Chapter 23

Acquired Neuropathies
Anthony A.Amato, M.D. Daniel Dumitru, M.D., Ph.D.
CHAPTER OUTLINE Immune-Mediated Polyneuropathies Guillain-Barr Syndrome and Related Disorders Acquired Chronic Demyelinating Polyneuropathies Sensory Neuronopathies and Autonomic Neuropathies Vasculitic Neuropathies Neuropathies Associated with Autoimmune Connective Tissue Diseases Sarcoidosis Idiopathic Perineuritis Hypereosinophilia Syndrome Isaacs Syndrome Neuropathies Associated with Infections Leprosy (Hansens Disease) Lyme Disease Diphtheria Human Immunodeficiency Virus Human T-Lymphotropic Virus-1 Cytomegalovirus Epstein-Barr Virus Herpes Varicella Zoster Virus Hepatitis B and C Neuropathies Associated with Endocrinopathies Diabetes Mellitus Hypoglycemia Acromegaly Hypothyroidism Neuropathies Associated with Systemic Diseases Uremic Neuropathy Gastrointestinal Diseases Liver Diseases Chronic Obstructive Pulmonary Disease Gout Critical Illness Polyneuropathy Neuropathies Associated with Malignancies Paraneoplastic Neuropathies Cryptogenic Sensory or Sensorimotor Polyneuropathy Neuropathies Related to Tumor Infiltration Noninfiltrative Neuropathies Associated with Lymphoproliferative Disorders and Monoclonal Gammopathies Acquired Amyloidosis Neuropathies Associated with Monocloncal Gammopathy of Uncertain Significance Neuropathies Associated with Bone Marrow Transplantation and Graft-vs.-Host Disease Toxic Neuropathies Chemotherapy Other Medications Industrial and Environmental Agents Heavy Metal Intoxication Neuropathies Related to Nutritional Deficiencies Thiamine (Vitamin B1) Pyridoxine (Vitamin B6) Cobalamin (Vitamin B12) Folic Acid Vitamin E Postgastrectomy Syndromes Hypophosphatemia Jamaican Neuropathy Alcoholic Neuropathy Chronic Idiopathic Sensory or Sensorimotor Polyneuropathy Illustrative Cases Acute Onset of Limb Weakness Progressive Lower Limb Numbness and Weakness

In the preceding chapters, we discussed our approach to patients with peripheral neuropathies and reviewed the hereditary neuropathies. This chapter concerns the acquired forms of neuropathy, which are more common than the hereditary neuropathies. We classify acquired polyneuropathies according to their presumed pathogenic basis or association with other systemic disorders (see outline above). It is important for the electromyographer to know how these neuropathies manifest clinically and to understand their associated laboratory abnormalities and pathogenic basis to comprehend fully how these features correlate with the electrophysiologic findings. Unlike the hereditary neuropathies, many of the acquired neuropathies are treatable. Therefore, we also describe our approach to treating patients with acquired peripheral neuropathy.

IMMUNE-MEDIATED POLYNEUROPATHIES
GUILLAIN-BARR SYNDROME AND RELATED DISORDERS
In 1859, Landry defined the major clinical features of this neuropathy and coined the term acute ascending paralysis. Subsequently, Guillain, Barr, and Strohl described the areflexia and the albuminocytologic dissociation in the cerebral spinal fluid (CSF) that accompanies the ascending paralysis.516 Unfortunately, the contributions of Landry and Strohl are often neglected, and the disorder is most commonly termed GuillainBarr syndrome (GBS). Haymaker and Kernohan reported the histopathologic features of 50 fatal cases of GBS in 1949.565
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Table 23-1. Diagnostic Criteria for Acute Inflammatory Demyelinating Polyradiculoneuropathy Required for diagnosis 1. Progressive weakness of variable degree from mild paresis to complete paralysis 2. Generelized hypo- or areflexia Supportive of diagnosis 1. Clinical features Symptom progression. Motor weakness rapidly progresses at first but ceases by 4 weeks. Nadir is attained by 2 weeks in 50%, 3 weeks in 80%, and 4 weeks in 90%. Demonstration of relative limb symmetry in terms of paresis. Mild to moderate sensory signs. Frequent cranial nerve involvement: facial (cranial nerve VII); 50% typically bilateral but asymmetric. Occasional involvement of cranial nerves III, IV,VI, X, XI, and XII. Recovery typically begins 24 weeks after plateau phase. Autonomic dysfunction may include tachycardia, other arrhythmias, postural hypotension, hypertension, other vasomotor symptoms. A preceding gastrointestinal illness (e.g., diarrhea) or upper respiratory tract infection is common. 2. Cerebrospinal fluid features Elevated CSF protein. CSF cell counts are < 10 mononuclear cell/mm3. 3. Electrodiagnostic medicine findings 80% of patients have evidence of NCV slowing/conduction block at some time during disease process. Patchy reduction in NCV attaining values < 60% of normal. Distal motor latency increase to > 125150% of normal. F-waves indicate proximal NCV slowing. About 1520% of patients have normal NCV findings. No abnormalities on nerve conduction studies may be seen for several weeks Findings reducing likelihood of diagnosis 1. Asymmetric weakness 2. Failure of bowel/bladder symptoms to resolve 3. Severe bowel/bladder dysfunction at initiation of disease 4. > 50 mononuclear cells/mm3 in CSF 5. Well-demarcated sensory level Exclusionary criteria 1. Diagnosis of other causes of acute neuromuscular weakness (e.g., myasthenia gravis, botulism, poliomyelitis, toxic neuropathy). 2. Abnormal CSF cytology suggesting carcinomatous invasion of the nerve roots.

The pathophysiology and neurophysiology of GBS were not uncovered until one century after the original clinical descriptions of the neuropathy. Thus, other pathophysiologic variants are often considered under the spectrum of GBS, including two axonal forms of GBS: acute motor-sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN), which are pathogenically distinct from the much more common AIDP. Some disorders that appear clinically different from AIDP (e.g., the Miller-Fisher syndrome of ataxia, areflexia, and ophthalmoplegia) may share similar pathogenesis and can be considered a variant of GBS.
Acute Inflammatory Demyelinating Polyradiculoneuropathy Epidemiology and Antecedent Illness. AIDP is the most common cause of acute generalized weakness. The exact annual incidence of AIDP ranges from 14/100,000 population, and there may be a slight male predominance.19,1121,1122 This neuropathy can occur at any age, with a peak age of onset in the third to fourth decade of life. Roughly 6070% of patients with AIDP note some form of acute illness (e.g., a viral syndrome) 13 weeks before the onset of neurologic symptoms.1121,1122 In a recent case-control study of 154 patient with GBS, serologic evidence of recent infections with Campylobacter jejuni (32%), cytomegalovirus (13%), Epstein-Barr virus (10%), and Mycoplasma pneumoniae (5%) was more frequent than in the control population.618 Because of the high incidence, recent attention has focused on C. jejuni infection. Fifteen to 45% of patients with AIDP have serologic evidence of recent Campylobacter enteritis.120,402,505,1091,1092,1340,1360,1369 The relationship between C. jejuni infection and the different variants of GBS (AIDP, AMSAN, and AMAN) is discussed in detail in the pathogenesis section of each disorder. Besides cytomegalovirus (CMV) and Epstein-Barr virus (EBV), other viral infections have been described in AIDP, including influenza, hepatitis A, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV).1078,1121,1122,1340,1403 In HIV infection, AIDP usually occurs at the time of seroconversion or early in the course of the disease. Vaccinations, most notably to swine flu, have been associated with an increased risk of GBS. Other disorders linked to GBS include other autoimmune disorders, acquired immunodeficiency syndrome, solid organ and bone marrow transplantation, lymphoma, and, possibly, recent surgery.22,1122 There may be an increased incidence of GBS postpartum.212a Clinical Features. Most patients initially note numbness and tingling in the distal regions of the lower limbs and shortly thereafter in the upper limbs.1121,1122 Aching, prickly, or burning neuritic pain sensations in the back and limbs are present in at least 50% of patients. Some patients experience numbness and paresthesias of the face. Large-fiber modalities (touch, vibration, and position sense) are more severely affected than small-fiber functions (pain and temperature perception). A few patients manifest only with sensory symptoms through the course of the illness, although electrophysiologic signs of motor involvement are typical.297,989a,1331 Progressive weakness usually ensues and is the major complaint of most patients. Muscle weakness may be mild and localized to the distal limbs or progress to such an extent as to render the patient completely quadriplegic and requiring assisted ventilation. Onset usually begins in the lower limbs and ascends to the arms, trunk, head and neck. In Roppers series, 56% had onset of weakness in the legs, 12% in the arms, and 32% simultaneously in the arms and legs.1121,1122 Mild facial weakness is apparent in at least half of the patients during the course of the

They noted that the earliest features of the disease were edema of the proximal nerves followed by degeneration of the myelin sheaths within the first week of the illness. Inflammatory cells were not appreciated until later in the course of the illness.565 In contrast, Asbury and colleagues found prominent perivascular inflammation not only in the spinal roots but also in ganglia, cranial nerves, and randomly along the whole length of peripheral nerves in all 19 autopsy cases of GBS.41 They also noted segmental demyelination adjacent to the areas of inflammation. Thus, the term acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is quite descriptive of the disease process, has been used synonymously with GBS.40,157,674,724,806,879,1117,1121 Subsequently criteria were developed to assist in the diagnosis of patients suspected of AIDP (Table 23-1).46

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illness. From 515% of patients develop ophthalmoparesis and ptosis. Occasionally, a descending presentation with onset in the cranial nerves and subsequent progression to the arms and legs is seen. The external urethral and anal sphincters are usually spared, although they may become involved in particularly severe disease states. Early progression of deep tendon reflex loss sometimes precedes and at other times follows the onset of sensory symptoms. Even minimally affected muscles have decreased stretch reflexes. Autonomic instability is common in AIDP with hypotension or hypertension and occasionally cardiac arrhythmias. Of note, neonatal GBS has been described in the infant of a mother with GBS, purportedly due to antibodies crossing the placenta.166 The disease usually progresses over the course of 24 weeks. At least 50% of patients reach their nadir by 2 weeks, 80% by 3 weeks, and 90% by 4 weeks.1121,1122 Progression of symptoms and signs for over 8 weeks excludes GBS and suggests the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) (see below). Subacute onset with progression of the disease over 48 weeks falls in a gray zone between typical AIDP and CIDP.603 Respiratory failure develops in approximately 30% of patients. Neck flexion and extension and shoulder abduction correlate well with diaphragmatic strength and are thus important to follow closely. Following the disease nadir, a plateau phase of several days to weeks usually occurs. Subsequently, most patients gradually recover satisfactory function over several months. However, only about 15% of patients are without residual deficits 12 years after disease onset and 510% of patients have disabling motor or sensory symptoms.1121,1122 The mortality rate is about 5%; patients die as a result of respiratory distress syndrome, aspiration pneumonia, pulmonary embolism, cardiac arrhythmias, and sepsis related to secondarily acquired infections.1121,1122 Risk factors for a poorer prognosis (slower and incomplete recovery) are age greater than 5060 years, abrupt onset of profound weakness, need for mechanical ventilation, and distal CMAP amplitudes less than 1020% of normal.243,245,866,894,895,1059,1312,1333,1360,1421,1423 Laboratory Features. Elevated CSF protein levels accompanied by no or only a few mononuclear cells is the characteristic laboratory finding (see Table 23-1) and is evident in over 80% of patients after 2 weeks. However, within the first week of symptoms, CSF protein levels are normal in approximately onethird of patients. In patients with CSF pleocytosis of more than 10 lymphocytes/mm3 (particularly with cell counts greater than 50/mm3), AIDP-like neuropathies related to Lyme disease, recent HIV infection, or sarcoidosis need to be considered. Elevated liver function tests are evident in many patients. In such cases, it is important to evaluate the patient for viral hepatitis (A, B, and C), EBV, and CMV infection. MRI of the spine can reveal enhancement of nerve roots.475 Antiganglioside antibodies, particularly anti-GM1 antibodies, have been documented in several patient series.526,1091,1092,1369 The presence of these antibodies correlates well with C. jejuni infection. Serologic evidence of recent antecedent C. jejuni infection is evident in 1545% of patients.120,402,505,618,1091,1092,1121,1122,1360,1369 Molecular mimicry between gangliosides expressed on nerve fibers and glycolipids present on C. jejuni may account for their association with AIDP and may play a role in the pathogenesis of the disorder. Histopathology. Macroscopic inspection of peripheral nerves reveals no significant abnormalities. On light microscopic evaluation, a perivascular mononuclear cell infiltrate consisting of macrophages and lymphocytes may be seen.40,596,821,1027,1121

The entire peripheral motor and sensory nervous systems, including cranial nerves can be involved from the most proximal aspects of the ventral and dorsal roots to the terminal regions of the intramuscular and sensory nerve fibers.651 There may be an initial preference for the nerve root region, areas where peripheral nerves are commonly entrapped (e.g., carpal and cubital tunnels), and the motor nerve terminals. The earliest pathophysiologic features are often appreciated at the nodes of Ranvier. Demyelination progresses from the loosened paranodal myelin to internodal demyelination. Monocellular infiltrates may be appreciated in areas of segmental demyelination. In significant disease states, polymorphonuclear cells, in addition to monocytes, may be associated with axonal degeneration. With disease resolution, remyelination can be observed with initial reductions in the myelin thickness and increases in the number of internodes compared with normal peripheral nerve. Immunohistochemistry studies show increased expression of matrix metalloproteinases MMP-7 and MMP-9 around blood vessels in the epineurium and endoneurium.686 MMP-9 is also increased in the serum, and levels correlate with the clinical severity in GBS.257 These matrix metalloproteinases are zinc-dependent endoproteinases, which may play a role in the inflammatory response in AIDP by digesting the basement membrane and disrupting the nerve-blood barrier. Recent autopsy studies of patients in China who died early in the course of their illness have shed light on the pathology of GBS, including AIDP, AMSAN, and AMAN.506,507,530,531 In two patients dying at 7 and 9 days, completely demyelinated peripheral nerves accompanied by extensive lymphocytic infiltrate were seen.530 However, in a patient who died only 3 days after symptom onset, the peripheral nerves had scant inflammatory infiltrate, and only a few of the nerves were completely demyelinated. Markers of complement activation (C3d and membrane attack complex) were demonstrated on the outermost surface of the Schwann cells. Electron microscopy (EM) revealed that these fibers had early vesicular changes in the myelin sheaths, beginning in the outer lamellae. Pathogenesis. AIPD has long been considered a T-cellmediated autoimmune disorder, given the inflammation apparent in the nerves and the resemblance to experimental allergic neuritis.555,556 Markers of T-cell activation, including soluble interleukin-2 receptor and interferon-, can be found in the serum of patients with AIDP.554 The humoral arm of the immune system has been implicated by clinical improvement following plasmapheresis. Furthermore, antinerve antibodies are detected in the serum of many patients, as discussed above.555,556 Injection of serum from patients with AIDP into nerves of animal models induces complement-dependent demyelination and conduction block.395,552,1174 Buchwald et al. investigated the effect of serum from 10 patients with GBS on mouse hemidiaphragm using a macro-patch-clamp technique.169 They observed depressed presynaptic transmitter release and, in some cases, the activation of postsynaptic channels. The neuromuscular blockade was independent of complement, and there was no link to the presence (in 6 patients) or absence (in 4 patients) of antibodies to GM1 or GQ1B. Recent observations suggest that the immunologic attack is directed against the Schwann cell abaxonal plasmalemma (the outermost surface of the myelin sheath).530 The nature of the myelin epitope is not known but is probably a glycolipid. Molecular similarity between the myelin epitope(s) and glycolipids expressed on Campylobacter, Mycoplasma, and other infectious agents, which precede attacks of AIDP, may be the underlying trigger for the immune attack. Antibodies directed against these infectious agents may cross-react with specific

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Table 23-2. Electrodiagnostic Medicine Criteria for Peripheral Nerve Demyelination* Conduction velocity reduced in 2 or more nerves 1. If CMAP amplitude is > 80% of lower limit of normal (LLN), the NCV must be < 80% of LLN. 2. If CMAP amplitude < 80% of LLN, the NCV must be < 70% of LLN. CMAP conduction block or abnormal temporal dispersion in 1 or more nerves 1. Regions to examine: Peroneal nerve between fibular head and ankle Median nerve between wrist and elbow Ulnar nerve between wrist and below elbow 2. Partial conduction block criteria CMAP duration difference between the above noted proximal and distal sites of stimulation must be < 15%; and A > 20% drop in CMAP negative spike duration, or baselineto-peak amplitude. 3. Abnormal temporal dispersion and possible conduction block CMAP duration difference between the above proximal and distal sites of stimulation is > 15%; and > 20% drop in CMAP negative spike duration or baseline-topeak amplitude. Prolonged distal motor latencies (DML) in 2 or more nerves 1. If CMAP amplitude is > 80% of LLN, the DML must be > 125% of the upper limit of normal (ULN). 2. If the CMAP is < 80% of LLN, the DML must be > 150% of ULN. Prolonged minimum F-wave latency or absent F-wave 1. F-waves performed in 2 or more nerves (1015 trials) 2. If the CMAP amplitude is > 80% of LLN, the F-wave latency must be > 120% of ULN. 3. If CMAP amplitude is < 80% of LLN, the F-wave latency must be > 150% of ULN.
* Three

of the four features must be present.46,245

antigens on the Schwann cell because of this molecular mimicry. These autoantibodies most likely bind to the Schwann cells and activate the complement cascade, leading to lysis of myelin sheaths. Inflammatory cells are subsequently recruited to complete the demyelinating process. Electrophysiologic Findings. A comprehensive review of the electrophysiologic literature regarding the various results in AIDP reveals both a number of consistent as well as contradictory findings.892a There are probably multiple reasons for these findings, but the most likely explanations include the time during the course of the illness when the patient is examined, different recording and stimulating techniques, failure to control temperature, and examination of insufficient number of nerves and muscles. AIDP is a dynamic disease with variable rates of progression in different patients. In addition, different aspects of the peripheral nervous system are affected with respect to proximal versus distal from one patient to the next, particularly during the diseases manifestation within the first several weeks. The electrophysiologic results are described in terms of the basic pathophysiology of demyelination with an occasional and variable secondary axonal loss component. Electrophysiologic criteria for demyelination have been developed to aid in the diagnosis of AIDP (Table 23-2).46 Motor Conduction Studies. The most studied aspect of the peripheral nervous system in AIDP is neural conduction along the motor nerve fibers. The various parameters examined are the distal motor latencies, CMAP amplitudes, conduction velocities, waveform duration and morphology, and F-waves. These

parameters are used for the purposes of diagnosis, prognosis, and gaining insight into the fundamental pathophysiologic processes operational in the disease. The electrophysiologic hallmarks of demyelination include prolonged distal latencies, slow conduction velocities, temporal dispersion, conduction block, and prolonged F-wave latencies. In line with the multifocal character of the disease, a hallmark is the asymmetric and multifocal character of the electrophysiologic abnormalities. Slowing of nerve conduction may be preferentially localized to distal nerve segments, proximal nerve segments, or diffusely throughout the peripheral nervous system.691,692,694,751,901,1395 We always perform F-wave studies in both upper and lower limbs in patients suspected of having AIDP because of the early predilection for the proximal nerve segments and spinal roots.9,243,245,459,1118 Abnormal F-waves can be expected in as many as 8090% of patients during the course of the disease.9,243,245,996 Several different types of F-wave abnormalities may be noted. The shortest F-wave latency in a series of 1015 applied stimuli is commonly used for diagnostic purposes. In patients with AIDP, this parameter is frequently abnormal (prolonged or absent), particularly early in the disease process, but usually peaks at about 45 weeks.9 Unfortunately, when the Fwave is used in this manner, it is possible for a single motor fiber to escape pathology and mediate a normal F-wave response. An average F-wave latency or the difference between the minimum and maximum F-wave latencies may be more appropriate; however, these techniques have not been studied in AIDP. With respect to late responses, H-reflexes also should be attempted in the lower limb as a method of assessing possible proximal neural conduction failure. It is also possible to demonstrate conduction block at the nerve root level by using nerve root stimulation techniques.89,899 It is possible to observe multiple A waves in patients with AIDP. An investigation documented that 93% of patients demonstrated multiple A waves in at least one limb within 7 days of symptom onset.718a In patients with significant axonal loss and loss of the CMAP, A waves are unlikely to be observed. Some research criteria for electrophysiologic evidence of demyelination have used a 20% reduction in the CMAP amplitude or negative peak area between proximal and distal sites of stimulation as evidence of conduction block (see Table 23-2, Fig. 23-1).46,245,249 However, other studies have used stricter criteria (e.g., 30 or 40% reduction in CMAP amplitude or area), and computer simulation studies suggest a 50% drop in amplitude is more appropriate for the electrophysiologic evidence of conduction block.998a,1098 It seems wise to use different criteria for arm and leg nerves since the peroneal and tibial nerve normally display more drop in CMAP amplitude with proximal stimulation than the median and ulnar nerve. A CMAP reduction of at least 30% for the arm nerves and 40% for the leg nerves seems appropriate.9 Of importance, there must be less than a 15% increase in the negative peak duration in comparing the proximal to distal response. This guideline ensures that a reduction in amplitude is not a result of excessive temporal dispersion, which increases the duration of the potential with a concomitant and compensatory reduction in amplitude, giving the appearance of conduction block (i.e., pseudoconduction block). If excessive temporal dispersion is found, it is difficult to state with assurance whether conduction block is present (Fig. 23-2).156 One method of distinguishing between conduction block and temporal dispersion is to use small-segment (e.g., stimulate every centimeter) stimulations in the hope of localizing a focal reduction in amplitude. If there is a gradual reduction in amplitude without

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Figure 23-1. The ulnar nerve is investigated 7 days following the onset of AIDP induced weakness.The peak-to-peak hypothenar CMAP decreases over 90% when the Erbs point stimulation site is compared with the wrist.The corresponding waveforms are noted above the graphic depiction of amplitude reduction.The accompanying graph describes the < 15% alteration in CMAP negative spike duration and peak-topeak potential duration, indicating essentially normal degrees of temporal dispersion.The net conclusion of these data is that the reduction in CMAP amplitude results from conduction block, not temporal dispersion. (From Brown WF, Feasby TE: Conduction block and denervation in Guillain-Barr polyneuropathy. Brain 1984;107:219239, with permission.)

an abrupt decline in CMAP area, temporal dispersion is the likely culprit. However, if a marked reduction in amplitude can be localized to a short segment (24 cm), conduction block is probably present.248 Excessive reductions in amplitude may be possible with moderate, but less than abnormal, degrees of temporal dispersion secondary to phase cancellation effects, whereby the negative and positive aspects of individual CMAP waveforms cancel each other.789 The concept of conduction block is critical to understanding the pathophysiologic basis of symptoms in AIDP. Loss of myelin leads to neural conduction failure. However, conduction block may occur without demyelination or before demyelination as a result of antibodies blocking ion channels at the nodes of Ranvier. Conduction block of nerve impulses leads to acute weakness and sensory loss. Subsequent reduction in function may be secondary to an associated axonal loss.156,1301 Some authorities suggest that conduction block is the earliest electrophysiologic abnormality in AIDP, being noted in 74% of patients within the first 2 weeks.156 The smaller myelinated nerve fibers may be affected first by conduction block with subsequent involvement of the larger fibers.1270 Conduction block in AIDP can be observed at common sites of entrapment, such as the carpal tunnel (median nerve), cubital tunnel (ulnar nerve), and fibular head (peroneal nerve).156,158 In patients with rapid recovery, particularly after plasmapheresis or intravenous immunoglobulin, the improved clinical status probably results from conduction block resolution rather than remyelination or regeneration of the axons.1081 Two important caveats about conduction block should be remembered.248 First, within 57 days after acute axonal loss, it is impossible to distinguish between axonal loss and conduction block because portions of nerve distal to the site of the lesion are still excitable and generate a corresponding CMAP. Second,

in acute disease presentations, relatively small reductions in CMAP amplitude may be a result of conduction block; however, in more chronic disease states or later in the acute disease process, alterations in conduction velocity may result in pseudoconduction block. Therefore, it is somewhat easier to be certain of conduction block in the acute time frame compared with the more chronic manifestations of disease. Examination of the phrenic and facial nerves may be of interest in patients with AIDP. Profound demyelination can most likely lead to significant axonal loss with diaphragmatic denervation.484,954,1449 In addition to nerve conduction studies of the phrenic nerve, needle EMG of the diaphragm may be performed.119 The facial nerve may be affected as well as the supraorbital nerve; they can be evaluated with both direct facial nerve stimulation and the blink reflex, which reveals abnormalities in either or both pathways.690 Within the first week, motor conduction studies can be normal or show only minor abnormalities. The maximum degree of motor conduction abnormality occurs within 38 weeks; 8090% of patients with AIDP have abnormalities in at least one of the motor nerve parameters (distal CMAP latency, F-wave latency, conduction velocity, conduction block) within 5 weeks of onset.9,10,243,245 Reports of lower percentages of patients with electrophysiologic abnormalities most likely result from examining the patients too early or incompletely. Using their own electrophysiologic criteria for demyelination, Albers and colleagues found that 70% of patients had demyelination in two or more nerves and 85% in one nerve.9 Meulstee and colleagues applied the electrophysiologic criteria for demyelination designed by Albers, Asbury, and Cornblath9,10,73,243,245 to 135 patients with AIDP sequentially studied during the Dutch-GBS PE (plasma exchange) and IVIG trials.892 The sensitivity of the criteria for diagnosing demyelination ranged from 336% during

