often did not have upper motor neuron signs or weakness. Myelopathy was graded in severity on a scale from I to III: grade I had infrequent myelopathic signs, grade II had symptoms similar to grade III but less frequently, and grade III was found to be associated with a steadily progressive spastic-ataxic paraparesis with urinary incontinence. Other diseases and coexisting infections that potentially could confuse the clinical picture include syphilis, low folic acid, megaloblasts in bone marrow,

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Karposi’s sarcoma, and infection with Pneumocystis carinii, Candida albicans, Mycobacterium avium-intracellulare, herpes simplex virus, cytomegalovirus, Giardia lamblia, Cryptosporidium, Salmonella, and Shigella. The diagnosis of myelopathy in HIV is difficult because of the high prevalence of both peripheral neuropathy and dementia in the late stages of HIV disease.42,151 In a retrospective case-control study of AIDS patients,42 100 of 215 autopsies (47%) in which the spinal cords were evaluated were found to have vacuolar myelopathy. Cases were defined as having autopsy evidence of vacuolar myelopathy, whereas controls did not. Myelopathy was defined as upper motor neuron signs (spasticity, hyperreflexia, pyramidal weakness, and upgoing toes) in the lower extremities out of proportion to findings in the upper extremities, and sensory neuropathy was defined as distal sensory symptoms (numbness, tingling, or pain) with distal loss of pain, temperature, or vibration sensation with reduced or absent ankle reflexes. Fifty-six of 100 patients with vacuolar myelopathy had been examined 3 months prior to death, and only 15 (27%) were found to have symptoms and signs of myelopathy, most commonly spastic paraparesis with a coexistent distal peripheral neuropathy. The most severe symptoms were spasticity and sensory ataxia because severe weakness and incontinence were late findings. Only two patients were noted to have a sensory level and only one had bowel and bladder incontinence. Symptoms were present from 3 to 16 weeks before diagnosis. Only four patients had thoracic MRIs, and all were normal. Patients with vacuolar myelopathy also had a higher frequency of distal sensory neuropathy (14 of 56) compared to controls (3 of 48). Patients with both myelopathy and neuropathy were more symptomatic because of combination of the two diseases. Only two patients developed symptomatic myelopathy before developing an AIDSdefining illness. Patients with vacuolar myelopathy were older and had M. avium-intracellulare and P. carinii pneumonia, likely markers of immunosuppression, because no direct evidence of either was found in spinal cords,42 suggesting that myelopathy occurs with more advanced HIV disease (i.e., after onset of AIDS). Correlation with CD4⫹ cell counts was not available. Based on this study, the diagnosis of myelopathy appeared to confer a poorer prognosis, because 13 of the 15 cases had survival times of less than 9 months. As discussed earlier, clinical diagnosis of AIDS-related vacuolar myelopathy is difficult. MRI findings are nonspecific: atrophy and diffusely increased intrinsic cord signal, which do not correlate with clinical deficits.34 A study of 69 patients, 35 with clinical evidence for myelopathy (leg stiffness, heaviness, cramps, numbness, subjective bladder dysfunction, and objective lower extremity weakness, upper motor neuron findings, or urinary incontinence) and 34 without myelopathy, who had

somatosensory evoked potential studies was undertaken to determine if evoked potentials could be useful for early diagnosis.185 Eighty-three percent of patients were found to have peripheral neuropathy (lower extremity paresthesias and pain, muscle cramps, and weakness, with distal muscle atrophy, sensory loss, or reflex loss), and 33% had both neuropathy and myelopathy. Concomitant disorders such as syphilis, toxoplasmosis, human T-cell lymphoma, and cobalamin deficiency had been excluded in these patients. Abnormalities of tibial, and not median, central conduction times were shown to correlate with the clinical diagnosis of myelopathy. Similar evoked potential findings had previously been reported in 23 patients with AIDS.72 There was no significant correlation with CD4 counts. The lack of abnormalities in the median central conduction times suggested a predilection for the thoracolumbar spinal cord in these patients. The derived spinal conduction time was found to be a more sensitive marker of spinal cord dysfunction in patients with normal tibial central conduction times and who also did not have objective signs of myelopathy. Myelopathy was defined pathologically as vacuolation in spinal white matter with lipid-laden macrophages.151 Vacuoles were most extensive in the middle to lower thoracic levels, more in the lateral than the posterior columns. The findings were often symmetrical in mild cases but asymmetrical in moderate to severe cases. Thin myelin sheaths surrounded the vacuoles, occasionally in continuity with the sheaths of a normally myelinated axon. Axons were disrupted only in areas of severe vacuolation. Wallerian degeneration was seen in some of the lateral corticospinal tracts. Reactive astrocytosis was rare, and there was no inflammation, organisms, or intranuclear viral inclusions. Few patients had central chromatolysis of anterior horn motor cells. The pathology of vacuolar myelopathy is not dying-back or wallerian-type degeneration but more similar to subacute combined degeneration caused by vitamin B12 or folate deficiency. Spinal roots and ganglia were noted to be unremarkable.10,63,151 A small number of cases have stained positive for anti–p24 HIV core protein.10 An association between vacuolar myelopathy and HIV encephalitis152 suggests that the presence of encephalitis may have an indirect effect on the spinal cord. A correlation between HIV DNA in the spinal cord and vacuolar myelopathy has not been demonstrated.