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Figure 23-2. Three patients with AIDP are investigated within 2 weeks of symptom onset, and the corresponding derived CMAPs are displayed. Considerable reductions in CMAP amplitude are noted when the most proximal response is compared with that evoked from the wrist. One may easily conclude that conduction block is present, based on the CMAP findings. However, negative spike duration and peak-to-peak CMAP duration exceed the 15% limit, documenting excessive temporal dispersion and suggesting that if conduction block is present, it cannot be differentiated from the excessive differential slowing effects on nerve conduction velocity. (From Brown WF, Feasby TE: Conduction block and denervation in GuillainBarr polyneuropathy. Brain 1984;107:219239, with permission.)

the first study (performed at a median of 6 days; range of 215 days after onset) to 1346% during the third study (performed at a median of 34 days; range of 2949 days after onset). Unfortunately, it is difficult to state with certainty the most sensitive motor conduction parameter in confirming a diagnosis of AIDP, because the specific nerves that were studied, the various motor conduction parameters, the timing of the studies in relationship to disease onset, and the definition of abnormal vary in the published studies. Some suggest that conduction block is the earliest recognizable electrophysiological abnormality in AIDP.156 However, Albers and colleagues noted that prolonged and diminished CMAP amplitude was the earliest

abnormality.9 Within 1 week of symptoms, the mean distal CMAP amplitudes were reduced to approximately 50% of normal and declined further over the next several weeks. The North American Guillain-Barr Syndrome Study Group reported prolonged distal motor latencies and prolonged or absent Fwaves as the earliest abnormal features.243,245 Early abnormalities of the distal CMAP amplitude and latency and F-waves reflect the early predilection for involvement of the proximal spinal roots and distal motor never terminals in AIDP. Subsequently, the slowing of conduction velocities, temporal dispersion of the CMAP waveforms, and conduction block become apparent. The motor conduction abnormalities remain at their nadir for approximately 1 month and then gradually improve over the next several weeks to months, but it may take a year or more for normalization.9 There does not appear to be a correlation between the nerve conduction velocities or distal motor latencies and clinical severity of the neuropathy,302,561,806,871,872 although distal CMAP amplitudes less than 1020% of normal are associated with a poorer prognosis.243,245,866,894,895,1059,1312,1333,1423 Sensory Conduction Studies. Multiple sensory nerves should be examined in both upper and lower limbs. The sural and superficial peroneal SNAPs can be evaluated in the lower limbs as well as the median, ulnar, and radial SNAPs in the upper limbs. Of note, upper limb SNAPs, particularly the median nerve, can be affected more severely and earlier than the sural SNAPs.9,930 The exact explanation is multifactorial. It has been suggested that recognized entrapment sites are more prone to being affected, accounting for slowing of the median SNAP across the carpal tunnel. The median nerve SNAP is recorded from the thinly myelinated terminal regions (or stimulated for orthodromic techniques), thus predisposing it to a relatively more early disruption of function. On the other hand, the sural nerve usually is studied at a relatively more proximal location in the leg, where it is more heavily myelinated and does not traverse any potential entrapment sites. The most likely explanation for the observation that upper limb SNAPs can be more abnormal than lower limb SNAPs is that the demyelinating process is multifocal rather than a length-dependent process (as in axonal neuropathies). Thus, unlike most axonopathies, in which the earliest and most severe abnormalities involve the distal lower limb nerves (e.g., the sural SNAP), demyelinating diseases are just as likely to affect the median and ulnar SNAPs as they are to affect the sural SNAPs. About 4060% of patients eventually demonstrate either amplitude or conduction abnormalities of various SNAPs; these findings may not be apparent during the first several weeks of the disease.989a,996,1120 It can take 46 weeks for SNAP abnormalities to peak, at which time significant and easily identifiable SNAP parameter alterations become obvious.9,1293 The parameter most adversely affected is SNAP amplitude, which is usually diminished or absent by the third or fourth week. Reduced SNAP amplitudes can result from secondary axonal degeneration, conduction block, or phase cancellation related to differential demyelination and slowing of the sensory nerve fibers. Sensory conduction velocities can be slow and distal latencies prolonged, but often they do not fall below 80% of the lower limit of normal. Rarely, some persons may present with what appears to be pure sensory symptoms and signs; however, careful investigation may reveal subtle motor nerve conduction abnormalities.297,989a,1331 With a pure sensory presentation, other disorders (acute sensory neuronopathy or ganglionopathy) must be ruled out and detailed neurophysiologic studies performed in an attempt to detect subclinical motor abnormalities.1027,1121

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SEP Conduction Studies. We do not routinely perform SEPs in patients evaluated for AIDP because virtually all of the information necessary for diagnosis and prognosis can be readily obtained using routine sensory and motor conduction techniques.996 However, SEPs have a theoretical advantage in that they allow the opportunity of investigating the proximal aspects of the nervous system not customarily accessible to routine SNAP techniques.446,459,1118,1382 Most studies have substantiated that the peripheral nervous system is variably affected, with some disease predisposition toward the proximal or nerve root regions. Central conduction times are found to be essentially normal. This may explain why patients demonstrate clinical sensory abnormalities and yet little in the way of electrophysiologic peripheral SNAP abnormalities.157 Specifically, a lesion in or about the dorsal root ganglion region may not result in injury to the nearby cell body but may cause sufficient demyelination to generate an ectopic focus (paresthesias) and block neural transmission, resulting in variable degrees of numbness. Of interest, brainstem auditory evoked responses have generally revealed normal results but a few patients have demonstrated some slowing of conduction.946,1118,1180 Needle EMG Examination. The needle EMG examination in patients with AIDP is primarily adjunctive to explore the possibility of other disease entities. The earliest motor finding in patients with AIDP is a reduced recruitment of MUAPs.9,11 A reduced number of normal-appearing MUAPs firing at rapid rates may be observed during low levels of force production, particularly in clinically weak muscles. Spontaneous potentials in the form of positive sharp waves and fibrillation potentials may first be seen between weeks 2 and 4, peaking at about the 615 weeks; potentials maximize earlier in proximal muscles than in distal muscles. These abnormal potentials can appear in both proximal and distal muscles simultaneously. Not unexpectedly, patients are more likely to have prominent positive sharp waves and fibrillation potentials when the CMAP is profoundly reduced.370,1076 From 15 weeks onward, there is a gradual decline in the degree of abnormal spontaneous activity. Myokymia can also be detected in patients with AIDP, especially in facial muscles.289,523,844,1387 These potentials are commonly observed within the first three weeks of clinical presentation, with a gradual taper over the ensuing weeks to months. During the first few weeks of the disease process, the MUAP duration, amplitude, and number of phases are normal. Over the course of the next 616 weeks, there is an increase in all of these MUAP parameters.9,841 Singlefiber EMG reveals a mild to moderate increase in fiber density, substantiating motor unit remodeling in patients with axonal loss.447 The mean jitter for individual muscles remains normal; however, occasional individual single muscle fibers may demonstrate mildly increased jitter, but of an insufficient degree to alter the value for all potential pairs. Autonomic Testing. Autonomic instability can be assessed by measuring the EKGs R-R interval variation. About 35% of patients demonstrate an abnormality.967,1048 An alternative method of assessing the sympathetic nervous system is to investigate the sympathetic skin response.1203,1249 Although of interest, this parameter does not really contribute to the diagnosis or prognosis in AIDP and can be rather variable from trial to trial. Treatment. Plasma exchange (PE)431,514 and intravenous immunoglobulin (IVIG)1059,1334 have been demonstrated in prospective controlled trials to be effective in the treatment of AIDP (Table 23-3). The North American Trial revealed that PE reduced the time necessary to improve one clinical grade, time to walk unaided, time on a ventilator, and the percentages of

patients improving after 1 and 6 months compared with the control group.514 The French Plasmapheresis Group confirmed the effectiveness of PE.431 PE is believed to remove autoantibodies, immune complexes, complement, or other humoral factors involved in the pathogenesis of AIDP. The total amount of plasma exchanged is 200250 ml/kg of patient body weight over 1014 days. The removed plasma is generally replaced with albumin. Thus, a 70 kg patient receives 14,00017,500 ml (1417.5 L) total exchange, which can be accomplished by 46 alternate day exchanges of 24 liters each. IVIG has replaced PE in many centers as the treatment of choice for AIDP because it is more widely available and easier to use than PE. The dose of IVIG is 2.0 gm/kg body weight infused over 25 days. The mechanism of action of IVIG is not known. In a prospective controlled trial of IVIG vs. PE, IVIG was shown to be at least as effective as PE.1334 Subsequent randomized studies confirmed the efficacy of IVIG in AIDP (see Table 23-3).148,1053 Of importance, one study noted no added benefit of IVIG after PE.1059 Treatment with IVIG or PE should begin as soon as possible, preferably within the first 710 days of symptoms. However, improvement with PE and IVIG is often not immediate. The mean time to improvement of one clinical grade in the various controlled, randomized PE and IVIG studies ranged from 6 days to as long as 27 days.431,514,1334 Thus, one may not see dramatic improvement in strength in patients during PE or IVIG treatments. Clinicians need to be aware of the time frame for improvement in AIDP. No evidence indicates that PE beyond 250 ml/kg182,431,612,1119 or IVIG greater than 2 gm/kg is of any added benefit in patients with AIDP and a stable deficit. Furthermore, there is no indication for PE followed by IVIG or vice versa. However, as many as 10% of patients treated with either PE431,1119 or IVIG182,612 develop a relapse after initial improvement. In patients who suffer such relapses, we give additional courses of PE or IVIG. Unlike chronic inflammatory demyelinating polyneuropathy (see below), corticosteroids do not appear beneficial in the treatment of AIDP; in fact, some patients have done worse.605 A small study of 25 patients treated with IVIG and intravenous methylprednisolone345 did better than a historical control group treated with IVIG alone.1334 However, a much larger British study of 142 patients treated with methylprednisolone or placebo (approximately half the patients in each group also were treated with PE) failed to demonstrate the efficacy of corticosteroids.515 AIDP in Children. The clinical, laboratory, and electrophysiologic findings in children with AIDP are similar to those noted in adults.64,311,143,821,1021a,1086 Almost 75% of children have an antecedent infection within two months of onset of symptoms. The major presenting complaint in children is pain. As in adults, generalized weakness, sensory loss (including sensory ataxia), cranial nerve and respiratory muscle weakness, and autonomic dysfunction can occur. Laboratory evaluation is remarkable for an elevated CSF protein as in adults. Sural nerve biopsies in children with GBS demonstrate similar histopathologic abnormalities as those described in adults.821 In large series of children with AIDP, electrophysiologic studies demonstrated prolonged or absent F-waves in 8188% within the first few weeks of symptoms.143,1086 During these first two weeks, 83100% of the children also had reduced CMAP amplitudes, and 2260% had mean CMAP amplitudes less than 20% of the lower limit of normal. In addition, temporal dispersion or conduction block of CMAPs was found in 6174% of cases. A reduction in nerve conduction velocity was noted in

944 PART IV

CLINICAL APPLICATIONS Table 23-3. Guillain-Barr Syndrome: Plasmapheresis and IVIG Trials Plasmapheresis Group Control Group 123 40 days 85 days 169 days 23 days 39 87 111 43% 31 days 111 days 45 days 74 53 27 days 55 days 27% 5 130 0.8 26 days 51days 21 (16.5%) IVIG Group

North American Trial Number of patients Time to improve 1 clinical grade Time to walk unaided (all patients) Time to walk unaided (ventilator patients) Time on ventilator % improved at 1 month % improved at 6 months French Trial Number of patients % of patients on ventilator after study Time to wean from ventilator Time to walk unaided Time in hospital Dutch IVIG Trial Number of patients % of patients improving 1 clinical grade after 4 weeks Time to improve 1 clinical grade Time to clinical grade 2 Ventilator dependent by week 2 Number of multiple complications PE/Sandoglobulin Trial Group Number of patients Mean change in clinical grade after 4 wk Time to wean from ventilator Time to walk unaided Number of patients unable to walk after 48 wk

122 19 days 53 days 97 days 9 days 59 97 109 21% 18 days 70 days 28 days 73 34 41 days 69 days 42 16 121 0.9 29 days 49 days 19 (16.7%)

North American Trial: Guillain-Barr Study Group: Plasmapheresis and acute Guillain-Barr syndrome. Neurology 1985;35:10961104; French Trial: French Cooperative Group on Plasma Exchange in Guillain-Barr Syndrome: Efficiency of plasma exchange in Guillain-Barr syndrome: Role of replacement fluids. Ann Neurol 1987;22:753761; Dutch IVIG Trial: van der Mech FGA, Schmidtz PIM, and the Dutch Guillain-Barr Study Group:A randomized trial comparing intravenous immunoglobulin and plasma exchange in Guillain-Barr syndrome. N Engl J Med 1992;326:11231129; Plasma Exchange/Sandoglobulin GBS Trial Group: Plasma Exchange/Sandoglobulin Guillain-Barr Syndrome Trial Group: Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barr syndrome. Lancet 1997;349:225230.This trial also had 128 patients randomized into a treatment group that received plasmapheresis (PE) followed by IVIG.There was no statistically significant improvement in any outcome measures in this group compared with the groups that received PE or IVIG alone.

two or more nerves in 48% of patients and in at least one nerve in 7084%. Prolonged distal motor latencies were evident in at least one nerve in 5775% of children. Abnormal SNAPs were reported in about 70% of patients, with decreased or absent responses in 5261% and prolonged distal latencies or slow conduction velocities in 954%. Needle EMG examination revealed fibrillation potentials and positive sharp waves in at least one muscle in 27% of children. Fortunately, most children with AIDP have a satisfactory recovery, even those with significant reductions in CMAP amplitude.143,1021a,1086
Acute Motor-Sensory Axonal Neuropathy Clinical Features. Feasby and colleagues initially reported this axonal variant of GBS in 1986.397 Although its existence was met with early skepticism,1311,1312 recent histologic studies confirm that AMSAN is a real disease entity.506,507 Clinically and at least by initial electrodiagnostic studies, patients with AMSAN are indistinguishable from those with AIDP.150,159,397,400,424,506,507, 821,841,894,896,1131,1312,1404 As with GBS, sensory abnormalities are noted initially in the hands or feet and progress later. Patients with AMSAN develop rapidly progressive and severe generalized weakness over only a few days as opposed to a couple of weeks in most patients with AIDP. Ophthalmoplegia may be noted as well as difficulty in swallowing. The muscles of facial expression are also profoundly weak. Most patients require ventilator

support during the course of the disease. Sensation to all modalities is reduced, and complete areflexia is usually evident. Autonomic disturbances can be observed with respect to blood pressure instability and cardiac arrhythmias. The prognosis of AMSAN is much poorer than in AIDP; most patients have a slow and incomplete recovery.894,896 Only a few children have been reported with AMSAN; there is some suggestion that the prognosis, although guarded, is better than in adults.1097 Laboratory Features. As in AIDP, albuminocytologic dissociation of the CSF protein is usually evident during the course of the neuropathy. In addition, recent infection with C. jejuni and antibodies directed against antinerve gangliosides, particularly GM1 antibodies, have been demonstrated in many patients with AMSAN.507,1446 Some authorities suggest that C. jejuni infection and GM1 antibodies are more commonly associated with axonal forms of GBS (i.e., AMSAN and AMAN) and poorer prognosis, but this is controversial.741,1446,1447 Some patients with antecedent C. jejuni infection and GM1 antibodies have typical AIDP and a good recovery.741,1369 Histopathology. Histologic evaluation performed early in the course of the disorder is the only way to differentiate axonal GBS from pseudoaxonal GBS because of their clinical, laboratory, and electrophysiologic similarities. In patients biopsied late in the disease, it can be difficult to distinguish primary axonopathy from secondary axonal degeneration. In several reports

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of patients with inexcitable motor and sensory conduction studies, the histopathology of sensory and motor nerves suggested severe demyelination rather than primary axonal degeneration.88,109,437,540,842 Nevertheless, some patients with inexcitable CMAPs and SNAPs clearly have had histologic abnormalities supportive of a primary axonal insult.397,400,506,507,816 In contrast to AIDP, demyelination and lymphocytic infiltrates are absent or only minimally present on nerve biopsy or at autopsy in patients with AMSAN. Rather, prominent axonal degeneration affecting the ventral and dorsal roots and the peripheral nerves is evident. As many as 80% of teased fibers reveal axonal degeneration, whereas demyelinating features are rare.397,400 Axonal degeneration leads to profound loss of both myelinated and unmyelinated axons. Griffin and colleagues reported the pathology of three patients with AMSAN who died early in the course of their illness.507 They demonstrated that prominent axonal degeneration of the spinal roots and peripheral nerves without demyelination or significant inflammation was an early histopathologic feature. They also noted that numerous macrophages were present in the periaxonal space of myelinated internode, as were rare intraaxonal macrophages. Similar histologic abnormalities are seen in AMAN (see below) but are not typical in AIDP. Pathogenesis. The pathogenic basis of AMSAN is unknown and only speculative. AMSAN is most likely due to an immunemediated attack directed against epitopes on the axon.507 The neural epitopes may be gangliosides, such as GM1 or GM1a, which are present on the nodal axolemma.1446,1447 AMSAN can follow C. jejuni infection, leading to production of antiganglioside antibodies due to molecular mimicry. Early in the course or with mild disease, binding of the antibodies to neural epitopes may result in only physiologic conduction block. Complement activation on nodal and later internodal axolemma and recruitment of macrophages may result in axonal degeneration. Electrophysiologic Findings. Nerve conduction studies reveal markedly diminished amplitudes or absent CMAPs within 710 days of onset.159,243,397,400,424,540,841,894,896,1404,1439 The SNAP amplitudes are also profoundly reduced or absent. As discussed earlier, low-amplitude CMAPs are one of the earliest electrophysiologic abnormalities noted in AIDP. Therefore, hypo- or inexcitability of the motor nerve does not necessarily imply axonal degeneration. Distal conduction block with or without demyelination can be responsible for the low-amplitude distal CMAPs.1311,1312 In fact, it may be impossible, at least initially, to distinguish AIDP from AMSAN by nerve conduction studies. Serial nerve conduction studies may be helpful in determining the underlying pathology and prognosis. Triggs reported 34 patients with GBS who had low-amplitude or unobtainable CMAPs.1311 Of the eight patients with unobtainable CMAPs, five made good recoveries (suggesting conduction block, not axonal degeneration), whereas three patients did poorly (presumably secondary to axonal degeneration). Of 26 patients who initially had low-amplitude CMAPs, serial conduction studies revealed decreasing amplitudes in 12 (suggesting worsening of conduction block or increasing axonal degeneration) and increasing amplitudes in nine (suggesting improvement of conduction block). Not unexpectedly, the patients believed to have electrophysiologic evidence of resolving distal conduction block had a better prognosis than patients whose distal CMAP amplitudes progressively declined. In three patients with AMSAN studied within the first week of symptoms, Brown recorded CMAP amplitudes as the stimulator was moved from the common distal sites of stimulation (wrist and ankle) to within 50100 mm of the motor point by

inching technique.159 In each case, the CMAPs after wrists and ankle stimulation were markedly reduced or absent. As the sites of stimulation were moved closer to the motor point, the CMAP potentials progressively increased in size. Nevertheless, the CMAP amplitudes never exceeded 10% of the lower limit of normal. These findings were interpreted as most consistent with axonal degeneration; however, distal demyelination with conduction block could not be excluded. These distal-most segments reportedly had slow conduction velocities, often to less than 30% of normal, and in one instance to less than 1 m/s. Ideally, the distal latencies of the CMAPs and the nerve conduction velocities, when obtainable, should be normal or only mildly affected. The presence of prolonged distal latencies, slow conduction velocities, or significantly dispersed distal CMAP waveforms in patients with low CMAP amplitudes should lead to the consideration of demyelination and conduction block of the distal motor nerve terminal rather than a primary axonal insult. In the presence of inexcitable motor nerves, it is impossible to distinguish AIDP from AMSAN. On the basis of its distinct histopathology, it appears that AMSAN does exist, although it is a rare condition. The needle EMG examination demonstrates markedly abnormal reductions in recruitment. Several weeks after the presentation of major motor weakness, abundant fibrillation potentials and positive sharp waves can be detected in most muscles, especially those located in the distal regions of the limbs.88,1446,1447 Treatment. No prospective treatment studies have been performed specifically for AMSAN. Because it is difficult to distinguish AIDP from AMSAN clinically or electrophysiologically, at least initially, treatment with either plasma exchange or IVIG is warranted.
Acute Motor Axonal Neuropathy Epidemiology. The first detailed descriptions of the AMAN variant of GBS were by McKhann and colleagues, who reported the clinical, laboratory, electrophysiologic, and histologic findings in cases of seasonal outbreaks of acute flaccid paralysis in northern China.867,868 They initially named the disorder Chinese paralytic syndrome. Because similar cases subsequently were described throughout the world, the term acute motor neuropathy was believed to be more appropriate.616,1359 In northern China, AMAN is the most common variant of GBS. AMAN appears to be less frequent in other areas of the world but is still quite common. Twenty seven of the 147 (18%) patients enrolled in the Dutch GBS trial comparing IVIG with PE were later classified as having AMAN.1334,1359 An antecedent illness has been described in 3085% of patients with AMAN in large series.526,821,868,1021a,1359 A preceding gastrointestinal infection can be elicited in 1060% of such cases. In addition, serologic evidence of a recent C. jejuni infection can be demonstrated in 6792% of patients.868,1359 Clinical Features. AMAN has been described in children and adults.585,616,821,867,868,1026,1359 As in AMSAN, there is an abrupt onset of generalized weakness. The distal muscles often are affected more severely than proximal limb muscles. Cranial nerve deficits and respiratory failure requiring mechanical ventilation can be seen in up to one-third of patients.867,868,1026,1359 Unlike AIDP and AMAN, sensory signs and symptoms are absent. Autonomic dysfunction in the form of cardiac arrhythmias, blood pressure fluctuations, and hyperhidrosis may occur. Deep tendon reflexes may be normal or absent. Of interest, some patients even develop hyperactive reflexes during the recovery period.616,868 The median time of recovery is similar to that in typical AIDP. Patients generally make a good recovery within

946 PART IV

CLINICAL APPLICATIONS

one year, but residual distal limb weakness is common.585 The mortality rate is less than 5%.868 Second attacks of the illness have been described in northern Chinese patients, but the actual recurrence rate is not known.868 Laboratory Features. As with AIDP and AMSAN, albuminocytologic dissociation is the rule.616,867,868,1021a,1359 The absence of prominent CSF pleocytosis helps distinguish AMAN from poliomyelitis, which it can mimic. Serology evidence of recent C. jejuni infection can be demonstrated in 6792% of patients.868,1359 Anti-GM1 and anti-GD1a antibodies are commonly detected in patients with AMAN and usually are associated with recent Campylobacter infection.526,586,868,1359 Histopathology. The earliest histologic abnormalities are noted at the nodes of Ranvier.530 The nodal gaps can be appreciably lengthened, when the rest of the nerve fiber appears otherwise normal. Immunocytochemistry reveals deposition of IgG and complement activation products (i.e., C3d and C5b-9) on the nodal and internodal axolemma of motor fibers and precedes features of axonal degeneration.530 Deposition of IgG and complement is also evident on the nodes of Ranvier on teased fiber analysis and EM.530 These features contrast with the findings in AIDP: early deposition of immunoglobulin and complement on Schwann cells rather than the axons.530 Macrophages are also evident over the nodes of Ranvier of large myelinated ventral motor root fibers.530 The macrophages probably are recruited into the affected nodes and periaxonal space via complement-derived chemotropic factors.530 These inflammatory cells insert through the Schwann-cell basal lamina into the nodal gap. Subsequently, the macrophages can be seen encircling the nodes and dissecting beneath the myelin sheath into the periaxonal space. As they enter the perixonal space, the axon retracts from the adaxonal Schwann cell. In severe cases, the axons then begin to degenerate, but the innermost myelin sheath (adaxonal lamella) appears intact. Ho demonstrated active degeneration and severe loss of large myelinated intramuscular nerve fibers on muscle biopsies that included the distal motor nerve terminals.585 Pathogenesis. Histopathology and immunologic studies suggest that AMAN is caused by an immune-mediated attack against an unknown epitope on the nodal axolemma. As noted above, serologic evidence of a preceding infection with C. jejuni and anti-GM1 and anti-GD1a antibodies can be identified in many patients with AMAN in addition to typical AIDP and AMSAN. It is speculated that antibodies directed against the lipopolysaccaride membrane of Campylobacter cross-react with specific epitopes on the nodal axolemma (e.g., GM1 or GD1a gangliosides).530 The binding of antibodies to the nodal axolemma with or without subsequent complement activation may decrease the sodium current or increase the potassium current, thereby resulting in conduction block.1283 In severe cases, axonal degeneration occurs via complement-mediated damage to the axons. The fact that many patients with AMAN syndrome recover quickly suggests that the low-amplitude or unobtainable distal CMAPs (see below) are due not necessarily to axonal degeneration but to distal conduction block. Diminished CMAP amplitudes and early recovery also may be seen if degeneration is limited to the distal motor nerve terminal.585 Electrophysiologic Findings. The characteristic electrophysiologic feature on nerve conduction studies in AMAN is low-amplitude or unobtainable CMAPs with normal SNAPs.585,616,867,868,1359 When CMAPs are obtained, the distal latencies and conduction velocities are normal. F-waves are also usually unobtainable but, when present, show normal latencies. As discussed in the AIDP and AMSAN sections, the decreased CMAP amplitudes may be

a reflection of distal conduction block or perhaps only degeneration of the distal motor nerve terminal as opposed to widespread axonal degeneration. Increased spontaneous activity in the form of fibrillation potentials and positive sharp waves and decreased recruitment of MUAPs usually can be appreciated.585,616,867,868,1359 Motor unit number estimate (MUNE) performed sequentially in 7 patients with AMAN demonstrated a marked decrease at the peak of illness.741a As clinical recovery began, CMAP amplitudes increased without a significant change in the MUNE. The investigators suggested that the primary mechanism of early recovery in AMAN may be collateral reinnervation, with resolution of conduction block and nerve regeneration occurring later. Treatment. No treatment trials have been devoted to AMAN, but it is likely that patients were included in some of the AIDP trials comparing PE and IVIG. As noted above, 27 of the 147 (18%) of the patients enrolled in the Dutch GBS trial comparing IVIG with PE were later classified as having AMAN.1334,1359 Subgroup analysis of the AMAN group suggested that IVIGtreated patients may recover faster than PE-treated patients. There was no significant difference in outcome, regardless of treatment (IVIG, PE, or PE followed by IVIG) between AIDP and AMAN in a subgroup analysis of 369 patients.526 Because of the ease of administration, we generally treat AMAN patients with IVIG, 2 gm/kg over 5 days, as in AIDP. PE is an alternative if IVIG is not available or is contraindicated.
Other Variants of Guillain-Barr Syndrome Other variants of GBS include Miller-Fisher syndrome (ataxia, areflexia, and ophthalmoplegia), idiopathic cranial polyneuropathy, pharyngeal-cervical-brachial weakness with or without ophthalmoparesis, and paraparetic weakness.645,1118,1124 These disorders may represent an oligosymptomatic form or forme-fruste of AIDP. Of these possible GBS variants, MillerFisher syndrome is best characterized. Clinical Features. In 1956, C. Miller-Fisher reported three patients with ataxia, areflexia, and ophthalmoplegiaa syndrome distinct from GBS.420 Since then, over 200 cases of Miller-Fisher syndrome (MFS) have been described either as case reports or small series of patients.96,923a,1121 There is a 2:1 male predominance with a mean age of onset in the early 40s. An antecedent infection occurs in over two-thirds of the cases. Diplopia is the most common initial complaint (3978%); ataxia is evident in 2134% of patients at onset. Whether the ataxia is secondary to sensory dysfunction or a cerebellar lesion is controversial. In our experience, most patients have sensory ataxia. Ophthalmoparesis can develop asymmetrically but often progresses to complete ophthalomoplegia. Ptosis usually accompanies the ophthalmoparesis, but pupillary involvement is uncommon. Other cranial nerves also can become involved. Facial weakness is evident in 3257%, dysphagia in 2640%, and dysarthria in 1340% of patients. Nearly one-half of patients describe paresthesias of the face and distal limbs. Areflexia is evident on examination in over 82%. Mild proximal limb weakness can be demonstrated in the course of the illness in approximately one-third of cases. Some patients progress to more severe generalized weakness similar to typical GBS.96,105,559,1213 Clinical return of function usually begins within about 2 weeks after the onset of symptoms, and full recovery of function is typically seen within 35 months. Laboratory Features. Most patients with MFS have elevated CSF protein without significant pleocytosis.96,1121 Serologic evidence of C. jejuni can be demonstrated in some patients as well as antiganglioside antibodies, in particular anti-GQ1b.213,923a,1448

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Histopathology. Biopsy and autopsy data are limited and need to be viewed cautiously because some cases that began with ophthalmoplegia, ataxia, and areflexia later evolved to severe quadriparesis characteristic of more typical AIDP.1055 These studies showed normal brainstem findings or only secondary chromatolysis of the oculomotor, trochlear, or abducens nuclei. Demyelination and mild inflammatory infiltrates were noted along the course of these cranial nerves. Lymphocytic infiltrates were also apparent in the sensory ganglia of peripheral nerves. Pathogenesis. The pathogenic basis of MFS is not known, although it is probably autoimmune. The primary site of the immune attack (i.e., PNS or CNS) is controversial.96,923a,1121 Most authorities believe that the clinical, electrophysiologic, and histologic findings point to the PNS, in particular the sensory ganglia and oculomotor fibers. Similar to other variants of GBS, recent antecedent infections, including enteritis due to C. jejuni, can be identified in most patients with MFS. Perhaps through molecular mimicry, autoantibodies directed against these infectious agents cross-react with neuronal epitopes. As noted above, anti-GQ1b antibodies can be detected in most patients with MFS. Of importance, oculomotor fibers and the sensory ganglion, which are prominently affected in MFS, are enriched with GQ1b. AntiGQ1b antibodies stain sensory neurons in the dorsal root as well as cerebellar nuclei. In mice infused with serum from patients with MFS, the GQ1b antibodies were observed to bind to neuromuscular junctions.1061 In a complement-dependent process, this resulted in massive quantal release of acetylcholine from nerve terminals and eventually blocked neuromuscular transmission. Electrophysiologic Findings. The most prominent electrophysiologic abnormality in MFS is reduced amplitudes of SNAPs out of proportion to prolongation of the distal latencies or slowing of sensory conduction velocities.304,434,622,11021142,1172,1397 Minimally slowed motor conduction velocities (still within 80% of normal) and prolonged F-waves have been reported in only a few patients. CMAPs in the arms and legs are usually normal. In contrast to limb CMAPs, mild to moderate reduction of facial CMAPs can be demonstrated in over 50% of patients with MFS.434 Blink reflex may be abnormal with facial nerve involvement. Reduced facial CMAPs coincide with the loss or mild delay of R1 and R2 responses on blink reflex testing.299,434,559 Evoked potential studies have given inconsistent results. Some studies report central conduction abnormalities on somatosensory, brainstem, and visual evoked responses.1058,1140 Other studies report normal evoked potentials or slowing localized to the peripheral nervous system.299,622,623,1118 EMG reveals minimal abnormalities.434,622 There is generally no abnormal spontaneous activity in limb or paraspinal muscles. However, fibrillation potentials may be detected in facial muscles. Decreased recruitment of MUAPs may be noted in weak muscles. During recovery, increased MUAP duration, amplitude, and polyphasia can be seen. Treatment. There are no controlled treatment trials of patients with MFS. However, it seems prudent to treat patients with either IVIG or PE, given the presumptive similarity in pathogenesis with AIDP.

ACQUIRED CHRONIC DEMYELINATING POLYNEUROPATHIES

Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy characterized by

a relapsing or progressive course. 73,78,147,351,560a,1131a,1168a The relapsing form was recognized as early as 1914 by Hoerstermann and was described as recurrent polyneuritis.588 The progressive form of the neuropathy was reported as progressive hypertrophic neuritis1133 and chronic Guillain-Barr syndrome (GBS).303 Austin initially described the steroid-responsive nature of CIDP in 1958. Dyck retrospectively reported the clinical, laboratory, electrophysiologic, and histologic features of 53 patients and termed the disorder chronic inflammatory polyradiculoneuropathy. 351 Torvik and Lundar proposed the name chronic inflammatory demyelinating polyradiculoneuropathy to underscore the demyelinating features. Subsequently, other large series of patients were reported73,130,276,353,477,864,887,1071,1297 and guidelines for the diagnosis of CIDP were developed.73 In 1991, the Ad Hoc Subcommittee of the American Academy of Neurology (AAN) proposed research criteria for the diagnosis of CIDP (Table 23-4).249 Modifications were recently proposed to distinguish CIDP from other forms of chronic acquired demyelinating polyneuropathy.1168a With increased recognition, CIDP has accounted for approximately 1033% of initially undiagnosed peripheral neuropathies.73,78,353,864 Clinical Features. Symptoms and signs of the neuropathy must be progressive for at least two months, which distinguishes CIDP from GBS or AIDP.73,249,1168a Some patients have a subacute onset over 48 weeks, a variant that Hughes termed subacute demyelinating.603 The subsequent natural history of these subacute cases may be that of AIDP (spontaneous remission) or CIDP (chronic relapses or progression), requiring treatment. Dyck describe four typical clinical courses of progression in patients with CIDP: (1) chronic monophasic (15%); (2) chronic relapsing (fluctuations of weakness or improvement over weeks or months); (34%); (3) stepwise progressive (34%); and (4) steady progressive (15%).351,363 The pattern of disease progression in CIDP is analogous to multiple sclerosis, affecting only the peripheral as opposed to central nervous system. CIDP most commonly presents in adults with a peak incidence at about 4060 years; there is a slightly increased prevalence in men.73,130,276,351,477,560a,864,1071,1297 The relapsing form has an earlier age of onset, usually in the twenties.73,351 Relapses have been associated with pregnancy.862 The association of CIDP with infections has not been studied as extensively as in AIDP; however, an infection has been reported to precede 2030% of CIDP relapses or exacerbations.864,1216 Most patients present with relapsing or progressive symmetric proximal and distal weakness of the arms and legs.73,130, 249,363,477,864,1131a,1168a,1297 Weakness of proximal lower limb muscles results in difficulty with ambulating, climbing stairs, and arising from a low soft chair or commode. Distal lower limb weakness may cause foot drop, leading to stubbing of toes and tripping. Distal upper limb weakness impairs fine motor dexterity (buttoning shirts, tying shoes, picking up small objects), whereas proximal weakness causes difficulties with performing activities requiring overhead hand use (grooming, putting books on a high shelf) and lifting or carrying heavy objects (groceries). Clinical examination usually confirms weakness in proximal and distal arm and leg muscles. The diagnostic criteria proposed by Barohn and colleagues require symmetric proximal and distal weakness.73,1168a However, the AAN criteria are looser clinically and do not require either proximal or symmetric weakness (see Table 23-4).249 Early in the course of the illness, only distal weakness may be observed. However, if weakness remains distal, other diagnoses need to be considered (e.g., hereditary demyelinating neuropathy, paraprotein-related

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Table 23-4. Research Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Clinical criteria 1. Mandatory Progressive or relapsing motor and sensory (rarely only motor or sensory) dysfunction of more than one limb of a peripheral nerve developing over at least 2 months. Hypo- or areflexia.This will usually involve all four limbs. 2. Supportive: Large-fiber sensory loss predominates over small-fiber sensory loss. 3. Exclusionary Mutilation of hands or feet, retinitis pigmentosa, ichthyosis, appropriate history of drug or toxic exposure known to cause a similar peripheral neuropathy, or family history of a genetically based peripheral neuropathy Sensory level Unequivocal sphincter disturbance Physiologic studies 1. Mandatory Nerve conduction studies, including studies of proximal nerve segments in which the predominant process is demyelination. Must have three of four: (1) Reduction in conduction velocity (CV) in two or more motor nerves: (a) < 80% of lower limit of normal (LLN) if amplitude > 80% of LLN. (b) < 70% of LLN if amplitude < 80% of LLN. (2) Partial conduction block or abnormal temporal dispersion in one or more motor nerves: peroneal nerve between ankle and below fibular head, median nerve between wrist and elbow, or ulnar nerve between wrist and below elbow. (a) Criteria suggestive of partial conduction block: < 15% change in duration between proximal and distal sites and > 20% drop in negative-peak (p) area or peak-to-peak (pp) amplitude between proximal and distal sites. (b) Criteria for abnormal temporal dispersion and possible conduction block: > 15% change in duration between proximal and distal sites and > 20% drop in p area or pp amplitude between proximal and distal sites.These criteria are only suggestive of partial conduction block because they are derived from studies of normal subjects.Additional studies, such as stimulation across short segments or recordings of individual motor unit potentials, are required for confirmation. (3) Prolonged distal latencies in two or more nerves: (a) > 125% of upper limit of normal (ULN) if amplitude > 80% of LLN. (b) > 150% of ULN if amplitude < 80% of LLN. (4) Absent F-waves or prolonged minimum F-wave latencies (1015 trials) in two or more nerves: (a) > 120% of ULN if amplitude > 80% of LLN. (b) > 150% of ULN if amplitude < 80% of LLN. 2. Supportive criteria Reduction in sensory CV < 80% of LLN Absent H-reflexes. Pathologic features 1. Mandatory: nerve biopsy showing unequivocal evidence of demyelination and remyelination. Demyelination by either electron microscopy (> 5 fibers) or teased fiber studies (> 12% of 50 teased fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination). 2. Supportive Subperineurial or endoneurial edema. Mononuclear cell infiltration. Onion-bulb formation. Prominent variation in the degree of demyelination between fascicles. 3. Exclusionary:Vasculitis, neurofilamentous swollen axons, amyloid deposits, or intracytoplasmic inclusions in Schwann cells or macrophages indicating adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, or other evidence of specific pathology. CSF studies 1. Mandatory Cell count < 10/mm3 if HIV-seronegative or < 50/mm3 if HIV-seropositive. Negative Venereal Disease Research Laboratory Test 2. Supportive: elevated protein. Diagnostic categories for research purposes. Definite: clinical A and C, physiology A, pathology A and C, and CSF A. Probable: clinical A and C, physiology A, and CSF A. Possible: clinical A and C and physiology A. Laboratory studies. Depending on the results of laboratory tests, patients meeting the above criteria are classified into the groups listed below.The following studies are suggested: CBC, routine chemistries,ANA, serum and urine immunoglobulin studies (including either immunofixation electropheresis or immunoelectropheresis), and HIV and hepatitis serology.The list of laboratory studies is not comprehensive. For instance, in certain clinical circumstances other studies may be indicated, such as thyroid functions, phytanic acid, long-chain fatty acids, porphyrins, and urine heavy metals.
From Cornblath DR, Asbury AK, Albers JW: Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991;41:617618.

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neuropathy, or distal acquired demyelinating neuropathy).661,1168a Although most patients (at least 80%) have both motor and sensory involvement, a few patients may have pure motor (10%) or pure sensory (510%) symptoms and signs.73,351,477,560a,1131a Whether patients with pure motor or sensory involvement, particularly when it is asymmetric, fall within the spectrum of CIDP or represent a distinctly different neuropathic disorder (e.g., multifocal motor neuropathy; see below) is debatable. As noted above, most patients have sensory involvement. Sixty-eight to 80% of patients complain of numbness in the hands or feet.130,351,477,864 Painful paresthesias are less common, occurring in 1550% of patients. Sensory examination is abnormal in 6884% of patients, primarily affecting large-fiber modalities (vibration and touch).73,130,351,477,864 An associated sensory ataxia, a positive Romberg sign, and a wide-based gait may be found. Enlarged nerves can be palpated in as many as 11% of patients.351 The term chronic sensory demyelinating neuropathy has been applied to the few patients who have only sensory symptoms and signs.264,986,987,1131a However, an electrodiagnostic medicine evaluation in such patients usually reveals abnormalities affecting the motor nerves.264,986,987 Some patients begin with only sensory symptoms and signs but later develop motor abnormalities.91 In our experience, most patients with a demyelinating neuropathy who have mainly sensory symptoms and signs with normal or only mild distal weakness have an IgM monoclonal gammopathy.661,1168a Whenever a pure sensory neuropathy is present, consideration should be given to other diseases as well, such as Sjgrens syndrome or paraneoplastic neuronopathy, both of which are associated with sensory ganglionitis.24 Most patients with CIDP have areflexia or hyporeflexia. Cranial nerve involvement occasionally occurs but is usually mild and not the presenting feature. Mild facial weakness is evident in 216%, diplopia secondary to ophthalmoplegia in up to 8%, dysarthria and dysphagia in 9%, and papilledema in 17% of patients.73,130,276,351,864 Vertigo related to vestibular involvement is a rarely reported complication.433 Some patients can develop dropped head syndrome secondary to neck extensor weakness.589 Respiratory insufficiency secondary to intercostal muscle and diaphragm weakness has been reported in 815% of patients.276,351 Autonomic dysfunction (e.g., incontinence and impotence) are less common, occurring in less than 5% of patients.351 Of interest, approximately 35% of patients with CIDP also have evidence of CNS demyelination clinically, electrophysiologically (evoked potential studies), or by MRI scans.130,398,570,886, 1005,1012,1131a,1139,1300,1319 The CNS abnormalities can precede or follow the onset of CIDP. Whether such patients have multiple sclerosis or if the CNS demyelination in CIDP represents a distinct immunologic disorder is not known. Patients also may develop a myelopathy due to compression of the spinal cord by hypertrophied nerve roots.313,340,740,893,902 Other medical conditions may be seen in association with CIDP or a CIDP-like neuropathy,21,73,247,1131a including HIV infection, hepatitis, inflammatory bowel disease, systemic lupus erythematosus, diabetes mellitus, monoclonal gammopathy of uncertain significance (MGUS), POEMS syndrome, lymphoma, and Castleman disease. Besides the association with the above lymphoproliferative disorders, CIDP or a CIDP-like neuropathy has been described as a paraneoplastic complication of small cell carcinoma of the lung, carcinoma of the pancreas and colon, cholangiocarcinoma, and melanoma.24,30,31,102,1398 In addition, a CIDP-like neuropathy may complicate bone marrow and solid organ transplantations, usually in the setting of graft-versus-host disease or transplant rejection.21,22,1289 Furthermore, a toxic-induced neuropathy

resembling CIDP has been associated with certain medications such as procainamide, cyclosporine, and tacrolimus.22,380 It is not known whether the pathogenesis, prognosis, and response to treatment of demyelinating neuropathies associated with these medical disorders are identical to those of idiopathic CIDP. For example, some patients with diabetes mellitus develop symmetric proximal and distal weakness, hyporeflexia, and elevated CSF protein and have demyelinating nerve conduction studies and nerve biopsies that fulfill research criteria for CIDP (see section on diabetic neuropathies).24a,241,479,627,729,1033,1261,1322 It is debatable whether such patients have an unusual form of diabetic neuropathy or superimposed CIDP. The demyelinating neuropathies associated with IgG and IgA monoclonal gammopathies of unknown significance (MGUS) are usually indistinguishable from CIDP; however, the neuropathies associated with IgM monoclonal neuropathies may have somewhat different clinical and electrophysiologic features as well as a distinct pathogenesis and response to therapy (see below). Laboratory Features. An elevated CSF protein (> 45 mg/dl) is found in 8095% of patients.73,130,351,477,1168a These large studies have reported CSF protein levels over 1200 mg/dl with a mean of about 135 mg/dl. As with AIDP, the cell count is usually normal, although up to 10 % of patients have > 5 lymphocytes/mm3.73,276,351,477,1071,1297 Leukocyte count in the CSF should be < 10/mm3 or < 50/mm3 in HIV-positive patients. Elevated CSF cell counts should lead to the consideration of HIV infection, Lyme disease, and lymphomatous or leukemic infiltration of nerve roots. Oligoclonal bands may be demonstrated in the CSF in approximately 65% of patients.274,1194 As many as 25% of patients with CIDP or a CIDP-like neuropathy have an IgA, IgG, or IgM monoclonal gammopathy.73,477,661,1168a,1217 Paraprotein-related CIDP is addressed in a separate section. Antibodies directed against myelin proteins (e.g., GM1 ganglioside, P0 and P2) are present in a small percentage of patients.610,680 One study reported a high titer of antitubulin antibodies in patients with CIDP,236 although other groups have not verified this observation.828,1342 MRI with gadolinium may reveal hypertrophy and enhancement of the nerve roots and peripheral nerves.313,340,740,893,902 Histopathology. The peripheral nerve and nerve root regions are affected, with occasional involvement of the central nervous system.73,130,363,726,887,1131a When the nerve roots are involved, the ventral rami, posterior rami, or both may be preferentially affected. Segmental demyelination and remyelination are the most prominent histologic abnormalities (Fig. 23-3) but are not present in every biopsy because of the multifocality of the disease process. Chronic demyelination and remyelination result in proliferation of surrounding Schwann cell processes, forming so-called onion-bulbs. However, these onion bulbs are not as prominent as in Charcot-Marie-Tooth disease. A total reduction in the number of myelinated fibers is also usually evident on biopsy. Analysis of teased nerve fibers is the best way to quantify histologic abnormalities. Large series have demonstrated segmental demyelination and/or remyelination in 2368%, axonal degeneration in 542%, mixed demyelinating and axonal features in 12.520%, and normal findings in 243.5% of teased nerve fibers.73,130,351,560a,1131a,1364a Endoneurial and perineurial edema also may be appreciated on biopsy. Schwann cell proliferation and edema can lead to a hypertrophic appearance of the nerve. The inflammatory component of CIDP is often not evident or is quite subtle on sural nerve biopsies (see Fig. 23-3). Barohn found small clusters of mononuclear inflammatory cells in only 10.7% of 56 sural nerve biopsies.73 The inflammatory cell infiltrate is evident in the epineurium, perineurium, or endoneurium and is

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Figure 23-3. CIDP. A, Sural nerve biopsy reveals many thinly myelinated nerve fibers with some nerve fibers surrounded by several layers of Schwann cell proliferation or onion bulbs (epoxy-embedded, touidine blue stain.). B, A macrophage can be seen engulfing an axon and digesting the myelin (epoxy-embedded, touidine blue stain.). C, Paraffins section reveals mononuclear inflammatory cells composed of lymphocytes and macrophages in the endoneurium (H&E stain.)

often perivascular. Dyck and colleagues reported perivascular inflammation, mainly in the epineurium, in 54% of patients and diffuse endoneurial inflammation in 23%.351 However, these inflammatory changes were reported as slight and difficult to distinguish from normal controls. In the largest series (95 nerve biopsies), conspicuous perivascular endoneurial inflammatory infiltrate was noted in only four specimens.130 The percentage of nerve biopsies demonstrating inflammatory cells is increased when immunostaining for lymphocytes and macrophages is performed.246,846,1364a The inflammatory component is composed of macrophages and CD8+ greater than CD4+ lymphocytes.846 Of note, a similar frequency of inflammatory cell infiltrate within nerves is seen in various neuropathies, including normal controls, raising concern about their pathogenic role.127,246 Matrix metalloproteinases (MMP) are a family of endopepsidases with overlapping substrate affinities for various extracellular matrix proteins. MMP-2 and MMP-9 (gelatinase A and B) have been shown to be upregulated in the peripheral nerves in patients with CIDP.778 T-cells are the predominant source of MMP-2 and MMP-9, which are capable of degrading components of the subendothelial basement membrane, thereby allowing inflammatory cells to disrupt the blood-nerve barrier and penetrate peripheral nerves. As evident from the above discussion, nerve biopsy findings in CIDP are not particularly sensitive or specific. In patients who fulfill the clinical and electrophysiologic criteria for CIDP and who have elevated CSF protein concentrations > 1 g/L, nerve biopsies have no additional diagnostic value. 911 However, if the clinical, electrophysiologic, and CSF findings do not fulfill criteria for CIDP, nerve biopsy is a useful diagnostic tool.