Neurosyphilis Neurosyphilis is a spectrum of disorders that can be divided into early and late stages.54,77,141,175 Early neurosyphilis includes asymptomatic neurosyphilis and meningovascular syphilis. Asymptomatic neurosyphilis refers to CSF pleocytosis or positive serology in the absence of symptoms or signs. Meningovascular syphilis refers to progressive vascular insufficiency leading to

Peripheral Nerve Involvement of Spinal Cord, Spinal Roots, and Meningeal Disease

infarction years after infection. Late or parenchymatous neurosyphilis includes general paresis; the progressive, chronic and dementing process; and tabes dorsalis. Late neurosyphilis occurs after decades of infection. Historically, 4% to 9% of patients with untreated syphilis developed symptomatic neurosyphilis.77 Neurosyphilis mimicking peripheral nerve disorders can be better understood by reviewing spinal cord pathology. Pure spinal involvement in syphilis is rare. In a series of 2231 syphilitic cases recorded at Boston City Hospital,1 only 31 cases (i.e., ⬍1% of all cases) were reported to have pure spinal involvement. A historical classification of spinal syphilis based on spinal cord pathology1 is discussed later: meningomyelitis, syphilitic spinal thrombosis, syphilitic amyotrophy, and syphilitic spinal pachymeningitis (tabes dorsalis). Mental status changes and cranial nerve involvement can occur during any stage of syphilitic infection. Recent use of electrophysiology and neuroimaging in the diagnosis of neurosyphilis is also discussed. The onset of syphilitic meningomyelitis is insidious.1,77,141 The presenting symptoms are weakness or paresthesias, with sphincter disturbances occurring less frequently. Sensory symptoms include numbness, coldness, and tingling. Vibration and joint position senses are impaired. Tone and reflexes are increased. In a case report of subacute meningomyelitis,98 the cervical cord was shown to be swollen, with diffuse high signal on T2-weighted images with gadolinium enhancement on MRI. The enhancing parenchymal lesions, which were relatively reduced on T1-weighted images, were described as having a “candle guttering appearance with flip-flop sign.” The abnormal enhancement in the superficial regions of the spinal cord under the pia mater suggested that neurosyphilis invaded the spinal cord from its surface. Pathologic changes of meningomyelitis are the result of infiltration of leptomeninges by lymphocytes and plasma cells,1 leading potentially to occlusive arteritis with secondary spinal cord ischemia or infarction.82 Persistence of inflammation can lead to damage of ventral roots. Polyradiculoneuropathy can also be a rare manifestation of syphilitic meningomyelitis, presenting with hypotonic lower extremity weakness with areflexia, without24,43 and with associated HIV infection.104 Good response to penicillin treatment was reported in all cases. Abnormal enhancement of the nerve roots and nodular enhancement of the cauda equina were demonstrated with MRI.24 Syphilitic spinal thrombosis1 can present as transverse myelitis or anterior spinal artery syndrome. Spinal arteries are suddenly thrombosed as a result of arteritis, leading to sudden flaccid paraplegia, caused by spinal shock, with urinary retention and anesthesia. Later, atrophic paralysis occurs as a result of anterior horn cell destruction with distal spastic paralysis caused by corticospinal tract destruction. Hyperplastic endarteritis, referred to as Heubner’s