Pathogenesis. The pathogenic basis of CIDP is presumably autoimmune. However, the exact role played by the humoral and cellular arms of the immune system in the pathogenesis of CIDP is not fully understood. The exact tissue antigen(s) and the interaction between the humoral and cellular arms of the immune response are not known. Several lines of evidence suggest involvement of humoral factors: the similarity between CIDP and AIDP and experimental allergic neuritis, improvement in patients after plasma exchange, and demonstration of immunoglobulin and complement on peripheral nerve tissues.276,363 However, large studies have found antimyelin antibodies by direct and indirect immunoflourescent techniques in only a few patients.363 Furthermore, passive transfer experiments of plasma from patients with CIDP into laboratory animals has generally produced negative results. Nevertheless, antibodies directed against axonal elements (e.g., ion channels) probably are involved early in the pathogenesis of CIDP, producing conduction block. The rapid improvement in some patients after PE or IVIG (see below) can be seen only with resolution of conduction block because improvement on the basis of remyelination alone would take longer. Ultrastructural studies indicate activation of macrophages with penetration of the basement membrane and displacement of the Schwann cell cytoplasm.363 The macrophages lyse the superficial myelin lamellae, penetrate along intraperiod lines, and finally engulf the disrupted myelin by endocytosis. The denuded axons shrink in diameter as much as 50%.363 Subsequently, remyelination occurs by recruitment of normal Schwann cells. Axons regain much of their original diameter after remyelination; however, the remyelinated internodes are shorter and thinner than normal. The laying down of new

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Schwann cell processes and basement membrane, particularly after several recurrences of demyelination and remyelination, leads to the typical onion-bulb appearance on biopsy. Physiologically, paranodal and internodal demyelination impairs the propagation of the action potential down the nerve. Demyelination of a nerve segment produces an increased transverse capacitance and reduced resistance in the area, which in turn cause a leakage of current and increase the time required for the longitudinal current to reach the next node of Ranvier. If the current leakage is excessive, there may not be enough current to depolarize the next node of Ranvier, which is necessary to continue propagating the action potential. Block of conduction, not slowing of velocity, is responsible for motor weakness. A recent study demonstrated that median CMAP amplitudes in patients with CIDP diminished by 40% after 60 seconds of isometric exercise suggesting that activity-dependent hyperpolarization results in worsening of conduction block.172a Conduction block along the nerve may be present in lieu of demyelination by the postulated binding and blocking of ion channels by antibodies. Conduction block may resolve prior to remyelination by removal of these antibodies. Electrophysiologic Findings. In performing nerve conduction studies in patients with suspected CIDP, we routinely evaluate median and ulnar CMAPs, SNAPs, and F-waves in the arms. Peroneal and posterior tibial CMAPs and F-waves and sural SNAPs are studied in the lower limbs. We study multiple nerves because of the multifocal nature of the disease process; some nerves can have normal conduction studies, whereas others nerves are abnormal. The probability of finding abnormalities in motor conduction increases in individual patients if multiple nerves are examined. Because there may be a preferential involvement of the nerve roots, it is important to assess the proximal segments of the nerves. Traditionally, F-waves have been used to assess proximal conduction. Recent studies demonstrate the utility of nerve root stimulation in diagnosing patients with CIDP.888 One must ensure a supramaximal stimulus, because submaximal stimulation can produce falsely slower conduction velocities, prolonged distal latencies, absent F-waves, and pseudoconduction block. Finally, demyelination can elevate the peripheral nerve excitation thresholds, thus requiring a greater current to stimulate the nerves. Motor Conduction Studies. Electrophysiologic evidence of demyelination affecting multiple CMAP parameters is the most useful diagnostic test.10,73,130,276,864,1005,1071,1168a,1227 It is mandatory to assess CMAP amplitude, temporal dispersion, conduction block, and F-wave studies for each of the above-noted nerves. The best-studied motor parameter is nerve conduction velocity. Characteristically, there is a significant reduction in motor nerve conduction velocity, usually to less than 70% of the lower limit of normal.10,73,152,249,1168a In addition, distal motor latencies are typically prolonged to 125150% of the upper limit of normal.10,152,249,1168a F-waves are often unobtainable or have prolonged latencies (> 125150% of the upper limit of normal) in patients suspected of CIDP.49a,152,442,986,1168a,1319 Subtle abnormalities, such as reduction in the total number of F-waves (not every stimulus producing an F-wave) or the difference between the shortest and longest measured F-wave latencies, also may be important but have not been addressed in a scientific fashion. A reduction in CMAP amplitude also can be seen at proximal and/or distal sites of stimulation. A significant drop in CMAP amplitude or negative peak area in the response obtained from proximal stimulation compared with distal stimulation is seen with conduction block. The pathophysiologic basis for true conduction block was described above. However, the multifocal nature of the demyelination can differentially affect the conduction

of individual motor nerve fibers, causing temporal dispersion of the CMAP. Pseudoconduction block can result from interphase shifting and cancellation of the negative and positive waveform subcomponents of individual motor unit potentials with other potentials. Therefore, percentage drop in amplitude or area used in defining conduction block by nerve conduction studies is controversial. The AAN criteria require a drop in amplitude or area of only 20% when there is no temporal dispersion (< 15% change in the duration of the negative peak between proximal and distal sites of stimulation).249 When temporal dispersion is greater than 15%, only possible conduction block can be assumed. Albers and Kelly used a 30% drop in amplitude to define conduction block but did not take into account temporal dispersion.10 Other authorities use different degress of amplitude drop depending on the specific nerve investigated998a Computer simulation studies suggest that temporal dispersion can result in up to a 50% drop in CMAP amplitude/area.1098 For this reason, we use a 50% drop in amplitude or area to define conduction block.660,1168 Furthermore, conduction block should be localizable by inching techniques to sites not commonly predisposed to compression. Diminished CMAP amplitudes at distal sites of stimulation may be secondary to either axonal loss or distal conduction block (conduction block between the distal site of stimulation [e.g., the wrist] and the motor nerve terminal). It is difficult to distinguish between conduction block and axonal loss when the terminal aspects of the nerve are involved several centimeters or even millimeters proximal to the muscles end-plate region by motor studies alone. A prolonged distal latency or dispersed waveform favors demyelination with conduction block or pseudoconduction block. Investigations have substantiated significant conduction block within a short distance of the endplate region, documenting the preferential distal involvement. Increased CMAP amplitudes, decreased conduction block, and slightly increased conduction velocity may be seen in association with improvement in strength.49,267,276,354,364,487,535,536,887a,1332 Clinical improvement is primarily the result of resolving conduction block. Some contribution to improvement may be related to some degree of collateral sprouting and regeneration of axons, but this process occurs at a comparatively much slower pace. Sensory Nerve Conduction Studies. None of the electrophysiologic criteria proposed for the diagnosis of CIDP mention sensory nerve conduction abnormalities. Most patients (> 80%) with CIDP have low-amplitude or unobtainable SNAPs in both upper and lower limbs.73,152,153,276,864,986,1071,1332,1372 When sensory responses are obtainable, the distal latencies are often prolonged and conduction velocities slow. The slowing is usually not as severe as that demonstrated in motor nerves. In a study of 18 patients using the near-nerve technique, sensory conduction slowing was only moderate in proportion to the degree of amplitude loss.723 In addition, conduction velocity was similar in proximal and distal segments, and conduction block was evident in a minority of sensory nerves. These findings suggest that some component of the reduced SNAP conduction velocities may be related to the loss of large myelinated sensory nerve fibers. A characteristic finding is abnormal median or ulnar SNAPs (e.g., reduced amplitude, prolonged latency, or slow conduction velocity) when the sural SNAPs are normal. This pattern suggests that the pathologic process is not length-dependent (as is typical of axonal neuropathies) and implies a primarily demyelinating disease. A similar discrepancy between the upper and lower limb SNAPs can be seen in a sensory ganglionopathy, but the electrophysiologic abnormalities in such cases are axonal, not demyelinating.

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Near-nerve needle recordings combined with the averaging of multiple responses may continue to reveal a small and temporally dispersed response. During the recovery phase, a moderate degree of improvement in SNAP parameters to the low normal ranges may be observed. However, continued demyelination/remyelination and even mild axonal loss often result in the complete absence of the SNAP. Evoked Potential Studies. Multimodality evoked potential studies have been performed in numerous patients diagnosed with CIDP. Visual evoked, brainstem auditory evoked, and somatosensory evoked potentials have revealed that central conduction along the pathways examined by the respective tests is unquestionably slowed in some patients.1012,1319 Anatomic lesions noted in corresponding white matter tracts on MRI scans substantiate these neurophysiologic abnormalities in central conduction pathways.398,562,886,1005,1372 Needle EMG Examination. Extensive documentation of needle EMG findings in patients with CIDP is lacking. Widespread fibrillation potentials and positive sharp waves are commonly detected in the intrinsic foot muscles and more proximal muscles, such as the tibialis anterior, peroneus longus, and occasionally gastrocnemius.10,73,267,351,979,986,1227 In patients with significant proximal weakness, occasional abnormalities can be observed in the quadriceps and hip girdle muscles. Paraspinal muscles reveal membrane instability in some patients. The upper limb has the same pattern of membrane instability (e.g., more commonly found in the hand intrinsic than the more proximal muscles). The degree of positive sharp waves and fibrillation potentials is relatively high during an exacerbation of the disease, with a reduction, (but not necessarily complete disappearance) during clinical remission. Single-fiber EMG demonstrates an increase in fiber density and jitter.447 Motor unit action potential amplitudes can be normal or increased in patients with CIDP, depending on the duration and severity of the disease. A reduced recruitment pattern is observed, with few motor units firing at high rates, especially in the distal limb muscles. In patients with chronic denervation and reinnervation, increased MUAP duration, amplitude, and phases can be seen. Electrophysiologic Criteria for Diagnosis. Various electrophysiologic criteria have been proposed for the diagnosis of CIDP.10,73,249,1168a The criteria developed by Barohn et al. require slowing of motor conduction velocity in at least two nerves to less than 70% of the lower limit of normal.73 However, they make no mention of distal latencies, conduction block, temporal dispersion or F-wave latencies abnormalities. Albers and Kelly proposed that three of the four following CMAP parameters must be abnormal: (1) slowing of conduction velocity in two or more nerves to < 75% of the lower limit of normal; (2) partial conduction block of 70% or temporal dispersion in one or more nerves; (3) prolonged distal latency of greater than 130% in two or more nerves; and (4) prolonged F-wave latency of at least 130% in one or more nerves.10 The AAN criteria for CIDP (see Table 23-4) modified the clinical and laboratory criteria proposed by Barohn and the electrophysiologic criteria of Albers and Kelly.249 The electrophysiologic criteria for CIDP adapted by the AAN also take into account the distal latencies, conduction block, temporal dispersion, and F-wave latencies in addition to conduction velocity slowing, but the degree of slowing is slightly different from the other proposed criteria and dependent also on the distal CMAP amplitudes.249 Bromberg compared the electrophysiologic criteria proposed by Albers and Kelly,10 Barohn,73 and the AAN and found no statistically significant difference in the sensitivity (range: 4864%)

in 70 patients who fulfilled clinical criteria for CIDP.150 Thus, many patients with CIDP do not fulfill electrophysiologic criteria for the diagnosis; this should not dissuade the clinician from treatment if the clinical features (progressive, symmetric proximal and distal numbness and weakness) and laboratory features (e.g., increased CSF protein) are compatible with the diagnosis. Treatment. Randomized control trials have demonstrated efficacy of corticosteroids, plasma exchange (PE), and intravenous immunoglobulin (IVIG) in the treatment of CIDP. Patients may respond to one mode of treatment when other forms of treatment have failed or become refractory. In a prospective, controlled trial, Dyck found no significant difference in efficacy between IVIG and PE.364 The treatment of choice may depend on the patients other medical problems (e.g., avoid IVIG in patients with renal insufficiency) and accessibility (e.g., unavailability of PE, expense of IVIG and PE, shortage of available IVIG). Corticosteroids. Austin was the first to demonstrate that steroids were beneficial in recurrent polyneuropathy,54 and several later series showed similar improvement with steroids.73,276,477,979,1071,1227 Dyck and colleagues confirmed the efficacy of prednisone in a randomized control trial.354 We treat patients with prednisone, 1.5 mg/kg (up to 100 mg) per day for 24 weeks, then switch to alternate-day treatment (e.g., 100 mg every other day).73,887 Patients are maintained on this dose of prednisone until their strength is normalized or there is a clear plateau in clinical improvement (usually around 6 months). Subsequently, the dose of prednisone is slowly decreased by 5 mg every 23 weeks to 20 mg every other day. At this point, we taper the prednisone no faster than 2.5 mg every 23 weeks. Using this mode of treatment, Barohn noted that the time of initial improvement ranged from several days to five months (mean: 1.9 months) and the time to maximal improvement averaged 6.6 months.73 Functional muscle recovery is first noted in the proximal limb muscles. Significant improvement in strength was noted in 95% of patients after one year of treatment. Intermittent high-dose intravenous corticosteroids may also be a useful therapy for CIDP and perhaps associated with fewer side effects.910 The significant side effects related to long-term corticosteroid treatment include osteoporosis, glucose intolerance, hypertension, cataract formation, aseptic necrosis of the hip, weight gain, hypokalemia, and type 2 muscle fiber atrophy. We prescribe calcium (10001500 mg/day) and vitamin D (400800 IU/day) for osteoporosis prophylaxis. In addition, in postmenopausal women, we recommend estrogen replacement, if not contraindicated, and also start alendronate (5 mg/day). We obtain baseline bone density studies and repeat the study every 6 months while patients are taking prednisone. If a patient has or develops osteoporosis, we start alendronate (10 mg/day). Alendronate also can be started to help prevent osteoporosis in patients who may be particularly susceptible (e.g., postmenopausal women, patients with borderline low DEXA scores) We obtain baseline and periodic fasting blood glucose and serum electrolyte levels. Patients need to be instructed about a low-sodium, low-carbohydrate diet to avoid excessive weight gain, hypertension, and diabetes mellitus. We recommend physical therapy and an exercise program to reduce these side effects. Plasma Exchange. PE was found to be effective in patients with CIDP in several retrospective, uncontrolled case reports or small series.238,396,423,510,788,1201,1310 Two prospective, randomized, double-blinded, placebo-controlled trials using sham PE

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demonstrated the efficacy of PE.354,535 Unfortunately response to treatment is transient, usually lasting only a few weeks. Thus, chronic intermittent PE or the addition of immunosuppressive agents is required. No specific guidelines have been established for treating CIDP with PE; treatment needs to be individualized. We have used PE, usually in combination with prednisone, in patients with severe generalized weakness because the response may be quicker to PE than to prednisone alone. We exchange approximately 200250 ml/kg body weight in 5 or 6 exchanges over a 2-week period. Some patients require more exchanges for maximal improvement. Thereafter, exchanges can be scheduled every 12 weeks and the duration between exchanges gradually increased. PE alone can be used but requires indefinite repeated treatments, which are costly, associated with adverse side effects, and technically difficult in some patients. We use PE alone in patients in whom we wish to avoid long-term prednisone (e.g., patients with poorly controlled diabetes mellitus or HIV infection) or in whom IVIG is contraindicated (e.g., patients with renal insufficiency). We also have used a trial course of PE in patients who do not fulfill all of the criteria for CIDP or those that have an underlying condition making the diagnosis difficult (e.g., diabetes and superimposed CIDP-like neuropathy).24a Because the response to PE is generally faster than the response to prednisone, one often can determine earlier whether such patients may have an immune-responsive neuropathy. Intravenous Immunoglobulin. Several uncontrolled studies have been reported showing improvement in CIDP patients with IVIG.55,247,332,386,477,1338,1353,1354 In 1990, Van Door report benefit of IVIG in a small double-blind, placebo-controlled trial.1337 However, another small trial study found no improvement with IVIG therapy.1354 Subsequently, larger double-blind, placebocontrolled, cross-over studies convincingly demonstrated that IVIG is efficacious in CIDP.536,1338 Dyck and colleagues compared PE with IVIG in an observer-blinded, randomized trial and found no clear difference in efficacy.364 For many authorities, IVIG has become the treatment of choice in CIDP. As with PE, patients require repeated courses of IVIG because improvement is only transient. The time frame and dose of IVIG treatments need to be individualized. Initially, we begin IVIG treatment with a dose of 2 gm/kg body weight over 25 days. Subsequent dosing depends on clinical response. One method of dosing is to repeat IVIG courses after subsequent relapses. However, we have found that after several relapses some patients do not improve to baseline and are left with a deficit even after treatment. Therefore, after the initial course of IVIG, we administer IVIG (2 gm/kg) every 4 weeks and gradually try to increase the interval between courses as tolerated. In this way, we try to avoid exacerbations of weakness. Some patients become refractory to IVIG, in which case PE may restore responsiveness to IVIG.92 IVIG is well tolerated by most patients. Of importance, a serum IgA level should be assayed in patients before administering IVIG. Patients who are IgA-deficient due to IgE anti-IgA antibodies or a congenital deficiency may develop anaphylactic reactions to IVIG, which may contain some IgA.341 In addition, IVIG should be used cautiously in patients with diabetes and avoided in those with renal insufficiency because it has been associated with renal failure secondary to acute tubular necrosis.1284 Some patients develop headaches, diffuse myalgias, and flu-like symptoms. A few patients have aseptic meningitis.144 Rare thrombotic complications (e.g. stroke, myocardial infarction) perhaps are related to hyperviscosity. In addition, neutropenia is common but rarely clinically significant.

Azathioprine. A few reports involving single cases or a small series of patients suggest that azathioprine at doses of 100300 mg/day with or without concurrent prednisone is effective in CIDP.186,1016,1043,1377 A prospective, randomized, but nonblinded, 9month study of 27 patients with CIDP noted no significant benefit when azathioprine (2 mg/kg/day) was added to prednisone.355 However, the dose of azathioprine was small (we go up to 3 mg/kg/day) and the duration of this study was too short. It can sometimes take longer than 9 months before any benefit is noted from azathioprine in other immunologic disorders. Whether azathioprine has a prednisone-sparing effect (i.e., allows a lower dose of prednisone) has not been adequately addressed. We usually do not treat CIDP with azathioprine alone, but it is an option in patients who cannot be given prednisone, PE, or IVIG. We have used azathioprine in combination with prednisone in patients resistant to prednisone taper. We begin azathioprine at a dose of 50 mg/day and gradually increase over a few months to a total dose of 3 mg/kg/day. Approximately 12% of patients receiving azathioprine develop fever, abdominal pain, nausea, and vomiting, requiring discontinuation of the drug.698 Other side effects include bone marrow suppression, hepatotoxicity, risk of infection, and future malignancy. We monitor CBC and LFTs every 2 weeks while adjusting the dose of azathioprine and once a month when the dose is stable. Cyclophosphamide. Only a few retrospective studies evaluated the use of cyclophosphamide in the treatment of CIDP. Both oral (50150 mg/day) and monthly pulses of intravenous cyclophosphamide (1 gm/m2) have been reported to be beneficial in some patients, either in combination with prednisone or in steroid-refractory cases.721,864,1071,1398 The major side effects of hemorrhagic cystitis, bone marrow suppression, increased risk of infection and future malignancy, teratogenicity, alopecia, nausea, and vomiting have limited its use. Monthly pulsed intravenous cyclophosphamide is associated with less risk of hemorrhagic cystitis. CBCs and urinalysis must be monitored frequently in patients treated with cyclophosphamide. Cyclosporine. Several retrospective reports suggest that cyclosporine can be effective in some patients with CIDP, even in those refractory to other modes of therapy, including prednisone, PE, IVIG, and cyclophosphamide.72,510,587,709,824 Cyclosporine has been associated with a decreased relapse rate in patients with the relapsing form of CIDP and improved strength and function in those with the chronic progressive form. The major side effects of cyclosporine include nephrotoxicity, hypertension, tremor, gingival hyperplasia, hirsuitism, and increased risk of infection and future malignancies (mainly skin cancer and lymphoma). We initially administer cyclosporine at a dose of 46 mg/kg/day orally, aiming for a trough level of 150200 mg/dl. Electrolytes and renal function need to be monitored closely. Interferons. There are a few reports of CIDP patients benefiting from -interferon.476,547,1147 Harada and colleagues reported a beneficial response to -interferon as a first-line treatment in one patient.547 Significant improvement with -interferon was reported in two patients, one a young child, who was unresponsive to prednisone, azathioprine, and cyclosporine.1147 Gorson et al. performed a prospective, unblinded study of -interferon in 16 patients with CIDP refractory to conventional therapies and found that 56% improved with -interferon.476 Recently, IVIG proved beneficial as a first-line therapy in previously untreated CIDP patients.887a A beneficial response to interferon -1a was reported in a child with relapsing CIDP.218 Subsequently, the same authors conducted a double-blind, placebo-controlled, cross-over study of interferon

954 PART IV

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-1a in 10 patients with CIDP and found no benefit.527 In addition, interferon -1a was not effective in a small study of four patients who failed to achieve a satifisfactory response to other forms of immunotherapy.736 Total Lymphoid Irradiation. Total lymphoid irradiation was reported to be effective in 3 of 4 patients unresponsive to prednisone or cyclophosphamide.1125 Prognosis. In our experience, more than 90% of patients improve with therapy; however, at least 50% demonstrate a subsequent relapse within the next 4 years and less than 30% achieve remission off medication.73,1168,1168a Other studies have reported that only 66% of patients respond to one of the three main therapies for CIDP (prednisone, PE, or IVIG).130,477 The differences in response rates among studies may relate to how the authors defined CIDP. We require symmetric, proximal, and distal arm and leg weakness to diagnose CIDP.1168a Patients with mainly sensory symptoms, mild distal weakness, or asymmetric motor involvement may fulfill AAN criteria249 and could have been included in other series of CIDP patients. These patients are much less responsive to specific forms of therapy and skew the prognosis in these series.1168a We have found that patients treated early are more likely to respond, underscoring the need for early diagnosis and treatment.1168,1168a Progressive course, CNS involvement, and particularly axonal loss have been associated with a poorer long-term prognosis.130 CIDP in Children. Monophasic, relapsing, and chronic progressive forms of CIDP can begin in childhood.167,218,232,389,442,560a, 816,1036,1146a,1147,1220,1227,1287,1318,1346 The clinical, laboratory, and electrophysiologic features are similar to those in adulthood. Children commonly present with difficulty in ambulating. Children respond to the standard forms of treatment, although prospective control trials have not been performed. With childhood onset, CIDP may be confused with a hereditary neuropathy (i.e., Charcot-Marie-Tooth disease [CMT]). Obviously, the family history is an important starting point. An electrodiagnostic medicine evaluation can be of considerable help in determining the correct diagnosis. CMT is associated with symmetric and diffuse involvement of the peripheral nerves. Thus, temporal dispersion and conduction block are not seen on electrophysiological studies.789 Furthermore, there is usually uniform slowing of conduction velocities of all the motor nerves in the arms and legs as well asymmetric involvement of proximal and distal segments. In contrast, the multifocal nature of CIDP results in nonuniform slowing of conduction velocities, temporal dispersion, and conduction block. Paraprotein-related Neuropathies and CIDP. Whether patients with paraproteins (i.e., monoclonal gammopathy) who have clinical, laboratory, and electrophysiologic criteria of demyelinating sensorimotor neuropathy should be classified as having CIDP is a matter of debate.661,1168a Dyck and colleagues suggest that paraprotein-related neuropathies should be separated from idiopathic CIDP.363 Criteria for CIDP developed by Barohn73 and the AAN249 allow for CIDP with concurrent illnesses, including monoclonal gammopathies of uncertain significance (MGUS). Lines of evidence suggest that paraproteins, particularly IgM monoclonal proteins, are involved in the pathogenesis of at least some types of idiopathic polyneuropathy. The incidence of paraproteins in patients with peripheral neuropathy is higher than in the general population.668 Furthermore, there is an increased incidence of peripheral neuropathy in patients with MGUS.748 Although IgG is the most common paraprotein in the general population, IgM is by far the most common monoclonal protein in patients with peripheral neuropathy.476,480,699,768,1064,1216,1217,1218,1437

The clinical and electrophysiologic features of polyneuropathy associated with monoclonal gammopathies are heterogeneous and imply a multifactorial pathogenesis. Most studies indicate that IgM-MGUS neuropathies are distinct from IgG and IgA-MGUS neuropathies.360,480,969 IgM-MGUS neuropathies are typically demyelinating but can be axonal. Demyelinating and axonal neuropathies seem to occur at relatively similar frequencies in IgG- and IgA-MGUS. The IgM-MGUS neuropathy seems to be less responsive to various immunotherapies than IgG- and IgA-MGUS neuropathies.360,423,661,969,972 At least 50% of the IgM-MGUS group have antibodies directed against myelin-associated glycoprotein (MAG). There does not appear to be any significant clinical, electrophysiologic, histologic, or prognostic (including response to treatment) differences between IgM-MGUS neuropathy with or without antiMAG antibodies. It is not clear whether MGUS-related demyelinating neuropathies are distinct from CIDP. Confusion has arisen because many papers about MGUS neuropathy do not distinguish between patients with electrophysiologic features consistent with demyelination and patients whose nerve conduction studies are consistent with an axonal or mixed axonal-demyelinating process.360,480 Most series have not taken into account the distribution of muscle weakness in patients with MGUS-neuropathies (e.g., whether they had distal weakness only or both proximal and distal weakness).661 Some series of patients with CIDP have chosen to exclude351,535,536 or include73,476 patients with MGUS. Recently, more attention has been devoted to subcategorizing the clinical and electrophysiologic features of the different types of MGUS-neuropathy (e.g., IgM vs. IgG/IgA and axonal vs. demyelinating neuropathy) and directly comparing the demyelinating subgroups of MGUS neuropathy with idiopathic CIDP. Yeung reported 62 patients with MGUS neuropathy (IgM 46, IgG 11, IgA 5).1437 Most patients presented with a late-onset distal and symmetric sensorimotor neuropathy. Sensory ataxia and tremor were common. There was no significant difference between the various subgroups, except that patients with IgM neuropathy had more significant tremor. Nerve conduction studies apparently were not significantly different from patients with idiopathic CIDP, but data and statistical analysis were not provided. However, nerve biopsies were significantly different in the IgM group compared with the IgG and IgA groups. Most IgM patients had features of demyelination on nerve biopsy along with widely spaced myelin sheaths and deposition of immunoglobulin on the nerves. In contrast, demyelinating features were uncommon, and widely spaced myelin sheaths and immunoglobulin deposition were not seen in patients with IgG and IgA neuropathy. Gosselin480 described the clinical, laboratory, and electrophysiologic features of 65 patients with MGUS neuropathy (IgM 31, IgG 24, IgA 10), and Suarez and Kelly1265 reported the features of 39 patients with MGUS neuropathy (23 IgM, 13 IgG, and 3 IgA). Slightly more than half of the IgM patients were anti-MAG positive. Clinical symptoms reflected mainly a sensory disturbance; patients in the IgM-MGUS group experienced more disability related to the sensory loss. Weakness was only a minor feature. In the series of Suarez and Kelly, nerve conduction studies revealed demyelination in only 2 patients in the IgG group and 8 patients in the IgM group; 10 patients in the IgM group had mixed axonal-demyelinating studies.1265 In both series, the nerve conduction studies revealed more slowing of conduction velocities and prolongation of the distal latencies in the IgM group compared with the IgG and IgA patients.480,1265 There were no significant clinical or electrophysiologic differences between IgM MAG-positive and IgM MAG-negative patients. Subsequently, the Mayo group performed a double-blinded trial of

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PE vs. sham pheresis in 21 patients with IgM and 19 IgG/IgAMGUS neuropathy.360 There was a trend toward improvement in the IgG/IgA group but not in the IgM group. Simmons and colleagues compared the clinical, laboratory, and electrophysiologic features of 77 patients with idiopathic CIDP but without MGUS with those of 26 patients with MGUS who fulfilled criteria for CIDP (13 IgM and 13 IgG/IgA).12161218 Patients with MGUS-CIDP had a more indolent course, more frequent sensory disturbance with ataxia, and less severe weakness than patients with idiopathic CIDP. There was no significant difference in the elevation of CSF protein levels in the two groups. They found no difference in various motor parameters between the MGUS-CIDP and the idiopathic CIDP groups; however, the MGUS-CIDP group had more severe sensory conduction abnormalities. Subgroup analysis of patients with IgMCIDP revealed a smaller terminal latencies index (TLI). The TLI can be calculated as follows: TLI = terminal distance (mm)/conduction velocity (m/s) distal latency (ms). A small TLI is indicative of distal accentuated demyelination. Although analyzing the response to treatment is limited by the retrospective nature of the study and varying therapeutic regimens, the idiopathic CIDP group had a significant greater improvement rate (88%) than the MGUS-CIDP group (50%).1216 In a long-term follow-up study, four patients with idiopathic CIDP were reclassified.1218 Two developed MGUS, one POEMS syndrome, and another Castlemans disease. Three MGUS-CIDP patients were also reclassified. One patient, who was unresponsive to treatment, was later found to have a plasmacytoma. Another unresponsive patient developed acute myelogenous leukemia. The third patient, who was initially responsive but then became resistant to therapy, developed multiple myeloma. The study illustrates that MGUS is not necessarily benign; as many as 25% of patients later develop an underlying malignancy.746,748,768 Furthermore, patients with CIDP who are or become refractory to therapy should be reevaluated for monoclonal gammopathy and underlying malignancy. Some series have focused only on IgM-MGUS neuropathy.203,649,672,1235 These studies have confirmed the observation of the above series of mixed MGUS neuropathies in that most patients with IgM-MGUS neuropathy have predominantly distal sensory signs and symptoms and demyelination on nerve conduction studies. Kaku and Sumner also noted that patients with anti-MAG IgM-MGUS had disproportionately prolonged distal latencies in comparison with the slowing of conduction velocities, which results in a short TLI (< 0.25).649 The TLI in the antiMAG positive patients was significantly shorter than in normal volunteers, patients with CMT type 1, and patients with idiopathic CIDP without MGUS. Other authors have commented on the shortened TLI in IgM-MGUS.969 Treatment is another controversial issue in regard to MGUS neuropathy, particularly in IgM-MGUS with or without antiMAG antibodies. Several retrospective studies and unblinded or uncontrolled prospective series have reported benefit with corticosteroids, PE, cytotoxic agents, immunoabsorption, and IVIG, even in IgM-MGUS neuropathy.107,237,672,964,971,1007,1064,1400 A major obstacle in designing and interpreting these studies, particularly in regard to IgM-MGUS, is that the disability of many patients is related predominately to sensory impairment, which is difficult to measure objectively. Katz and colleagues treated 10 patients with IgM-MGUS and distal acquired demyelinating symmetric neuropathy with a variety of immunomodulating therapies.661 Three patients reported symptomatic improvement in sensory symptoms, but none had objective improvement in

the motor examinations. There are only a few prospective, controlled treatment trials of IgM-MGUS neuropathy. A doubleblind, placebo-control study (PE vs. sham pheresis) was performed in patients with MGUS neuropathy, as previously mentioned.360 Improvement was noted in only IgG and IgA MGUS neuropathy, but it did not reach statistical significance. Dalakas performed a double-blind, placebo-controlled, crossover study of IVIG in 11 patients with demyelinating IgMMGUS neuropathy.282 Only modest benefit from IVIG was noted: two patients had improvement in strength, and one had less sensory impairment. An open-label, randomized, prospective trial comparing IVIG (10 patients) with interferon- (10 patients) in IgM-MGUS neuropathy also found modest benefit from IVIG.830 There was improvement in sensory deficits as measured by the Clinical Neuropathy Disability Score with interferon-; however, there was no improvement in clinical motor function or motor nerve conduction studies.830 The same investigators subsequently performed a prospective, doubleblind placebo-controlled trial of interferon- in IgM-MGUS neuropathy and found no beneficial response.831 Axonal Variant of CIDP. A few reports in the literature suggest that there is an axonal variant of CIDP,219,334,644,657,924,1321 although its existence is controversial.401 The basis for the suggestion of an axonal variant of CIDP is that some patients did not fulfill electrophysiologic criteria for demyelination on nerve conduction studies or nerve histopathology was more suggestive of an axonopathy or normal. However, one-third of patients with CIDP do not fulfill the strict research criteria for the diagnosis, as discussed above.150 Furthermore, nerve histopathology is neither sensitive nor specific and can be normal or show features more suggestive of an axonopathy rather than a demyelinating polyneuropathy.73 In fact, if one carefully reads the reports suggesting an axonal CIDP, many were associated with slow conduction velocities and prolonged distal latencies and F-waves, although not in the demyelinating range. Surprisingly, one report classified patients as having chronic relapsing axonal polyneuropathy (based on histopathology) despite nerve conduction velocities between 25 and 30 m/s in the median, ulnar, and tibial motor nerves.644 Conduction block greater than 50% in multiple nerves was evident from nerve conduction data in another report.657 One series of five patients commented on normal sural nerve conduction studies.1321 Normal sural SNAPs in combination with abnormal upper limb SNAPs are more suggestive of a demyelinating process or perhaps a ganglionopathy than an axonopathy. Of note, most patients reported with axonal CIDP had elevated CSF protein, similar to typical CIDP. In addition, most patients with axonal CIDP improved within weeks to a few months of starting some form of immunotherapy. This time frame is too short for improvement based on regeneration of axons and is more consistent with remyelination or reversal of conduction block. Perhaps, as in GBS (e.g., acute motor axonal neuropathy, acute motor and sensory axonal neuropathy), futures studies will prove the existence of an axonal CIDP. For now, however, we agree with Feasby that the concept of an axonal form of CIDP is premature.401
Distal Acquired Demyelinating Symmetric Neuropathy It may be more helpful to classify patients with acquired demyelinating polyneuropathies, particularly patients with MGUS, by pattern of weakness (i.e., whether the patients have no weakness/only mild distal weakness or if they demonstrate both proximal and distal weakness). Recently, Katz and colleagues described the clinical and electrophysiologic features of 53 consecutive patients with an acquired symmetric demyelinating

956 PART IV

CLINICAL APPLICATIONS Comparison of the Chronic Acquired Immune-Mediated Demyelinating Polyneuropathies CIDP DADS None or only mild symmetric distal weakness Yes; distal and symmetric Symmetrically reduced or absent Demyelinating features, excluding CB Abnormal Usually elevated IgM usually present (most anti-MAG positive) Rarely present Demyelinating/remyelinating features are common with Ig deposition evident in paranodal regions Poor Poor Poor Poor MADSAM Asymmetric distal > proximal, arms > legs Yes; asymmetric Asymmetrically reduced or absent Demyelinating features, including CB Abnormal Usually elevated Rarely present MMN Asymmetric, distal > proximal, arms > legs No Asymmetrically reduced or absent Demyelinating features, including CB Normal Usually normal Rarely present

Table 23-5. Clinical features Weakness

Symmetric proximal and distal weakness Yes; symmetric Symmetrically reduced or absent Demyelinating features including CB Abnormal Usually elevated Occasionally present, usually IgG or IgA

Sensory loss Reflexes Electrophysiology CMAPs SNAPs Laboratory findings CSF protein Monoclonal protein

GM1 antibodies Rarely present Sensory nerve biopsies Demyelinating/remyelinating features are common

Rarely present Demyelinating/remyelinating features are common

Frequently present Demyelinating/remyelinating features are scant, if present at all

Treatment response Prednisone Plasmal exchange IVIG Cyclophosphamide

Yes Yes Yes Yes

Yes Not adequately studied Yes Not adequately studied

No No Yes Yes

CIDP = chronic inflammatory demyelinating polyneuropathy, DADS = distal acquired demyelinating symmetrical, MADSAM = multifocal acquired demyelinating sensory and motor, MMN = multifocal motor neuropathy, CMAPs = compound motor action potentials, SNAPs = sensory nerve action potentials; CB = Conduction block, CSF = cerebrospinal fluid, MAG = myelin-associated glycoprotein, IVIG = intravenous immunoglobulin. (From Amato AA, Barohn RJ: Clinical spectrum of chronic inflammatory demyelinating polyneuropathies. Muscle Nerve 2001;24:311324, with permission.)

neuropathy.661 Of the 53 patients, 23 had proximal and distal arm and leg weakness, defined by the authors as necessary for the diagnosis of CIDP. Only 5 patients with CIDP (22%) had a monoclonal gammopathy (4 IgG kappa and 1 IgM lambda). In contrast, 30 patients had only distal symptoms (8 pure sensory loss, 12 distal sensory loss plus ankle dorsiflexor and foot intrinsic weakness). The term distal acquired demyelinating symmetric (DADS) neuropathy was applied to these patients (Table 23-5).661,1168a Monoclonal proteins were detected in 20 of 30 cases of DADS neuropathy (18 IgM kappa, 2 IgG kappa). Anti-MAG antibodies were found in 67% of patients with IgMDADS neuropathy. The patients with IgM-DADS neuropathy were older (mean age: 62 years) than patients with idiopathicDADS neuropathy (mean age: 47 years) who had no associated monoclonal protein or patients with CIDP (mean age: 51 years). The authors found no significant electrophysiologic differences between IgM-DADS, idiopathic DADS, or CIDP, including analysis of the terminal latency index. Most importantly, patients with IgM-DADS neuropathy demonstrated a poor response to immunotherapy, whereas patients with idiopathic DADS and CIDP (with or without an associated monoclonal protein) usually improved with therapy. In contrast, patients with idiopathic DADS or CIDP usually demonstrated objective improvement with immunotherapy. Distinguishing the acquired forms of chronic demyelinating polyneuropathies by clinical phenotype (i.e., pattern and distribution of involvement) is useful in predicting the presence of IgM monoclonal proteins and, more importantly, response to treatment.1168a Further support

for classifying patients by clinical phenotype is evident in the following discussions of multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM) (see Table 23-5).
Multifocal Motor Neuropathy Multifocal demyelinating neuropathy with conduction block was first described by Lewis and colleagues in 1982.790 They described five patients with asymmetric motor and sensory loss who had persistent conduction block on conduction studies of motor nerves. The patients also had objective sensory abnormalities on nerve conduction studies and sensory nerve biopsies. Most of the following reports described patients with pure or predominantly motor multifocal neuropathies with conduction block or other electrophysiologic features of demyelination. This entity became known as multifocal motor neuropathy (MMN).50,189,406,407,660, 647,722,1025,1027,1029,1049,1050,1131 Nevertheless, many articles about MMN credit Lewis790 and colleagues with the initial description. We consider patients with objective sensory loss in addition to motor dysfunction to have a different neuropathy, termed multifocal acquired demyelinating motor and sensory (MADSAM) neuropathy. Some patients with objective sensory abnormalities and probable MADSAM neuropathy have been included in some series of MMN. The contamination of MADSAM neuropathy in some series of patients with MMN creates some difficulty in interpreting laboratory data and therapeutic response rates because of the distinct differences between MMN and MADSAM neuropathy (see Table 23-5).

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Clinical Features. Multifocal motor neuropathy (MMN) is an immune-mediated demyelinating neuropathy characterized clinically by asymmetric weakness and atrophy, typically in the distribution of individual peripheral nerves.50,189,209,406,647,660,722, 1027,1028,1049,1131,1168a,1289a MMN is commonly misdiagnosed as amyotrophic lateral sclerosis (ALS); however, as noted above, the muscle involvement is in the distribution of individual peripheral nerves, not spinal roots. The incidence of MMN is much less than that of ALS; some large neuromuscular centers diagnose one case of MMN for every 50 patients with ALS.209 The male-to-female ratio is approximately 3:1. The age at onset of symptoms is usually early in the fifth decade of life, ranging from the second to eighth decade of life. Typically, diagnosis is delayed by several years because of the slow, insidious progression and misdiagnosis of the disorder. In a selective series of 16 patients with MMN (no patients with even mild sensory abnormalities were included), the average age of onset was 40.5 years (range: 2064 years) with an average duration of illness of 7.6 years (range: 220 years) at the time of diagnosis.660 Patients develop focal muscle weakness accompanied by cramps and fasciculations, usually beginning in the distal upper limbs. Onset in the lower limbs also can occur. Patients generally present with intrinsic hand weakness, wrist drop, or foot drop. In a series of patients with MMN, initial involvement was in the arms in 12 (75%) and in the legs in four patients (25%).660 Weakness typically progresses over several years to involve other limbs. Mild sensory symptoms have been described, but if there is objective sensory loss, one should consider MADSAM neuropathy. Rare patients may develop respiratory weakness due to involvement of the phrenic nerves.122a Physical examination reveals weakness in a multifocal pattern in the upper and lower limbs, paralleling a peripheral nerve(s) as opposed to the spinal segmental/root distribution seen in motor neuron disease. A helpful feature is the lack of atrophy in weak muscle groups early in the course of the illness; however, decreased muscle bulk can result in time from secondary axonal degeneration. Fasciculations may be observed in affected limb muscles. Sensory examination should be normal, as previously discussed. Deep tendon reflexes are highly variable in that unaffected regions can be normal, whereas weak and atrophic muscles are usually associated with depressed or absent reflexes. Occasionally, normal or even mildly hyperactive reflexes can be elicited, but corticospinal tract signs (i.e., clonus, spasticity, extensor plantar responses) are not seen. Cranial nerve abnormalities in MMN have been described646,1072 but are uncommon. The above symptoms and signs can appear quite similar to a lower motor neuron variant of ALS.647,1025,1027,1029 The observation of fasciculations, weakness, and essentially preserved sensation is certainly suspicious for an anterior horn cell disorder. However, the multifocal peripheral nerve involvement, as opposed to spinal root level of dysfunction, combined with sparing of muscle bulk points to the diagnosis of MMN. For example, a patient may have reduced strength in the ulnar-innervated hand intrinsic muscles, yet the median-innervated thenar muscles are completely normal, obviating a C8/T1 spinal level disorder. Laboratory Features. In contrast to CIDP and MADSAM, CSF protein is usually normal in patients with MMN. Twenty to 84% of patients with MMN have detectable IgM antibodies directed against gangliosides, mainly GM1 but also GM2.648,660,718,765, 1031,1050,1150 The importance of these antibodies in terms of pathogenesis is unknown and continues to be vigorously debated. We have not found these antibodies useful for diagnosis of MMN. In high titers the antibodies appear to be rather specific for MMN,

but the sensitivity of the test is too low. The most sensitive and specific test is the nerve conduction study (see below). The presence or absence of antiganglioside antibodies in a patient who has electrophysiologic abnormalities consistent with MMN adds little to the diagnosis. Pathogenesis. MMN is believed to be immune-mediated. Early descriptions of MMN led to debate as to whether MMN is a distinct entity or simply a variant of CIDP.101,133,140,204,207, 763,1027,1028,1168a,1303 Although opinions still vary, MMN is generally regarded as a distinct entity because it represents a relatively uniform group of patients who differ significantly from patients with CIDP in terms of laboratory features, histopathology, and response to treatment. The disparity between motor and sensory nerve involvement suggests that the autoimmune attack may be directed against an antigen specific for the motor nerve. The pathogenic role for antiganglioside antibodies is not known. According to some reports, reduction of antibody titer correlates with clinical improvement after immunotherapy1049,1050; however, other studies have demonstrated no such correlation.205,965 Furthermore, there has been no correlation between the presence or absence of antiganglioside antibodies and response to immunotherapy in some series.133,660,832,1285 Sera from patients with MMN injected into rat sciatic or tibial nerves in-vivo and in vitro was shown to induce conduction block in some studies37,1107,1169,1320 but not in others.557 Anti-GM1 sera raised from immunized rabbits produced abnormalities in sodium and potassium channels in isolated rat myelinated motor nerve fibers.1283 An immune attack directed against an ion channel may account for conduction block of neural impulses, and a secondary inflammatory attack may result in demyelination. However, this hypothesis is only speculative. As noted above, not all patients with MMN have detectable antiganglioside antibodies; at best, these antibodies can be considered only a marker of the disease.209 Electrophysiologic Findings. In MMN, there is often evidence of conduction block in multiple upper and lower limb nerves (Fig. 23-4).50,133,189,406,648,722,774a,1025,1027,1028,1049,1050,1131,1285,1289a Conduction block is not located at the expected common nerve entrapment sites, but in the mid-forearm or leg, upper arm, across the brachial plexus, or nerve root region. The region of blockade can be localized to relatively small regions of nerve between 30100 mm when short-segment (1-cm intervals) stimulation is used. Conduction block may be present not only in multiple different nerves but also at several locations along the course of the same nerve. Across the focal segment displaying conduction block, conduction velocity is markedly reduced, suggesting demyelination. A reduction in the distal CMAP amplitude can be seen in chronic lesions due to secondary axonal loss. There are no universally accepted criteria for defining definitive conduction block.248,998a,1098,1168a,1271,1289a A completely absent response to proximal stimulation with a persevered response to distal stimulation is considered sound evidence of conduction block, provided this finding persists for more than 58 days. When there is a greater than 50% amplitude reduction from proximal to distal stimulation sites, temporal dispersion is not present, and a focal region of nerve (e.g., 3050 mm) can be identified with the drop in amplitude, it is reasonable to conclude that conduction block is present, although not without some doubt, particularly in chronic lesions. In chronic disorders with severe axonal loss, remodeling of motor units can create MUAPs with long durations that may phase-cancel with other motor units. The result is a reduction of the CMAP amplitude with proximal stimulation secondary to the normal dispersion of motor nerve conduction velocities, hence producing pseudoconduction block. This finding

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Figure 23-4. Motor and sensory nerve conduction studies of the left median nerve in a patient with multifocal motor neuropathy with conduction block. A, Stimulation of the median nerve in a control subject demonstrating normal temporal dispersion and reduction in both CMAP and SNAP amplitude.The marked reduction in SNAP amplitude is a normal phenomenon secondary to significant temporal dispersion and phase cancellation. B,The patient demonstrates a significant reduction in CMAP amplitude between 30 mm and 57 mm proximal to the wrist with an associated increase in CMAP temporal dispersion and fragmentation of the CMAP. Note that sensory conduction across the same nerve is essentially unaffected and quite similar to the control nerve. (From Krarup C. Stewart JD, Sumner AJ: A syndrome of asymmetric limb weakness with motor conduction block. Neurology 1990;40:118127, with permission.)

may be observed in motor neuron disease, giving the false impression of conduction block, but careful analysis reveals an absence of focal reduction in amplitude. Instead, a gradual reduction in MUAP size is seen with increasing separation of stimulation sites. The previously defined criteria of conduction block with respect to AIDP and CIDP may be valid, but debate continues. Further investigations are required to resolve the issue. Although motor conduction block has been considered the electrodiagnostic hallmark of MMN,50,133,189,406,646,722,1025,1027,1029, 1030,1049,1050,1131,1289a other features of demyelination (i.e., prolonged distal latencies, temporal dispersion, slow conduction velocities, and prolonged or absent F-waves) are typically present on motor nerve conduction studies.205,235,660,1013,1094 Diagnosis does not require conduction block if other features of demyelination are present.660,1013 The electrophysiologic features of demyelination have been noted to improve with treatment in some but not all cases.774a The sensory nerves characteristically demonstrate normal SNAP parameters using surface or near-nerve recording techniques.189,648,660,763,1131 Of importance, there are no sensory conduction abnormalities in the mixed peripheral nerve in the region where conduction block can be demonstrated in motor

fibers. For example, if a blockade of neural conduction is found in the median nerve CMAP at the mid-arm level, median nerve SNAPs should be documented with stimulation at the wrist and mid-forearm segments. There should be no significant reduction of SNAP amplitude above that normally anticipated or slowing of SNAP conduction velocity across the same segment of blocked motor fibers. A marked reduction in SNAP amplitude normally found in sensory nerves (phase cancellation) can confound this attempt. Near-nerve needle recording techniques for SNAPs can be used to maximize the amplitude and help distinguish the presence or absence of conduction block over a focal neural segment in the sensory nerve fibers, particularly with sequential stimulation sites every centimeter. Needle EMG findings depend on several factors.189,646,660,763,1131 Unaffected muscles should demonstrate no abnormalities. When a clinically weak muscle is investigated, the numbers of motor units with rapid firing rates are reduced. This finding is documented with or without axonal loss because conduction block and denervation appear essentially the same with respect to MUAP recruitment. When secondary loss of axons has occurred, positive sharp waves and fibrillation potentials are commonly detected in degrees commensurate with the amount of nerve

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injury and clinical wasting. A muscle with clinical weakness but preserved bulk is likely to reveal few if any fibrillation potentials and positive sharp waves. Fasciculation potentials and, rarely, myokymic discharges may be noted. Single-fiber EMG reveals increased fiber density and jitter in clinically weak and unaffected muscles.757 These abnormalities improve after treatment. Histopathology. Most reports of sensory nerve biopsies in MMN describe normal findings, mild loss of myelinated fibers, or minimal axonal degeneration.965,1025,1027,1030,1049 Some groups have noted scant findings of demyelination and remyelination on sural nerve biopsies.133,251 Corse et al. reported that sensory nerve biopsies of 11 patients with MMN showed a slightly increased number of thinly myelinated large caliber axons, with small onion bulb formations; these demyelinating features were never extensive.251 They described no evidence of subperineurial or endoneurial edema or mononuclear inflammatory cell infiltrate in the epineurium or endoneurium.251 The histologic features on sensory nerve biopsy in MMN are in sharp contrast to those seen in CIDP. A few reports of motor nerve and mixed motor and sensory nerve biopsies have demonstrated features of demyelination and remyelination, small onion bulb formation, and mild perivascular inflammation.50,647 Of note, the demyelination appeared asymmetric between and within nerve fascicles in at least one reported case.647 Treatment. In contrast to CIDP and MADSAM neuropathy, few patients (<3%) with MMN improve with high doses of corticosteroids or PE.50,200,324,406,647,722,965,1025,1049 Azathioprine has been administered in a few patients without noticeable improvement.205,722,1025 Anecdotally, we have found a similar lack of efficacy with azathioprine. Intravenous cyclophosphamide was the first immunosuppressive agent demonstrated to be effective in MMN; over 70% of reported patients improved clinically after treatment.406,722,763,1025,1049,1285,1289a No double-blinded, placebo-controlled trials have been performed with cyclophosphamide; however, a similar degree of improvement has not been seen with prednisone, PE, or azathioprine, suggesting that the improvement is not just a placebo response. The initial dose of intravenous cyclophosphamide in large series of patients has been 3 gm/m2 given over an 8-day period. Subsequently, monthly courses of intravenous cyclophosphamide (0.51.0 gm/m2) or oral cyclophosphamide (2 mg/kg) can be instituted after 1 month. However, this high dose of intravenous cyclophosphamide (3 gm/m2) is associated with alopecia, nausea and vomiting, hemorrhagic cystitis, and significant bone marrow suppression. We have rarely used cyclophosphamide, given its short-term and long-term side effects, since the reported efficacy of IVIG in MMN. In patients who cannot tolerate IVIG, we recommend lowering the initial intravenous pulse of cyclophosphamide to 0.5 or 1.0 gm/m2 to avoid severe side effects. The subsequent doses can be titrated upward or downward as tolerated. Patients should be treated with mesna and well hydrated to avoid hemorrhagic cystitis. Nausea can be managed with ondansetron or gransetron. IVIG is now the treatment of choice in MMN. Efficacy has been demonstrated in numerous studies,57,205,268,646,660,832,1289a including one double-blinded placebo-controlled trial.56,774a IVIG is given initially in a dose of 2 gm/kg over 25 days with subsequent maintenance courses as necessary, similar to the management of CIDP. Oral cyclophosphamide in combination with IVIG may prolong the interval between IVIG infusions.891 Improvement usually is noted within a few days or first few weeks of treatment. Unfortunately, not all patients with MMN respond to IVIG. Some series have noted that later age of onset832 and patients who have significant muscle atrophy133 do

not respond as well to treatment. We give three courses of monthly IVIG before concluding that a patient has failed treatment.
Multifocal Acquired Demyelinating Sensory and Motor Neuropathy As discussed above, patients with MMN should have no objective sensory abnormalities clinically or on NCS. Several series, however, have included patients with mild objective sensory deficits or abnormal sensory NCS.133,251,722,832,965 Whether such patients constitute a separate nosological entity, represent a focal variant of CIDP, or simply have MMN with mild sensory involvement is the subject of some debate. Recently, there have been several series of patients who resemble MMN but have objective sensory abnormalities clinically, electrophysiologically, and histologically. The term multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy was coined to describe this suspected variant of CIDP (see Table 23-5).1168,1168a Although we believe that MADSAM neuropathy probably represents an asymmetric form of CIDP, the concept is useful because it emphasizes that the disorder is not merely a variant of MMN with associated sensory findings. Therefore, we favor using theterm MADSAM neuropathy to underscore the distinction between these patients and patients with MMN. However, as an alternative to MADSAM neuropathy, the eponym LewisSumner syndrome also has been used in recognition of the clinicians who first described this neuropathy.790 Clinical features. There are now over 50 well-described patients with MADSAM neuropathy.23,456,478,790,973,989,1131a,1168,1168a,1303,1329,1330 The signs and symptoms of MADSAM neuropathy are essentially those of mononeuropathy multiplex. There is a 2:1 male predominance. The average age of onset is in the early 50s (range: 1477 years). Onset is usually insidious and slowly progressive with initial involvement usually in the arms; however, the legs also can be be initially involved and often become affected over time. There is usually a 23 year lag from the onset of symptoms to diagnosis. Motor and sensory losses conform to a discrete peripheral nerve distribution rather than a generalized stocking or glove pattern. Some patients describe pain and paresthesias. Cranial neuropathies have been reported, including optic neuritis, oculomotor, trigeminal, and facial nerve palsies. Most patients have decreased or absent muscle stretch reflexes in a multifocal, asymmetric distribution; however, some have complete areflexia. Laboratory Test Results. There are differences in CSF protein and GM1 antibodies between patients with rigorously defined MADSAM neuropathy and MMN (see Table 23-5).989,1168,1168a CSF protein is elevated in 6082% of patients with MADSAM neuropathy (mean level of around 70 mg/dl).23,456,478,790,973,989,1168,1303,1329,1330 The frequency of CSF protein abnormalities and concentration is less than that normally seen in patients with typical generalized CIDP but clearly different from MMN, in which CSF protein concentration is usually normal. In MMN in which patients with sensory signs were excluded, only 1 of 11 patients with MMN had an elevated CSF protein.660,1168 As noted previously, most patients with MMN (range: 5690%) have antibodies to GM1. In contrast, only 1 of 45 tested patients with MADSAM neuropathy have had detectable GM1 antibodies.456,478,989,1168,1303,1329,1330 In patients with demyelination localized to the cervical roots or brachial plexus, MRI scans have demonstrated enlarged nerves, which enhance in some, but not all, cases.23,1303,1329,1330 Histopathology. Sensory nerve biopsies demonstrate many thinly myelinated, large-diameter fibers and scattered demyelinated fibers in most reported cases (Fig. 23-5).456,478,790,973,989,1168,1303,1329