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arteritis (with infiltration of vessel wall adventitia and media by lymphocytes and plasma cells and narrowing of vessels by subintimal fibroblasts), and myelomalacia have been described pathologically. Syphilitic amyotrophy in isolation is controversial but has been described in combination with syphilitic meningomyelitis, spinal vascular neurosyphilis, or tabetic neurosyphilis.1 It is characterized by painless and subacute weakness with lower motor neuron signs, often with a lack of progression and response to antibiotic treatment.55 Therefore, it may mimic motor neuron disease such as progressive muscular atrophy or ALS.82 Persistent meningeal inflammation causing destruction of the anterior horn cells or ventral roots can lead to atrophy, areflexia, and fasciculations. Syphilitic arteritis can cause infarction of the ventral horn without long tract involvement, particularly in the cervical spinal cord. Five percent to 10% of patients with tabes dorsalis are estimated to have muscular weakness and atrophy. Shrinkage and hyperchromatism of anterior horn cells with astrocytosis throughout the ventral horns has been described.1 The classic symptoms of tabes dorsalis or syphilitic spinal pachymeningitis are lightning-type pains, ataxia, and urinary incontinence with absent reflexes and impaired vibration and position sense in the lower extremities.1,3 Patients are ataxic, pupils are abnormal (Argyll-Robertson), and nociceptive loss is severe, leading to trophic lesions, ulcers, and Charcot joints. Strength is often normal. CSF examination reveals absent to mild pleocytosis, mildly elevated protein, and a positive Venereal Disease Research Laboratory (VDRL) test, although in some cases the CSF findings are minimal. Persistent inflammation of the meninges is postulated to lead to inflammation and eventually fibrosis of the posterior roots with degeneration of posterior columns.82 Dorsal root ganglia and peripheral nerves are less affected.3,82 Gummas, or focal nodular lesions in or around dura mater, may also develop. The clinical picture, however, is that of a rapidly growing tumor with pain and paresthesias, spastic paraplegia, and incontinence of bowel and bladder. Microscopically, there is granuloma formation with or without necrosis with lymphocytes, plasma cells, fibroblasts, and histocytes.1 Electrophysiologic studies in tabes dorsalis can be normal except for absent tibial H reflexes. Median nerve somatosensory evoked potentials were found to be normal, whereas tibial nerve somatosensory evoked potentials were abnormal—findings consistent with a disorder of the posterior columns.47,190 In vitro sural nerve studies in a patient with impaired pain and temperature sensation revealed normal A␣, A␦, and C fibers with normal number and sizes of myelinated and unmyelinated nerve fibers per unit of fascicular area, findings consistent with preservation of the dorsal root ganglia and their peripheral axons.51,70,182

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Diagnosis of neurosyphilis, caused by the spirochete Treponema pallidum, requires serologic testing77,175 using rapid plasma reagent (RPR) and VDRL tests. A positive RPR should be confirmed with the fluorescent treponemal antibody absorption (FTA-ABS) test or the microhemagglutination–T. pallidum (MHA-TP) assay. The FTA-ABS is very specific; thus a negative FTA-ABS essentially excludes syphilis as a diagnosis. However, the FTA-ABS may remain positive indefinitely and cannot be used as an indicator of active disease. Although the sensitivity of the CSF VDRL test is 30% to 70%, the specificity is very high. Treatment for neurosyphilis77,141 consists of penicillin G sodium, 12 to 24 million units per day intravenously (2 to 4 million units every 4 hours) for 10 to 14 days, or penicillin G procaine, 2 to 4 million units per day intramuscularly with probenecid 500 mg orally four times a day for 10 to 14 days. Tetracycline (500 mg orally four times a day for 30 days) can be given in case of penicillin allergy. Treatment will halt the progression of the disorder, and CSF pleocytosis and elevated protein will improve by 6 months. CSF serologic tests can be reactive for a year after therapy. CSF should normalize by 1 to 2 years.

Bulbospinal Muscular Atrophy (Kennedy’s Disease) Bulbospinal muscular atrophy is an X-linked recessive inherited lower motor neuron disease that presents with primarily motor symptoms, although there is subclinical sensory neuron involvement as well. Polo et al.154 examined sensory electrophysiologic abnormalities in patients with bulbospinal muscular atrophy and found abnormalities in central afferent pathways, represented by abnormal somatosensory evoked potentials and increased wave I latency on brainstem auditory evoked potentials. Peripheral sensory nerve action potentials were variably affected, suggesting predominant involvement of central afferent pathways in these patients versus peripheral sensory axonopathy.154 Studies using laser-evoked potentials, trigeminal blink reflex testing, masseter inhibitory reflex, and jaw jerk testing revealed findings consistent with impairment of large-diameter afferent fibers and central sensory neurons.9 Sural nerve biopsies and postmortem examinations of patients with bulbospinal muscular atrophy demonstrate loss of large myelinated fibers9,114 with secondary segmental demyelination and remyelination in the sural nerve and loss of myelinated fibers in the dorsal columns.114 There was a shift in size distribution of dorsal root ganglion neurons, with reduced numbers of largediameter cells and an increase in small-diameter neurons. There was evidence of androgen receptor mRNA in dorsal root ganglia, sural nerve, and spinal cord,114 which may explain why the afferent system is also involved in this disease, because Kennedy’s disease is caused by a genetic

defect in the androgen receptor gene. These pathologic findings would imply that, in bulbospinal muscular atrophy, the sensory involvement is one of neuronal loss with central and peripheral axonal degeneration.114

MENINGEAL DISEASE Allanore et al.6 reported a case of a patient with a history of breast cancer who presented with symptoms of sciatica that progressed to also include urinary incontinence and lower extremity weakness. Serial MRI studies of this patient’s lumbosacral spine showed a focal dural mass at L2 that was a leptomeningeal metastasis.6 Such a case illustrates the importance of considering meningeal disease even with initial peripheral clinical manifestations. Pain and weakness in this case was due to an intradural mass lesion, presumably compressing dorsal and ventral roots and eventually the spinal cord.

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