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to MMN, the sensory studies are also abnormal. SNAPs are usually absent or small in amplitude, similar to those in patients with generalized CIDP. EMG may reveal fibrillation potentials and positive sharp waves as well as polyphasic, long-duration MUAPs that recruit early. The electrophysiologic abnormalities improve with treatment. Treatment. Although prospective, controlled trials have not been performed, retrospective series have demonstrated that most patients with MADSAM neuropathy improve with IVIG treatment.23,456,478,790,973,989,1168,1303,1329,1330 A similar response to IVIG is noted with CIDP and MMN. In contrast to MMN but similar to CIDP, most patients with MADSAM neuropathy also demonstrate improvement with steroid treatment.23,456,790,973,989,1168,1303 This difference illustrates the importance of distinguishing MADSAM from MMN, in which cyclophosphamide is the only other medication reported to be beneficial besides IVIG.
Figure 23-5. Mutlifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome. Sural nerve biopsy demonstrates a mild loss of myelinated nerve fibers and many thinly myelinated fibers, some surrounded by early onionbulb formations (epoxy-embedded, touidine blue stain).

SENSORY NEURONOPATHIES AND AUTONOMIC NEUROPATHIES

Idiopathic Sensory Neuronopathy/Ganglionopathy

Subperineurial and endoneurial edema and mild onion bulb formations also may be appreciated as in CIDP. Teased fiber preparations reveal demyelinated or remyelinated internodes in 388% of the fibers. A smaller percentage of teased fibers show features of axonal degeneration (range: 06%). Prominent, asymmetric loss of large myelinated nerve fibers between and within fascicles may be seen on nerve biopsies.1168 Similar asymmetric abnormalities had been reported in three other patients with MADSAM neuropathy.456,973 Asymmetric involvement was apparent on motor nerve biopsy in one patient with MMN at the site of conduction block.647 Asymmetric fiber loss with demyelination may represent the pathologic correlate of the clinical neurologic findings of asymmetric demyelinating mononeuropathy multiplex. Although this feature can suggest an ischemic process, axonal loss secondary to severe multifocal demyelination may cause a similar clinical picture. There has been no evidence of necrotizing vasculitis on any reported biopsies, although some have noted nonspecific, mild perivascular inflammation.790,989,1303 A biopsy specimen from the brachial plexus in one patient demonstrated prominent infiltrates consisting of mainly T-cells and, to a lesser extent, B-cells.1329 Pathogenesis. The pathogenic basis for MADSAM neuropathy is not known. We believe that MADSAM falls into the spectrum of CIDP and probably has a similar pathogenesis.23,1168,1168a MADSAM neuropathy and CIDP are similar with respect to CSF and sensory nerve biopsy findings as well as response to corticosteroids. MADSAM neuropathy meets the CIDP criteria formulated by the Ad Hoc Subcommittee of the American Academy of Neurology (AAN) AIDS Task Force.249 In contrast to the CIDP classifications established by Dyck351 and Barohn,73 the AAN criteria do not require symmetric deficits. The pathogenic basis for the asymmetric involvement is unclear. We believe that MADSAM and CIDP are distinct from MMN, as demonstrated by objective sensory abnormalities and differences in laboratory results, histopathology, and response to steroids.1168a Electrophysiologic Findings. As with CIDP and MMN, nerve conduction studies in MADSAM neuropathy demonstrate conduction blocks, temporal dispersion, prolonged distal latencies, prolonged F-waves, and slow conduction velocities in one or more motor nerves.23,456,478,790,973,989,1168,1168a In contrast

This disorder is believed to be caused by an autoimmune attack directed against the dorsal root ganglia; hence the terms sensory neuronopathy and ganglionopathy are more appropriate than sensory neuropathy. The differential diagnosis of sensory neuronopathy includes paraneoplastic syndrome, which is typically associated with anti-Hu antibodies, and sensory ganglionitis related to Sjgrens syndrome. Certain medications or toxins, infectious agents, and other systemic disorders also are associated with a sensory neuronopathy. These causes of sensory neuronopathy are discussed in their relevant sections. Despite extensive evaluation, many cases of sensory neuronopathy have no clear etiology; so-called idiopathic sensory neuronopathy is discussed below. Clinical Features. Idiopathic sensory neuronopathy has been reported in over 100 patients.44,277,411,537,705,1232,1257,1419,1445 There is a slight female predominance, and the mean age of onset is 49 years (range: 1881 years).1232 The neuronopathy can present acutely with an abrupt onset over a few hours or develop more insidiously over several months or years. The course can be monophasic with a stable or remitting deficit, chronic progressive, or chronic relapsing. A few patients experience a flu-like illness with or without diarrhea shortly before the onset of symptoms. The most common presenting complaint is numbness, often described as a dead or novocaine-like feeling.1419 Hyperesthesia with prickly, lancinating pain can also develop during the course but is usually not the presenting or most prominent symptom. Numbness can begin in the face, trunk, or limbs. Symptoms begin asymmetrically and in the upper limbs in nearly one-half of patients. Usually, the sensory symptoms are generalized, but they can remain asymmetric. Because of the prominent large-fiber sensory loss, patients describe clumsiness of the hands and gait instability. Marked reduction in vibration and position sense is evident on examination. The deficit can be more impaired in the arms than legs, unlike length-dependent axonal neuropathies. Pain and temperature sensations are less affected. Manual muscle testing is usually normal. Some muscle groups may appear weak because of impaired modulation of motor activity due to the proprioceptive defect. Patients often complain of weakness when referring to difficulty with gait or clumsiness. However, these symptoms are related to the severe sensory

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ACQUIRED NEUROPATHIES 961

ataxia resulting from the loss of proprioception. Most patients have difficulty in knowing the position of their feet and hands in space. This problem can be readily demonstrated by having the patient perform the finger-nose-finger test with eyes open and then closed. Patients may have only mild dysmetria with eyes open. However, when the eyes are closed, patients consistently miss their nose and the examiners stationed finger. When the eyes are closed, the upper limbs also may begin to move in space, so-called pseudoathetoid movements. Patients exhibit a positive Romberg sign and, not surprisingly describe more gait instability in the dark. Deep tendon reflexes are decreased or absent, whereas plantar reflexes are flexor. Idiopathic sensory neuronopathy is a diagnosis of exclusion. A detailed history and examination are essential to exclude toxin-induced neuronopathy, paraneoplastic syndrome, or disorder related to connective tissue disease (e.g., Sjgrens syndrome).24,504 Of importance, the sensory neuronopathy can precede the onset of malignancy or sicca symptoms (i.e., dry eyes and mouth); therefore, these disorder should always be kept in mind. Pertinent laboratory and malignancy work-up should be ordered. One also should inquire about sicca symptoms. We refer patients to ophthalmology for Rose-Bengal stain and Schirmers test. A lip or parotid gland biopsy is obtained in all suspected patients. Subacute sensory neuronopathy also has been associated with recent Epstein-Barr virus infection.1138 Laboratory Features. The CSF protein is normal or only slightly elevated in most patients.1413 However, the CSF protein can be markedly elevated (reportedly as high as 300 mg/dl) when examined within a few days in cases with hyperacute onset. Only rare patients exhibit CSF pleocytosis.1419 MRI scan can reveal gadolinium enhancement of the posterior spinal roots.1371 Increased signal abnormalities on T2-weighted images may be seen in the posterior columns of the spinal cord.770 Some patients have a monoclonal gammopathy (IgM, IgG, or IgA).277,1419 Antiganglioside antibodies, particularly anti-GD1b antibodies, have been demonstrated in some cases of idiopathic sensory neuronopathy associated with IgM monoclonal gammopathy.281 Antineuronal nuclear antibodies (anti-Hu and anti-Purkinje cell antibodies) should be assayed in all patients with sensory neuronopathy to evaluate for paraneoplastic syndrome. Likewise, antinuclear, SS-A, and SS-B antibodies should be ordered to look for evidence of Sjgrens syndrome, which also can present with a sensory neuronopathy. Histopathology. Sensory nerve biopsies demonstrate a reduction in the total number of myelinated nerve fibers. Some studies have shown a preferential loss of large myelinated fibers compared with small myelinated fibers.347 However, in a study of 22 sural nerve biopsies, Windebank et al. found no difference in the median myelinated fiber diameter from control biopsies.1419 They noted significant loss of both large and small myelinated nerve fibers as well as axonal atrophy. Usually there is a lack of inflammation in peripheral nerve specimens, although a mild, nonspecific perivascular infiltrate occasionally is seen.1419 Segmental demyelination is also absent on nerve biopsies. An autopsy performed 5 weeks after onset of idiopathic sensory neuronopathy in one man revealed widespread inflammation involving sensory and autonomic ganglia.537 These ganglia were severely depleted of neurons, and Wallerian degeneration of the posterior nerve roots and dorsal columns was evident. However, the motor neurons and roots were spared. Immunohistochemical analysis suggested a CD8+ T-cellmediated cytotoxic attack against the ganglion neurons.

Pathogenesis. The disorder is believed to be caused by an autoimmune attack directed against the dorsal root ganglia. Serum from patients with idiopathic sensory neuronopathy immunostains dorsal root ganglia cells in culture and inhibits neurites.1335 The neuronal epitope to which the autoantibodies are directed is still unknown, but the ganglioside GD1b has been hypothesized to be the target antigen.281 GD1b is localized to neurons in the dorsal root ganglia, and antibodies directed against this ganglioside have been detected in some patients with idiopathic sensory neuronopathy. Rabbits immunized with purified GD1b develop ataxic sensory neuropathy. Pathologic examination of the affected rabbits revealed loss of the cell bodies in the dorsal root ganglia and axonal degeneration of the dorsal column of the spinal cord and of the sciatic nerve. No evidence of demyelination or an inflammatory infiltrate was noted. Haifellner and colleagues autopsy of a patient with acute idiopathic sensory neuronopathy suggested a T-cellmediated ganglionitis.537 Of note, antiganglioside antibodies, including anti-GD1b, were detected in this patients serum. Electrophysiologic Findings. The most prominent electrophysiologic abnormality is absent or low-amplitude SNAPs.6,271, 411,663,705,1232,1257,1371,1419,1445 When SNAPs are obtainable, the distal sensory latencies and nerve conduction velocities are normal or only mildly abnormal. Motor nerve conduction studies either are normal or reveal only mild abnormalities. The CMAP amplitudes are reduced in less than 20% of patients.1419 Motor nerve conduction velocities are normal or only slightly decreased. Likewise, distal motor latencies and F-waves are usually normal. In addition, H-reflexes and blink reflexes typically are unobtainable.51,1419 An abnormal blink reflex favors a nonparaneoplastic etiology for sensory neuronopathy but does not exclude an underlying malignancy.52 However, the masseter reflex or jaw jerk, which is abnormal in patients with sensory neuropathy, is usually normal in patients with sensory neuronopathy,51 because the masseter reflex is unique among the stretch reflexes in that the cell bodies of the afferent limb lie in the mesencephalic nucleus within the CNS. The sensory cell bodies innervating the limbs, in contrast, reside in the dorsal root ganglia of the PNS. In regard to facial sensation and the blink reflex, the afferent cell bodies lie in the gasserian ganglia outside the CNS. Needle EMG is usually normal, although a few patients may have positive sharp waves and fibrillation potentials in the distal upper and lower limb limb muscles.1419 Myokymic discharges were recorded in one patient with chronic progressive sensory neuronopathy.1445 Some degree of MUAP alterations, suggesting chronic motor unit remodeling, is described in a few patients. Decreased recruitment is not a prominent feature. Treatment. Various modes of immunotherapy have been tried, including corticosteroids, PE, and IVIG.277,537,1371,1419,1445 However, it is difficult to assess efficacy of any specific treatment regimen because none has been studied in a prospective, double-blinded, controlled fashion. Furthermore, a few patients may improve spontaneously, and many stabilize even without treatment. Once the cell body of the sensory neuron is destroyed, it will not regenerate. Thus, there is no indication to treat a patient with a stable deficit. In the acute setting or in patients with a chronic progressive deficit, a trial of immunotherapy may be warranted.
Idiopathic Autonomic Neuropathy Clinical Features. Young et al. were the first to report a detailed clinical, laboratory, and histologic description of acute

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pandysautonomia.1441,1442 Subsequently, there have been several small reports, most limited to one or two patients with idiopathic autonomic neuropathy.35,86,231,388,407,553,566,818,874,889,950,1041,1077, 1230,1262,1266,1288,1348,1434 There appears to be heterogeneity in onset, type of autonomic deficits, presence or absence of somatic involvement, and degree of recovery. Recently, the Mayo Clinic reported the largest series in a detailed study of 27 patients with idiopathic autonomic neuropathy who were followed for a mean of 32 months.1266 Approximately 20% of patients had selective cholinergic dysfunction, and 80% of patients had various degrees of widespread sympathetic and parasympathetic dysfunction. The most common symptom was orthostatic dizziness or lightheadedness (about 80% of patients). Gastrointestinal involvement, as indicated by complaints of nausea, vomiting, diarrhea, constipation, ileus, or postprandial bloating is the second most common symptom (over 70% of patients). Thermoregulatory impairment with heat intolerance and poor sweating was also present in most patients. Blurred vision, dry eyes and mouth, urinary retention or incontinence, and impotence are often present. As many as 30% of patients also described numbness, tingling, and dysesthesia of the hands and feet. Muscle strength was normal. Most patients had a monopathic course with progression followed by plateau and slow recovery or stable deficit.1266 Although some patients exhibit complete recovery,1348,1442 recovery tends to be incomplete in most.1266 Laboratory Features. The CSF often reveals slightly elevated protein without pleocytosis.1266 There are no serologic or immunologic abnormalities in the blood. Supine plasma norepinephrine levels are not different, but standing levels are significantly reduced compared with normal controls.1266 Specialized tests to look for abnormalities of the autonomic nervous system are required for diagnosis.865,875,1088 Cardiovascular studies reveal orthostatic hypotension and reduced variability of the heart rate to deep breathing in over 60% of patients.1077,1266 An abnormal response to Valsalva maneuver (i.e., exaggerated fall in blood pressure during early phase II of the response, absent recovery of systolic and diastolic blood pressure during late phase II, or reduced or absent overshoot of systolic and diastolic pressures during phase IV) can be demonstrated in over 40% of patients. Summated quantitative sudomotor axon reflex test (QSART) scores are abnormal in 85% of patients.1266 Most patients have abnormal thermoregulatory sweat tests with areas of anhidrosis
Table 23-6. Vasculitides Associated with Peripheral Neuropathy

in 1297% of the body. Gastrointestinal studies can demonstrate hypomotility anywhere from the esophagus to the rectum. Histopathology. Nerve biopsies have been performed on only a few patients.35,407,950,1262,1266,1440,1442 Reduced density of mainly small diameter myelinated nerve fibers has been described. Stacks of empty Schwann cell profiles and collagen pockets can be seen. Scant epineurial perivascular inflammation may be seen. Pathogenesis. The disorder is thought to result from an autoimmune attack directed against peripheral autonomic fibers or the ganglia. A subset of patients may have antibodies directed against calcium channels, which are present on presynaptic autonomic nerve terminals. Electrophysiologic Findings. Routine nerve conduction studies and EMG are usually unremarkable.1266 Motor conduction studies are normal. Most patients have normal sensory conduction studies, although a few have diminished amplitudes and slightly prolonged distal latencies. Quantitative sensory testing may reveal abnormalities in thermal thresholds.818 Sympathetic skin response may be absent.388,406,1440 Needle EMG is generally normal, but in one report stimulated single-fiber studies demonstrated increased jitter.1077 With increased rate of stimulation the amount of jitter decreased. The authors speculated that the mechanism was autoantibodies directed against calcium channels on presynaptic autonomic nerve terminals and, to a lesser extent, the neuromuscular junction. However, whether autoantibodies to calcium channels were present in this patient was not reported. Treatment. Conclusions about the efficacy of immunotherapy are limited by the retrospective and uncontrolled nature of most reports. PE, prednisone, IVIG, and other immunosuppressive agents have been tried with variable success.566,1077,1230,1266 The most important aspect of management is supportive therapy for orthostatic hypotension and bowel and bladder symptoms.865,875 Fluodrocortisone is effective for increasing plasma volume. Fluodrocortisone is administered only in the morning or in the morning and at lunch to avoid nocturnal hypertension. We begin treatment at 0.1 mg/day and increase by 0.1 mg every 34 days until blood pressure is controlled. Midodrine, a peripheral 1-adrenergic agonist, is also effective and can be used in combination with fluodrocortisone. Midodrine is started at 2.5 mg/day and can be gradually increased to 40 mg/day in divided doses (every 24 hours) as necessary. Gastrointestinal hypomotility can be treated with metaclopramide, cisapride, or erythromycin. Bulking agents, laxatives, and enemas may be needed in patients with constipation. Urology should be consulted in patients with neurogenic bladders. Patient may require cholinergic agonists (e.g., bethanechol), intermittent selfcatheterization, or other modes of therapy.

Primary vasculitis Large vessel vasculitis; giant cell (temporal) arteritis Medium and small vessel vasculitis Polyarteritis nodosa Churg-Strauss syndrome Wegeners granulomatosis Microscopic polyangiitis Isolated angiitis of the nervous system Secondary vasculitis Vasculitis associated with connective tissue diseases Vasculitis associated with malignancies Vasculitis associated with infections Vasculitis associated with cryoglobulinemia Vasculitis associated with hypersensitivity reaction (leukocytoclastic angiitis)uncommonly associated with a peripheral neuropathy

VASCULITIC NEUROPATHIES
Definition/Classification. Vasculitis is a histologic diagnosis requiring transmural inflammation and necrosis of the blood vessel walls. Mere perivascular inflammation is a nonspecific finding and does not necessarily indicate vasculitis (necrotizing vasculitis). Necrotizing vasculitis results in ischemia in tissue supplied by the injured vessels. Vasculitic disorders can be classified based on the caliber of involved vessel (i.e., small, medium, or large vessel), whether the vasculitis is primary (e.g., polyarteritis nodosa, Churg-Strauss disease, Wegeners granulomatosis) or secondary to other systemic disorders (connective tissue diseases, infection, drug reactions, malignancy), or whether the vasculitis is systemic or isolated to the peripheral nervous system (PNS) (Table 23-6).519,701,1125a

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Figure 23-6. Diagrammatic representation of the three patterns of peripheral nerve involvement commonly encountered in vasculitic neuropathies. In true mononeuritis or mononeuropathy multiplex, individual nerves create an asymmetric pattern of clinical involvement. In this example, the patients demonstrate a combination of right peroneal, right superficial radial, and left ulnar nerves affected. In overlapping mononeuritis multiplex, multiple neighboring nerves are involved on both sides of the body.There is a certain degree of asymmetry when the same nerve on the left vs. the right is considered, thus distinguishing this form of dysfunction from distal symmetric polyneuropathy.The distal symmetric polyneuropathy is what its name implies: symmetric with respect to the nerves and degree of involvement when the two sides are compared. (From Kissel JT, Mendell JR:Vasculitic neuropathy. Neurol Clin 1992;10:761781, with permission.)

Clinical Features. All of the vasculitic disorders have certain clinical features in common, with variations on a central theme of vascular compromise.519,563,697,700,701,1125a,1159 Each specific disease has unique characteristics of its primary systemic manifestations, but there is significant overlap of clinical manifestations, particularly in terms of peripheral nerve involvement. Three patterns of peripheral nerve involvement can be appreciated (Fig. 23-6).701 The first is a mononeuropathy multiplex or multiple mononeuropathies. Several individual nerves may be affected, creating a distinctly asymmetric pattern of involvement. A second pattern, so-called overlapping mononeuropathy multiplex, is formed when the same nerves on both sides of the body are affected but to differing degrees and in differing distributions. The result is a generalized, yet asymmetric pattern of involvement. Finally, over time fairly uniform and generalized involvement of peripheral nerves can develop, producing the classic glove-and-stocking deficit similar to most distal symmetric polyneuropathies. The mononeuropathy multiplex patterns (simple and overlap forms) are the most common, found in 6070% of cases at the time of diagnosis, whereas a distal symmetric polyneuropathy is evident in approximately 3040% of patients.697 The differential diagnosis of patients with a mononeuropathy multiplex pattern is quite broad (Table 237).997,1022 We prefer the terms multiple mononeuropathies or mononeuropathy multiplex to mononeuritis multiplex because

the latter term implies a histologically defined rather than a clinically defined syndrome.1022 The most common symptom in patients with vasculitis is a burning dysesthetic type of pain confined to the anatomic distribution of the affected nerve(s). Usually, both motor and sensory fibers are affected, resulting in numbness and weakness conforming to specific nerve distributions. In patients with the distal symmetric pattern, sensory loss and weakness are located in the typical glove-and-stocking distribution. Histopathology. In patients with suspected vasculitic neuropathies, the sural, superficial sensory peroneal, and superficial radial sensory nerves are the most appropriate to consider for biopsy.701 We prefer the superficial peroneal nerve, if it is clinically involved, because the peroneus brevis muscle can be biopsied at the same time. The diagnostic yield is increased when both nerve and muscle are biopsied.234,697,700,701,1159 The definitive histologic diagnosis of vasculitis requires transmural inflammatory cell infiltration and necrosis of the vessel wall (Fig. 23-7).697,700,701,997,1020,1393 Immunocytochemistry often reveals deposition of immunoglobulin (IgM and/or IgG), complement, and membrane attack complement on blood vessels. Another important observation is the asymmetric nerve fiber loss between and within individual nerve fascicles. Active Wallerian degeneration is evident on plastic/epoxy resin sections and teased fiber preparations.

964 PART IV Table 23-7.

CLINICAL APPLICATIONS Mononeuropathy Multiplex: Differential Diagnosis

Ischemic neuropathies Polyarteritis nodosa Wegeners granulomatosis Churg-Strauss syndrome Connective tissue disorders associated with vasculitic neuropathies (e.g., SLE, RA, MCTD) Nonsystemic vasculitis neuropathy Remote effect of cancer Diabetic microangiopathy Amyloidosis Atherosclerotic vascular disease Drug-induced (e.g., amphetamine, sulphonamides) Demyelinating neuropathies Multifocal motor neuropathy (MMN) Multifocal acquired sensory and motor neuropathy (MADSAM) Paraproteinemic polyneuropathies (e.g., IgM monoclonal gammopathies) Hereditary liability to pressure neuropathy HIV-associated demyelinating neuropathy Infectious neuropathies Leprosy Herpes zoster Lyme disease HIV-associated with cytomegalovirus Hepatitis B and C Compression neuropathy Primary compression neuropathies (e.g., traumatically induced) Secondary compression neuropathies (e.g. , superimposed on generalized peripheral nerve disease; e.g., diabetes mellitus and carpal/cubital tunnel syndrome) Neoplastic infiltration Neurofibromatosis Local infiltration by tumor tissue Granulomatous infiltration Sarcoid Sensory perineuritis Lymphomatoid granulomatosis Other disorders Lumbosacral plexus neuropathy Brachial plexus neuropathy
Modified with permission from references 997 and 1122.

mononeuropathy multiplex pattern reveals asymmetric SNAP abnormalities. For example, the left sural and right superficial peroneal SNAPs may be absent or reduced in amplitude, whereas the right sural and left superficial peroneal SNAPs are relatively unaffected. The same comments apply to the upper limbs. Motor conduction studies reveal similar findings to those noted for sensory nerves. The CMAP is commonly absent or significantly reduced in the affected nerves. Distal latencies are normal or slightly prolonged, whereas conduction velocities are normal or only mildly reduced compared with the lower limit of normal. Fwaves may be difficult to obtain in nerves with severe axonal loss. When obtainable, F-waves latencies are normal or only slightly prolonged. With mononeuropathy multiplex, an asymmetric pattern of motor conduction abnormalities between limbs can be demonstrated. Of interest, it is possible to observe conduction block in some patients with vasculitic neuropathies.624,800,860,907,1115 The cause probably is related to ischemia, which produces conduction failure, and can be observed in patients either with mononeuropathy multiplex or generalized sensorimotor forms of involvement. The needle EMG examination characteristically demonstrates fibrillation potentials and positive sharp waves in muscles innervated by the affected nerve. Reduced recruitment of MUAPs is also evident in the distribution of the affected nerves. In long-standing disease, motor unit remodeling results in MUAPS of long duration and relatively increased amplitude, which fire in reduced numbers. The distal muscles are more likely than the proximal muscles to demonstrate such abnormalities. Documenting fibrillation potentials in a specific nerve distribution can be quite helpful in delineating the pattern of a mononeuropathy.
Primary Systemic Vasculitic Disorders Affecting Large and Medium-sized Vessels Giant Cell Vasculitis. There are two forms of giant cell arteritis (GCA): temporal arteritis and Takayasu arteritis.Only temporal arteritis has been associated with peripheral neuropathy.162,176,193,468,716 GCA affects medium-sized and large vessels, particularly the aortic arch and all its branches, including the internal and external carotid arteries and vertebral arteries. Patients usually complain of headaches and diffuse myalgias. Jaw and tongue claudication is not uncommon. Vision loss secondary to ischemic optic neuropathy occurs in 823% of patients.176,716 Stroke is another important complication. Approximately 14% of patients with temporal arteritis have peripheral nerve involvement, resulting in multiple mononeuropathies, radiculopathies, plexopathies, or generalized sensorimotor peripheral neuropathy.176 Corticosteroids are usually highly effective in patients with GCA. Laboratory evaluation is remarkable for elevated ESR in 97% of patients.176 The temporal artery is often tender, and a cord can be palpated. Unfortunately, as many as one-third of temporal artery biopsies lack definitive features of arteritis.176 The classic histologic feature is an inflammatory infiltrate with giant cell formation in the blood vessels. Primary Systemic Vasculitic Disorders Affecting Medium-sized and Small Vessels Polyarteritis Nodosa. Polyarteritis nodosa (PAN) is the most common of the necrotizing vasculitides with an incidence ranging from 29 per million.162,193,517519,700,701,1125a The onset is usually between 40 and 60 years of age. PAN is a systemic disorder

Electrophysiologic Findings. The electrodiagnostic medicine findings noted in this section pertain to all of the specific disorders listed below. Polyarteritis nodosa is used as a template disease to illustrate what can be anticipated in vasculitic axonal sensorimotor neuropathies. To be sure, there are minor variations for each disorder and individual patients, but the descriptions noted are generally applicable. The interested reader is encouraged to pursue the specific citations noted for each disease about particular electrodiagnostic medicine findings. The description of electrophysiologic findings pertains to individual nerves in patients with mononeuropathy multiplex as well as to all involved nerves in a more generalized sensorimotor peripheral neuropathy.81,132,563,579,697,982,997,1345,1393 Sensory nerve conduction studies typically reveal SNAP amplitude reductions in the distribution of the affected nerves. A

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Figure 23-7. Vasculitis. A, Sural nerve biopsy demonstrates necrotizing vasculitis with obliteration of the vessel lumen. B, Immunoperoxidase stain demonstrates deposition of complement (C3) in the walls of affected blood vessels.

involving small- and medium-caliber arteries in multiple organs. Fifty to 70% of patients with PAN have evidence of peripheral neuropathy. Mononeuropathy multiplex is the most common pattern of involvement, and the sciatic nerve or its peroneal or tibial branch is the most frequently affected nerve. Cranial neuropathies and CNS involvement are uncommon (< 2% of patients).519 Besides the peripheral neuropathy, multisystem dysfunction is also present, consisting of varying degrees of hepatic, renal, muscular, skin, and gastrointestinal involvement. However, the lungs are generally spared. Myalgias and arthralgias are frequent (3070% of patients). Skin lesions, including petechiae, papules, livido reticularis, subcutaneous nodules, and distal gangrene, may be evident in 2560% of patients.519 Vasculitis of the gastrointestinal tract can manifest as abdominal pain or bleeding. Ischemia of the kidneys can lead to renal failure. Orchitis is also a classic symptom of PAN. Constitutional symptoms of weight loss, fever, and loss of appetite are usually noted. Laboratory evaluation is remarkable for elevated ESR greater than 60 mm/hr in 7889% of patients.519 Rheumatoid factor, Creactive protein, and alpha-2 globulins also are elevated. Leukocytosis with normochromic anemia usually is seen. As many as one-third of cases are associated with hepatitis B antigenemia.517,519 In addition, hepatitis C and HIV infection have been reported with PAN.519 Abdominal angiograms may reveal a vasculitic aneurysm, which may be helpful in patients with nondiagnostic biopsies. PAN primarily affects medium-sized arteries; however, smaller vessels may be involved.519,701 The infiltrate is composed mainly of CD8+ T-cells and macrophages. Polymorphonuclear cells may be evident in the area of fibrinoid necrosis. Immunocytochemistry can demonstrate deposition of IgM, IgG, complement, and membrane-attack complement on blood vessels. Granuloma formation and eosinophilic infiltration are not present on nerve biopsies; their absence can be useful in distinguishing PAN from Churg-Strauss syndrome. The pathogenic mechanism of PAN is unknown. Kissel and Mendell suggest a T-celldependent, endothelial cell-mediated process; complement-mediated vascular damage plays a secondary role.701 Churg-Strauss Syndrome (Allergic Angiitis/Granulomatosis). Churg-Strauss syndrome (CSS) is a rare disorder that manifests much like PAN.162,193,222,240,519,560,983,1125a The incidence is

roughly one-third that of PAN, but the frequency of PNS and CNS involvement is similar. In contrast to PAN, patients with CSS usually present with respiratory involvement. They typically develop allergic rhinitis, nasal polyposis, and sinusitis followed by asthma. In CSS, asthma begins later in life, whereas common asthma usually develops before the age of 35 years. Pulmonary infiltrates are present in nearly one-half of patients, usually in association with asthma and hypereosinophilia. Symptoms and signs of systemic vasculitis occur an average of 3 years after onset of asthma. Rather than an ischemic nephropathy, as in PAN, 1649% of patients with CSS develop necrotizing glomerulonephritis. Besides the differences in respiratory and renal system involvement, the other systemic manifestations of CSS are similar to those in PAN. In particular, multiple mononeuropathies are found in 6475% of patients.519 Laboratory evaluation is remarkable for eosinophilia, often > 109/L, leukocytosis, and elevated ESR, C-reactive protein, rheumatoid factor, and serum IgG and IgE levels. The association of eosinophilia with asthma is highly suggestive of the diagnosis. CSS also is associated strongly with antineutrophil antibodies (ANCA), primarily myeloperoxidase or p-ANCA, because of its perinuclear staining pattern. These p-ANCA antibodies are present in as many as two-thirds of patients.519 Histopathology reveals necrotizing vasculitis involving medium-sized and small arteries and veins. The inflammatory infiltrates consist mainly of CD8+ cytotoxic T-lymphocytes and CD4+ helper T-lymphocytes. Eosinophils are also present in the infiltrate but not as extensively as the T-lymphocytes. Less commonly, intravascular and extravascular granulomas are evident in and around these blood vessels.519,560,794 Wegeners Granulomatosis. Wegeners granulomatosis is a rare disorder consisting of necrotizing granulomatous involvement of the upper and lower respiratory tract and glomerulonephritis.162,335,393,590,621,634,701,963,1125a,1259 The early symptoms of respiratory disease (nasal discharge, cough, hemoptysis, and dyspnea) and facial pain help to distinguish this from other vasculitic disorders. About 3050% of patients may have some form of neurologic dysfunction, although only 1520% have peripheral neuropathy. Either a mononeuropathy multiplex or generalized symmetric pattern of involvement can be found. The presence of peripheral neuropathy correlates with the severity of renal involvement.621 Cranial neuropathies, particularly the second, sixth, and seventh nerves, are involved in approximately

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10% of cases as a result of extension of the nasal or paranasal granulomas rather than vasculitis.963 Laboratory evaluation is remarkable for the presence of antineutrophil antibodies directed against proteinase-3.621 The immunofluorescent staining pattern is diffuse within the cytoplasm; thus the name c-ANCA. The specificity of c-ANCA for Wegeners granulomatosis is 98% and the sensitivity is 95%. The vasculitis is similar to PAN, affecting medium-sized and small blood vessels. Granulomatous infiltration of the respiratory tract and necrotizing glomerulonephritis also are seen. The lack of peripheral eosinophilia and eosinophilic infiltrates on biopsy and the absence of asthma help to distinguish Wegeners granulomatosis from CSS. Microscopic Polyangiitis. The clinical symptoms of microscopic polyangiitis (MPA) are similar to those of PAN, except that the lungs are often involved.519,701,1173 Inflammation of pulmonary capillaries leads to diffuse alveolar damage and interstitial fibrosis. MPA is about one-third as common as PAN; the average age at onset is 50 years. Polyneuropathy complicates 1436% of cases.519,701,1173 Impaired renal function, as illustrated by increased BUN and creatinine as well as hematuria, is evident in most patients. Kidney biopsy reveals the presence of focal segmental thrombosis and necrotizing glomerulonephritis. Extracapillary proliferation forms crescents in the majority of glomeruli. Hepatitis serology is negative. Laboratory evaluation usually demonstrates the presence of p-ANCA antibodies, although c-ANCA antibodies occasionally can be detected. As the name implies, microscopic polyangiitis affects small arterioles, venules, and capillaries.519,701 Unlike PAN, there are few or no immune deposits on the blood vessels. Behets Syndrome. Behets syndrome is characterized by recurrent oral and genital ulcerations associated with inflammation of the eye.428,935,1280,1375 Additional manifestations include arthritis, thrombophlebitis, skin lesions, and vasculitic lesions involving the small to medium-sized arteries. The cause is unknown. Men are believed to be affected more commonly than women. The central nervous system is affected (brainstem strokes, meningoencephalitis, psychosis) more frequently than the peripheral nervous system. Either a mononeuropathy multiplex or generalized sensorimotor peripheral neuropathy may be present.
Secondary Systemic Vasculitides Vasculitis Associated with Connective Tissue Disease. Peripheral neuropathy is a frequent complication in patients with underlying connective tissue diseases; however, true vasculitis as the basis of the neuropathy is much less common.606,997 Secondary vasculitis associated with connective tissue disease is most common in rheumatoid arthritis, followed by systemic lupus erythematosus, Sjgrens syndrome, and, less frequently, systemic sclerosis. The clinical, histologic, and electrophysiologic features are similar to those of PAN. The different forms of peripheral neuropathy associated with connective tissue disorders are discussed in more detail in a subsequent section. Infection-related Vasculitis. Vasculitis with peripheral nervous systemic complications can result from a number of infectious agents.452 The most common agents associated with vasculitis of the PNS are viruses, including herpes varicella zoster, cytomegalovirus (CMV), human immunodeficiency virus (HIV), and hepatitis B and C. Mononeuropathy multiplex related to HIV or CMV infection occurs in up to 3% of patients with AIDS.145,1158 Hepatitis B and C can cause PAN, a medium-sized

systemic vasculitis, but also are associated with small-vessel vasculitis related to cryoglobulinemia (discussed below). Lyme disease caused by the spirochete, Borrelia burgdorferi, also is associated with a variety of peripheral neuropathies, which can caused by vasculitis. These disorders are discussed more fully in the section, Neuropathies Related to Infection. Malignancy-related Vasculitis. Various malignancies have been associated with vasculitis of the peripheral nervous system. The most common are small cell carcinoma of the lung (SCCL) and lymphoma, but carcinoma of the kidneys, bile duct, prostate, and stomach also have been described.639,809,845,985,990,1165,1307,1357,1443 However, most of the reported cases are not associated with necrotizing vasculitis. Rather, transmural and perivascular inflammation of small blood vessels without necrosis is the most common histopathologic feature.990 As noted previously, this is a nonspecific abnormality. Of note, several cases of SCCL were associated with anti-Hu antibodies. Patients with the paraneoplastic anti-Hu syndrome can present with symmetric or asymmetric sensory loss, dysesthesias as well as motor weakness and clinically and electrophysiologically may resemble patients with true peripheral nervous system vasculitis.24 Lymphomas can be complicated by nonvasculitic paraneoplastic neuropathies.24 Furthermore, lymphomatous infiltration of the nerves can cause multiple mononeuropathies or generalized neuropathy. Nevertheless, rare cases of vasculitic neuropathy have been reported in patients with cancer. Drug-induced Hypersensitivity Vasculitis. In contrast to systemic necrotizing vasculitis, hypersensitivity vasculitis secondary to drug reactions is a self-limited process.701 Nevertheless, short-term treatment with corticosteroids is often necessary and useful. Cutaneous manifestations predominate the clinical picture. Vasculitis of the CNS is much more common with drugs of abuse (e.g., amphetamine, cocaine, opioids), but the PNS occasionally is involved.161,1254 The pathogenesis most likely relates to a complement-mediated leukocytoclastic reaction.701 Vasculitis Secondary to Essential Mixed Cryoglobulinemia. Cryoglobulins are immunoglobulins that precipitate out of solution when exposed to a cool temperature but dissolve into solution when warmed. Cryoglobulins are circulating immune complexes, usually immunoglobulins directed against polyclonal immunoglobulins. There are three types of cryoglobulins. Type I cyroglobulins are composed of monoclonal immunoglobulins, usually IgM, directed against polyclonal IgG. Type I cryoglobulins most frequently occur in patients with plasma cell dyscrasias. Type II cryoglobulins are composed of a combination of monoclonal IgM and polyclonal immunoglobulins directed against polyclonal IgG. Type III cyoglobulins are a mixture of polyclonal IgM, IgG, and IgA directed against polyclonal IgG. Type II and III are the most common and are also called mixed cryoglobulinemia. Mixed cryoglobulinemia can be associated with other diseases, such as a lymphoproliferative disorders, connective tissue diseases, and hepatitis B and C. Essential mixed cryoglobulinemia (ECM) refers to situations in which mixed cryoglobulinemia is found without a systemic disorder other than viral hepatitis. Recent studies have revealed that most cases of EMC are associated with hepatitis C antigenemia. The incidence of peripheral neuropathy in patients with various type of cryoglobulinemias ranges from 2590%.184,291,412,450,682,800,945,1125,1295,1327 Most patients also demonstrate a painful, distal, symmetric polyneuropathy, but a mononeuropathy multiplex pattern also may occur. The neuropathy can result from ischemia due to hyperviscosity or vasculitis related to immune-complex deposition in small

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epineurial blood vessels. Electrophysiologic studies are similar to those in PAN. Sensory studies demonstrate an absence or reduction in the SNAP amplitudes, affecting the lower limb nerves to a greater degree than the upper limb nerves.184,291,412, 450,682,800,945,1295,1327 When present, conduction velocities are mildly reduced; however, a few patients demonstrate significant reductions in velocity. Motor studies reveal an absence or significant reduction in the CMAP amplitude of the lower limb nerves. One patient has been reported with evidence of conduction block.800 In long-standing disease, the median and ulnar nerves display similar findings. Nerve conduction studies show borderline normal or somewhat reduced conduction velocities, with an occasional nerve having a conduction velocity reduced to less than 70% of the lower limit of normal. F-wave studies are abnormal in most patients at some time during the course of the disease. Needle EMG examination demonstrates fibrillation potentials and positive sharp waves with a reduced number of voluntary MUAPs in the distal upper and lower limb muscles.
Nonsystemic Vasculitis Nonsystemic or Isolated PNS Vasculitis. Vasculitis isolated to peripheral nerves accounts for 3058% of vasculitic neuropathy.292,358,563,697,955,1020,1125a,1159,1163 The clinical, electrophysiologic, and histopathologic features of isolated peripheral nerve vasculitis are quite similar to those of PAN, except that other organ systems are not significantly involved. There can be subclinical involvement of muscle, as apparent on muscle biopsies, but the clinical manifestations of the disease suggest preferential involvement of the peripheral nerves. In fact, some have suggested that vasculitis may be more likely to be evident on peroneus brevis muscle biopsies than on a superficial peroneal nerve biopsy,1159 although this has not been our experience.234 Patients can manifest with multiple mononeuropathies or a generalized symmetric sensorimotor polyneuropathy. Laboratory testing may demonstrate elevated ESR or low ANA titers. The vasculitis typically involves small and mediumsized arteries of the epineurium and perineurium. Immune complex deposition on these blood vessels can be appreciated. The trigger for this rather selective vasculitis is not known. Matrix metalloproteinases (MMP) are a family of endopepsidases with overlapping substrate affinities for various extracellular matrix proteins. MMP-2 and MMP-9 (gelatinase A and B) are upregulated in the peripheral nerves in patients with nonsystemic vasculitis.778 T-cells are the predominant source of MMP-2 and MMP-9, although stroma cells of the perineurium and endoneurium are an additional source. These MMPs are capable of degrading components of the subendothelial basement membrane, thereby allowing inflammatory cells to disrupt the bloodnerve barrier and penetrate into peripheral nerves. Of importance, the prognosis is considerably better than that for systemic vasculitic disorders. Survival rates are similar to age-matched controls. Furthermore, the neuropathy may be more likely to respond to corticosteroids alone or to require a shorter duration of cyclophosphamide. Treatment of Vasculitic Neuropathy Systemic vasculitis is treated intially with a combination of corticosteroids and cyclophosphamide.169,517,519,560,701 Corticosteroids were used to treat systemic vasculitis in the 1950s, and the 5-year survival rate increased from 10% to 55% by the midto-late 1970s.519 The addition of cyclophosphamide to corticosteroids further increased the 5-year survival rate to over 80%.519

Hypersensitivity vasculitis and isolated PNS vasculitis can be treated with prednisone alone. We generally initiate corticosteroid treatment with pulsed methylprednisolone (1 gm intravenously every day for 3 days), then switch to oral prednisone (1.5 mg/kg/day, up to 100 mg/day) as a single dose in the morning. After 24 weeks, we switch to alternate-day prednisone (100 mg qod). Collateral treatment includes calcium and vitamin D supplementation as well as bisphosphonates to prevent and treat steroid-induced osteoporosis, as discussed in the section about chronic inflammatory demyelinating polyneuropathy. Cyclophosphamide is started at the same time as corticosteroids and can be given orally or in intravenous pulses. Oral cyclophosphamide at a dose of 1.02.0 mg/kg is a more potent suppressor of the immune system but is associated with more adverse side effects (e.g., hemorrhagic cystitis) than intravenous pulses. We prefer monthly intravenous pulses of cyclophosphamide at a dose of 5001000 mg/m2 of body surface area. Sodium 2-mercaptoethane sulfonate (mesna) is given to reduce the incidence of bladder toxicity, and ondansetron is used to diminish nausea. Patients should be vigorously hydrated to minimize bladder toxicity. After intravenous pulses of cyclophosphamide, the leukocyte count drops with a nadir after 718 days, during which time the risk of infection is greatest. We check complete blood counts and urinalysis before each treatment. Urinalysis is obtained every 36 months after treatment because of the risk of future bladder cancer. We continue with high-dose corticosteroids and cyclophosphamide treatment until the patient begins to improve or the deficit at least stabilizes, usually within 46 months. Subsequently, prednisone is gradually tapered by 5 mg every 23 weeks. Pulsed cyclophosphamide is generally continued for at least 1 year. If patients do not respond to pulsed cyclophosphamide, oral dosing should be tried before concluding that the patient failed cyclophosphamide treatment. Patients with CSS often require continued low-doses of prednisone secondary to associated asthma. Relapses are uncommon in PAN, MPA, and isolated PNS vasculitis but occur in as many as 50% of cases of Wegeners granulomatosis.519,621 Such patients may require lifelong immunosuppressive therapy. There is less experience with other immunosuppressive agents in the treatment of vasculitis. In an open-label study of low-dose methotrexate (0.150.3 mg/kg/week) in combination with corticosteroids, marked improvement was noted in 76% of patients with Wegeners granulomatosis and remission occurred in 69%.1239 Azathioprine, cyclosporine, tacrolimus, and chlorambucil may be tried in refractory cases.169 Several prospective but uncontrolled series have suggested that IVIG can be beneficial in the treatment of systemic vasculitis.704,805 However, other studies failed to demonstrated much improvement with IVIG.1101 Patients with hepatitis B- or C-related PAN require special treatment. Conventional treatment with high-dose corticosteroids and cyclophosphamide may allow the virus to persist and replicate, thus increasing the risk of liver failure. Some suggest using corticosteroids only during the first few weeks of treatment to manage life-threatening manifestations of systemic vasculitis.519 Afterward the corticosteroids are abruptly discontinued. Plasma exchange and antiviral agents such as vidarabine or -interferon are used to control the course of the illness. Using this protocol, the 7-year survival rate of hepatitis B-related PAN was 83%, HBeAG/HBeAB conversion rate was 51%, and total viral clearance was seen in 24% of casesa substantial

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improvement from that seen with corticosteroids with or without cyclophosphamide or plasma exchange.518 As noted above, hepatitis C has been implicated in most cases of mixed cryoglobulinemia. Several studies have reported that interferon (3 million units 3 times/week) is efficacious in treating hepatitis C-related mixed cryoglobulinemia.62,122,175,294,317,343,455,682 As with PAN due to hepatitis B or C, a short course of corticosteroids may be required to control the initial manifestations of systemic vasculitis. Plasma exchange may be beneficial in patients who continue to deteriorate on -interferon.

NEUROPATHIES ASSOCIATED WITH AUTOIMMUNE CONNECTIVE TISSUE DISEASES

Sjgrens Syndrome

Clinical Features. The central feature of Sjgrens syndrome is the sicca complex, characterized clinically by xerophthalmia (dry eyes), xerostomia (dry mouth), and occasional dryness of other mucous membranes. There is a significant female predominance, and onset is typically in middle adult life. The CNS manifestations can mimic transverse myelitis or multiple sclerosis. Peripheral neuropathy occurs in 1050% of patients with Sjgrens syndrome.451,490,492,504,678,826,883,1125a,1336 Peripheral neuropathy or neuronopathy can be the presenting feature of Sjgrens syndrome and may occur before any sicca symptoms. Most patients have an axonal sensorimotor neuropathy characterized by numbness and tingling in the distal portions of the limbs.451,490,883 A burning sensation and paresthesias can also occur. Muscle weakness may be present but is milder than the sensory symptoms. Necrotizing vasculitis is uncommon in Sjgrens syndrome but may be responsible for as many as onethird of the cases of neuropathy associated with the disorder. Rarely, autonomic neuropathy is the primary manifestation.481a A particularly interesting complication of Sjgrens syndrome is sensory neuronopathy or ganglionitis.39,451,490,492,504,546,758,1125a,1336 Patients develop progressive numbness and tingling of the limbs, which may also involve the face. The onset can be acute or insidious. Symptoms can involve the arms more than the legs, and involvement can be quite asymmetric or even unilateral. Physical examination demonstrates reduced sensation to all modalities, especially position sense and vibration. A sensory ataxia with pseudoathetosis is often evident. A positive Romberg sign is noted in patients with lower limb involvement. Sensation also may be diminished in the trigeminal nerve distribution. Many patients have signs of autonomic insufficiency with Adies pupils, anhidrosis, fixed tachycardia, and orthostatic hypotension. Decreased or absent deep tendon reflexes are seen. Muscle strength testing is usually normal, although the examination may reveal some weakness secondary to impaired sensory modulation of motor activities. Laboratory Features. Most patients with Sjgrens syndrome have antinuclear, SS-A/Ro, and SS-B/La antibodies in the serum. The CSF is usually normal. Schirmers test and Rose-Bengal stain are useful for diagnosing keratocunjuctivitis. The diagnosis is confirmed by demonstrating a lymphocytic invasion of salivary glands on a biopsy of the parotid gland or lips.650 Histopathology. Peripheral nerve biopsies in patients with the more typical symptoms of sensorimotor polyneuropathy demonstrate axonal degeneration and some degree of secondary segmental demyelination.451,490,883 Rarely, necrotizing vasculitis can be seen. Nonspecific perivascular inflammation involving

perineurial or endoneurial blood vessels is more commonly seen. A decreased density of small unmyelinated fibers may also be seen. In patients with a sensory neuronopathy, biopsy of sensory nerves reveals a reduction in the total number of myelinated fibers, particularly those of larger caliber.451,490,504 Perivascular lymphocytic (CD8 T-cells) inflammation of the endoneurial or perineurial vessels also may be found.504 Biopsy of the dorsal root ganglion has demonstrated lymphocytic (mainly CD8 Tcells) infiltration and degeneration of cell bodies.504 Pathogenesis. The pathogenetic basis of the distal sensory or sensorimotor polyneuropathy is unknown but is presumably autoimmune. Some cases may be caused by necrotizing vasculitis. The sensory neuronopathy appears to be caused by an autoimmune attack directed against the sensory ganglia. The specific antigen(s) and trigger of the autoimmune attack are not known. Electrophysiologic Findings. In patients with the distal sensorimotor form of peripheral neuropathy, there is marked abnormality in the SNAPs as evidenced by a significant reduction in amplitude and mild to moderate reductions in velocity.451,490,883 Some degree of abnormality in motor conduction can also be detected with mild reductions in amplitude and slowing of conduction velocity. Distal latencies are not usually altered to a significant degree. Needle EMG examination reveals some degree of fibrillation potentials and positive sharp waves with MUAP alterations suggestive of motor unit remodeling (i.e., increased amplitude and duration with reduced recruitment). In patients with sensory neuronopathy, nerve conduction studies also show preferential involvement of the SNAPs with significant reductions in amplitude or complete absence of the response in both upper and lower limbs.39,451,490,504,546,758,826 In contrast to length-dependent axonopathies (e.g., the distal sensorimotor neuropathy associated with Sjgrens syndrome), the upper limbs can be more severely affected than the lower limbs in sensory neuronopathies. There can be asymmetric involvement electrophysiologically. Motor conduction studies are minimally affected, if at all. EMG is normal. If the trigeminal nerve is affected, blink reflexes are also abnormal.52 In fact, an abnormal blink reflex is more suggestive of a sensory neuropathy due to Sjgrens syndrome as opposed to a paraneoplastic etiology.52 An important electrophysiologic feature that helps to distinguish an axonal sensory neuropathy from a sensory neuronopathy or ganglionopathy is the preservation of the masseter reflex or jaw jerk in the latter.51 The masseter reflex is unique among the stretch reflexes in that the cell bodies of the afferent limb lie in the mesencephalic nucleus within the CNS. In contrast, sensory cell bodies innervating the limbs reside in the dorsal root ganglia of the PNS. Furthermore, the gasserian ganglion, which is responsible for conveying sensory nerves responsible for facial sensation and the blink reflex, lies outside the CNS as well. Treatment. There is no specific treatment for neuropathies related to Sjgrens syndrome. When vasculitis is suspected, immunosuppressive agents may be beneficial. Unfortunately, the sensory neuronopathy is poorly responsive to immunotherapy. Once the cell body has degenerated, recovery is unlikely. However, some investigators have suggested mild improvement or at least some stabilization of function with various forms of immunotherapy.39,504
Rheumatoid Arthritis Rheumatoid arthritis (RA) affects approximately 1% of the population, and peripheral neuropathy is evident in at least one-half of cases. Vasculitis is present in 825% of patients with RA,

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making it the third most common cause of vasculitic neuropathy after PAN and isolated PNS vasculitis.196,1052,1125a,1187,1247,1401 Vasculitic neuropathy develops in 4050% of patients with RA.1187,1401 The vasculitic neuropathy usually manifests 1015 years after manifestations of other symptoms of RA, although in rare patients the neuropathy is the presenting feature.495,1075,1187 Rheumatoid vasculitis can present with mononeuropathy multiplex, overlapping mononeuropathy multiplex, or generalized symmetric pattern of involvement. Laboratory elevation is remarkable for the presence of antinuclear antibodies (ANA), elevated ESR, and rheumatoid factor in the serum. Electrophysiologic features are similar to those in other forms of necrotizing vasculitis. As many as 75% of patients with RA have clinical or electrophysiologic evidence of a mild sensory neuropathy without definite necrotizing vasculitis on nerve biopsies. Nerve histopathology in such cases reveals thickening of the epineurial and endoneurial blood vessels as well as perivascular inflammation. Some of these cases may be related to a low-grade vasculitis that was missed on biopsy because of sampling error. However, the mechanism may be related to other undefined factors or toxic medications.
Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a common connective tissue disease with a prevalence in adults of 1 in 2000. The diagnosis is based on the presence of multiple organ system involvement and laboratory criteria.1286 Central nervous system complications are more common, but peripheral neuropathies also occur. Anywhere from 227% of patients with SLE clinically develop a peripheral neuropathy.60,162,193,467,606,607a,863,878,997, 1125a,1178,1226,1430a Most patients manifest with slowly progressive distal sensory loss. Many patients have a mild autonomic neuropathy.1430a Large prospective series have reported electrophysiologic abnormalities in 2456% of patients with SLE.607a,878,1226 Nerve conduction studies generally demonstrate a generalized, primarily sensory axonopathy with absent or diminished SNAP amplitudes. Mild reduction in CMAP amplitudes and a slight slowing of motor conduction velocities also can be seen. Endoneurial mononuclear inflammatory infiltrate and increased expression of class II antigens within nerve fascicles and on endothelial cells have been demonstrated on nerve biopsies in some cases, suggesting an autoimmune pathogenesis.863 A few patients present with multiple mononeuropathies presumably secondary to necrotizing vasculitis.377,606,697 The longer the disease progresses, the more likely the multiple mononeuropathies are to fuse and overlap, creating an increasingly symmetric neuropathy. Electrophysiologic features are similar to those with any form of necrotizing vasculitis. Rare patients display a generalized sensorimotor polyneuropathy quite similar to AIDP or CIDP.508,1090 Such patients can have demyelinative features on nerve conduction studies and nerve biopsies. Immunosuppressive therapy is beneficial in SLE patients with neuropathy related to vasculitis. Immunosuppressive agents are less likely to be effective in patients with a generalized sensory or sensorimotor polyneuropathy without evidence of vasculitis. Patients with an AIDP or CIDP-like neuropathy should be treated accordingly (see sections on AIDP and CIDP). Systemic Sclerosis (Scleroderma) Scleroderma manifests as progressive fibrosis of the skin, gastrointestinal tract, kidney, and lung.319,392,579,772,773,1290 Peripheral

neuropathy occurs in 514% of patients and usually manifests as a distal symmetric, mainly sensory polyneuropathy. The pathogenic basis of the neuropathy is not known, but true vasculitis is quite rare, if it occurs at all. Cranial mononeuropathies also can develop. The most commonly affected cranial nerve is the trigeminal, as demonstrated by numbness, dysesthesias, and electric shock-like or pricking/tingling sensations involving the face. Occasional involvement of the seventh and ninth cranial nerves also can occur. One investigation found a number of different disorders associated with involvement of the trigeminal nerve: undifferentiated connective tissue disease (47%), mixed connective tissue disease (26%), scleroderma (19%), rheumatoid arthritis (2%), Sjgrens syndrome (2%), systemic lupus erythematosus (2%), and dermatomyositis (1%).532 The CREST syndrome (calcinosis, Raynauds phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis) is considered a limited form of scleroderma. Multiple mononeuropathies have been described in a small percentage (12%) of patients with CREST syndrome. The clinical, electrophysiologic, and histologic features suggest a necrotizing vasculitis as the cause of the neuropathy.366
Mixed Connective Tissue Disease Mixed connective tissue disease (MCTD) represents an overlap syndrome of SLE, scleroderma, and polymyositis. There has been no detailed study of neuropathy in patients with MCTD, although one small study reported a mild distal axonal sensorimotor polyneuropathy in 10% of patients.87

SARCOIDOSIS
Clinical Features. Sarcoidosis is a multisystem granulomatous disorder affecting the liver, spleen, mucous membranes, parotid gland, muscle tissue, and central and peripheral nervous system.307,707,850,1402,1407,1454 The cause is unknown. Women are affected more commonly than men. The clinical presentation of sarcoidosis is highly individualized and ranges from an incidental observation on chest radiographs with hilar adenopathy to profound functional incapacitation and death. Nonspecific constitutional symptoms of fever, weight loss, and fatigue are the presenting complaints of most patients. Hilar adenopathy is noted on chest radiographs with transient erythematous subcutaneous nodules about the pretibial region accompanied by arthralgias. Palpable peripheral lymph nodes may be noted. A common finding on presentation is acute granulomatous uveitis, which can progress to significant visual impairment or even blindness. Mucosal lesions of the nose and sinuses are common. The peripheral or central nervous system is involved in about 5% of patients with sarcoidosis.307,707,850,1402,1407,1454 The most commonly affected regions of the central nervous system are the meninges, hypothalamus, and pituitary gland. The peripheral aspects of the nervous system frequently affected are the cranial and peripheral nerves, especially about the nerve root region. A common presentation is a mononeuropathy multiplex pattern of remitting cranial nerve palsies. Essentially any cranial nerve can be involved in the remitting and relapsing course of the disease. The most commonly involved cranial nerve is the seventh nerve, which can be affected bilaterally. The second and eighth cranial nerves are also frequently affected. Some patients may present with a clinical pattern quite similar to a radiculopathy of single or multiple nerve roots. With generalized root involvement, patients may present with signs

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and symptoms quite similar to AIDP or CIDP. The most common involvement of the peripheral nervous system is a subclinical mononeuropathy multiplex, which can be demonstrated by electrodiagnostic medicine evaluation. Less commonly, some patients present with symptoms and signs suggestive of a slowly progressive primarily sensory, motor, or sensorimotor peripheral neuropathy. Histopathology. The major histopathologic finding is noncaseating granulomas in various tissues. When the peripheral nerves are affected, nerve biopsy can reveal profuse infiltration of the nerve by multiple sarcoid tubercles, affecting all regions of the supporting neural structures (endoneurium, perineurium, and epineurium) associated with lymphocytic angiitis. There is a combination of axonal loss and demyelination. Pathogenesis. Sarcoidosis is an autoimmune disorder although the cause and pathogenic mechanism are unclear. Peripheral neuropathy may result from direct compression, ischemia, a combination of these two insults, or other ill-defined factors. The cranial nerves and mononeuropathies of the peripheral nervous system are likely to result from direct neural invasion and compression. The AIDP and CIDP-like neuropathies may result from diffuse infiltration of nerve and nerve roots or poorly defined immunologic compromise related to sarcoidosis itself. Electrophysiologic Findings. In patients with subclinical neuropathy, the most common finding is an absence or reduction in SNAP amplitudes in a mononeuropathy multiplex pattern.195 Such patients have normal motor conductions and CMAP amplitudes. The needle EMG examination is also normal. In patients with the symmetric sensorimotor peripheral neuropathy, the SNAPs may be absent or reduced in amplitude.446,941,981 Sensory nerve conduction velocities are mildly to moderately slow but usual do not exceed more than 20% slowing of the lower limit of normal. A few patients may have more profound slowing, which indicates a demyelinating as opposed to axonal component of nerve damage. Motor nerve conduction studies also reveal reduced or absent CMAPs amplitudes in the lower limbs with decreased or borderline normal CMAPs in the upper limbs. The nerve conduction velocities are usually within 7580% of the lower limit of normal. Patients with a polyradiculopathy may have normal SNAPs but abnormal CMAPs, as expected.707 Needle EMG examination in patients with long-standing disease and evidence of a clinical sensorimotor peripheral neuropathy or polyradiculopathy is consistent with axonal loss lesions. There are significant degrees of positive sharp waves and fibrillation potentials. MUAP duration, amplitude, and polyphasia are increased, whereas recruitment is decreased. Despite the frequent occurrence of cranial neuropathies, especially the facial nerve, there is a lack of information about electrodiagnostic medicine evaluation of cranial nerves. One expects to see reduced facial nerve CMAPs amplitudes and some degree of abnormal spontaneous activity on needle EMG. Blink reflexes also may demonstrate either absence or amplitude reductions in R1 and possibly R2. Treatment. Patients with neurosarcoidosis, particularly of the cranial nerves, may respond well to corticosteroid treatment.707,980 If patients are resistant to corticosteroids, other immunosuppressive agents can be tried (e.g., cyclosporine). The electrophysiologic abnormalities may resolve to various degrees with treatment. Unfortunately, after cessation of treatment, patients appear to return to a propensity for developing compromise of the nervous system.

IDIOPATHIC PERINEURITIS
Perineuritis is a nonspecific histologic abnormality with inflammation and thickening of the perineurium. Perineuritis can be seen on nerve biopsies of patients with neuropathies associated with diabetes mellitus, connective tissue diseases, ulcerative colitis, vasculitis (including cryoglobulinemia), and lymphoma and other malignancies.190,394,714,1215,1251,1436 Perineuritis also has been described in patients who fulfill clinical and electrophysiologic criteria for AIDP or CIDP.190,955a,1251 In these various conditions, perineuritis evident on biopsy does not imply a distinct neuropathic disorder. However, there have been several reports of patients without an underlying systemic disorder in whom perineuritis was the most prominent feature on biopsy.42,849 Such cases with idiopathic perineuritis may represent a distinct neuropathic disorder. Clinical Features. The clinical presentation is variable. Patients with perineuritis related to diabetes or vasculitis develop a mononeuropathy multiplex picture with sensory loss, dysesthesias, hyperpathia, and weakness in the distribution of multiple individual nerves. Other patients develop chronic, progressive, symmetric motor and sensory loss indistinguishable from AIDP or CIDP. Finally, a subgroup of patients may have a distinct neuropathy, which we term the idiopathic perineuritis group. Wartenberg was the first to allude to this group of patients, who complain of migrating areas of sensory loss.1386 Patients described pain when the nerves where stretched. Unfortunately, no histology was described in these cases. Matthews reported a patient with migratory sensory neuritis of Wartenberg; however, the nerve biopsy did not mention features of perineuritis.848 Asbury et al. first coined the term perineuritis in their detailed description of two patients who developed pain and dysesthesias in the distribution of cutaneous nerves, affecting mainly the distal upper and lower limbs.42 The predominant histologic abnormality was inflammation confined to the perineurium. Of note, the authors did not believe that their patients had the sensory neuritis described by Wartenburg because of their less prominent pain. Other idiopathic cases have been described with similar features.849,1251 The course can be remitting and relapsing. Hypesthesia and hyperpathia are noted on examination. A positive Tinels sign is often present over involved nerves. Large-fiber sensory functions are typically less affected than small-fiber modalities. Muscle strength is usually preserved, but cases with generalized weakness, suggestive of AIDP or CIDP, have been reported.190,1251 Deep tendon reflexes are typically normal in patients with pure sensory symptoms. Laboratory Features. Laboratory evaluation is usually normal in patients with idiopathic perineuritis, including ANA, ESR, liver function tests, serum protein electropheresis, and vasculitic profile.42,849 In addition, CSF protein is usually normal in patients with pure sensory symptoms. The presence of an abnormal laboratory work-up should lead to the consideration of an underlying systemic disorder, such as vasculitis. Patients who fulfill the clinical and electrophysiologic criteria for CIDP typically have elevated CSF protein.190,1251 Likewise, elevated CSF protein may be seen in diabetic patients with multiple mononeuropathies or lumbosacral polyradiculoplexopathies. Histopathology. The most prominent histologic abnormality is thickening and fibrosis of the perineurium.42,849,1251 Chronic inflammatory cell infiltrates composed of lymphocytes and macrophages should be confined to the perineurium. Mild perivascular inflammation may be evident. Some investigators have reported deposition of immunoglobulins in the epi-, peri, and

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endoneurium190,955a; however, this subsequently was demonstrated to be a nonspecific finding and can be seen in normal controls. A loss of myelinated nerve fibers due to axonal degeneration may be seen. Perineuritis, thickened perineurium, and the loss of nerve fibers can be asymmetric between and within fascicles, suggesting a possible ischemic basis. Pathogenenesis. Whether perineuritis is a distinct disorder is debatable. The pathogenic basis is unknown but probably autoimmune. Perineuritis may cause damage via ischemia, impairment of nutrient and toxin flow to and from nerve fibers in the endoneurium, or direct humoral or cellular autoimmune attack against the nerve fibers. Electrophysiologic Findings. The major electrophysiologic abnormality in idiopathic perineuritis is reduced or absent SNAPs.42,849,955a Motor nerve conductions and EMG are normal unless patients have mononeuropathy multiplex or radiculoplexopathy with motor and sensory involvement (as is the case in patients with diabetes vasculitis or CIDP).190,1215,1251 Treatment. The small number of patients studied and the retrospective nature of such reports limits conclusions about treatment. Patients have variable responses to immunotherapy. Patients with true vasculitis or CIDP should be treated with immunosuppression, IVIG, or PE. Prednisone appears to diminish pain in patients with idiopathic pure sensory neuritis, although this positive effect does not necessarily persist. Furthermore, the natural history of the disorder may be one of remissions and relapses. We have tried prednisone and IVIG in such idiopathic cases with variable success but have not used more aggressive immunosuppression (e.g., cyclophosphamide) in patients with mainly sensory disturbances.

in potassium channels have been demonstrated in hereditary episodic ataxia, in which patients also experience generalized myokymia. The clinical and electrodiagnostic features as well as the treatment of Isaacs syndrome are discussed in greater detail in Chapter 16.

NEUROPATHIES ASSOCIATED WITH INFECTIONS

LEPROSY (HANSENS DISEASE)
Clinical Features. The microorganism Mycobacterium leprae (an acid-fast bacteria) causes leprosy. It is most commonly found in Southeast Asia, Africa, South America, and Europe, but it is endemic in certain areas of the United States (i.e., Hawaii, Texas), and its prevalence may be increasing with the rise in HIV infection. Three primary clinical manifestations of the disease are commonly recognized: tuberculoid, lepromatous, and borderline leprosy (Table 23-8).20,635,938,1111,1148 The hosts immunologic status determines which form of the disease develops. In tuberculoid leprosy, the cell-mediated immune response is intact, leading to focal, circumscribed inflammatory lesions involving the skin or nerves.20,906,938,1103 The skin lesions appear as well-defined, scattered hypopigmented patches and plaques with central anesthesia and raised, erythematous borders. The organism has a predilection for the cooler regions of the body (e.g., face, limbs) rather than warmer regions such as the groin or axilla. The more superficial nerves in the vicinity of the skin lesions also may be affected. In addition, there is a predilection for involvement of specific nerve trunks, including the ulnar nerve at the medial epicondyle, the median nerve at the distal forearm, the peroneal nerve at the fibular head, the sural nerve, the greater auricular nerve, and the superficial radial nerve at the wrist.1390 These nerves can become encased within granulomas, leading them to be thickened and easily palpable. The most common neurologic manifestation of tuberculoid leprosy is mononeuropathy or mononeuropathy multiplex. In lepromatous leprosy, cell-mediated immunity is significantly impaired, resulting in an extensive infiltration of the bacilli process.20,906,938,1103 Clinical manifestations tend to be more severe in the lepromatous subtype, but as in the tuberculoid form, cooler regions of the body are more susceptible. The organisms multiply virtually unchecked and disseminate hematogenously, producing confluent and symmetrical areas of rash, anesthesia, and anhidrosis.336 Facial involvement frequently causes madarosis (loss of eyebrows and eyelashes) and deepening of the natural skin folds to produce the so-called leonine facies. Typically, a slowly progressive symmetric sensorimotor polyneuropathy develops over time. In early disease, the superficial cutaneous nerves of the pinnae and distal limbs are affected. Continued multiplication and infiltration of the organism into the epi-, peri-, and endoneurium result in the appearance of a progressive stocking-glove neuropathy. Distal weakness ensues as the motor nerves become involved in the infiltrative process. Large sensory fiber modalities are relatively spared, as are the muscle stretch reflexes. As with the tuberculoid subtype, nerve trunks can be affected with time, leading to superimposed mononeuropathies. In advanced disease, facial neuropathies can occur. Patients with borderline leprosy have the highest incidence of neurologic complications.20,906,938,1103 They can show clinical and histologic features of both lepromatous and tuberculoid

HYPEREOSINOPHILIC SYNDROME
Hypereosinophilic syndrome is characterized by eosinophilia associated with various skin, cardiac, hematologic, and neurologic abnormalities.223,331,914,1405 A vasculitic component usually is not involved with this disease except for the skin. The multiple organ dysfunction, including the peripheral nervous system, is believed to result from the eosinophilia or some byproducts of the eosinophils. A peripheral neuropathy may occur in 614% of patients, manifesting as either generalized peripheral neuropathy or mononeuropathy multiplex. Some patients have an associated inflammatory myopathy. Clinical and electrophysiologic evidence clearly suggests that the disorder is characterized by an axonal sensorimotor peripheral neuropathy. The pathogenic basis for the neuropathy is not known but may be autoimmune.

ISAACS SYNDROME
Isaacs syndrome (also know as neuromyotonia or syndrome of continuous muscle fiber activity) may be inherited, but the sporadic form is more common. The disorder manifests clinically by muscle twitching (myokymia) at rest, muscle stiffness and cramps that are worse after activity, and excessive sweating. The syndrome can occur with or without other signs or symptoms of a peripheral neuropathy. The acquired disorder may be associated with other autoimmune conditions (e.g., myasthenia gravis, CIDP), thymoma, and cancer (e.g., lymphoma, small cell carcinoma of the lung)the latter perhaps on a paraneoplastic basis. Some patients with the acquired form of neuromyotonia have autoantibodies directed against the voltage-gated potassium channels of peripheral nerves. Mutations

972 PART IV

CLINICAL APPLICATIONS Clinical, Laboratory, Immunological, and Histopathological Features of Leprosy Mid-Borderline Leprosy (BB) Positive or negative (25-mm induration 24 Moderate Cell-mediated immunity: unstable (can range and switch from intact to absent) Size, number, and appearance of skin lesions are intermediate between those seen in TT and LL poles Lepromatous Leprosy (LL) Negative (02-mm induration) 56 High (up to 10) Cell-mediated immunity: absent Th2 > Th1 lymphocytes Cytokines expressed: IL4, 5, 10 Multiple, symmetric small macules and papules; older lesions form plaques and nodules

Table 23-8. Lepromin test Bacterial index Immunology

Tuberculous Leprosy (TT) Positive (> 5-mm induration) 0 Cell-mediated immunity: intact Th1 > Th2 lymphocytes Cytokines expressed: IL2, -IF Few localized and well-demarcated large skin lesions; erythematous macules and plaques with raised borders Centers of lesions may be hypopigmented Localized granulomas and giant cells encompassed by dense lymphocytic infiltrate extending to epidermis Fite stain: negative for bacteria Mononeuropathy of superficial cutaneous nerves or large nerve trunks (i.e., ulnar, median, peroneal nerves), multiple mononeuropathies Pure neuritic leprosy may be seen Dapsone: 100 mg/day Rifampin: 600 mg/day Duration: 12 months

Morphologic index Low (down to 0)

Skin lesions

Histopathology

Granulomas with epithelioid cells but no giant cells Not localized by zones of lymphocytes Lymphocytes, if present, are diffusely infiltrating Fite stain: slight positive Neuropathies can range in the spectrum seen in TT to LL

Scant lymphocytes, but if present they are diffuse along with organism-laden foamy macrophages Fite stain: marked positive Distal symmetric sensory and sensorimotor polyneuropathies are more common than mononeuropathy Pure neuritic leprosy is not seen Dapsone: 100 mg/day Rifampin: 600 mg/day Clofazimine: 50 mg/day Duration: 2 years or until skin smears (MI) is 0

Neuropathies

Treatment*

As for LL

* Treatment recommended by Hansens Disease Center, Carville LA. The features of the borderline tuberculoid (BT) form range between the TT and BB forms.The features of the borderline lepromatous (BL) form range between BB and LL forms of leprosy. From Altman D,Amato AA: Lepromatous neuropathy. J Clin Neuromusc Dis 1999;1:6873, with permission.

forms of leprosy (Fig. 23-8). The impaired cellular immunity of borderline patients results in mycobacterial spread but is still active enough to generate an inflammatory response. The immunologic state is considered unstable in borderline patients in that the immune response and clinical manifestations can shift up and down the spectrum. Thus, patients can develop generalized symmetric sensorimotor polyneuropathies, mononeuropathies, and mononeuropathy multiplex, including multiple mononeuropathies in atypical locations, such as the brachial plexus. Rarely, patients with leprosy present with an isolated peripheral neuropathy without skin lesions.1111 Lepromatous neuropathy should be suspected in patients without skin lesions who live in endemic areas. Virtually all cases of pure neuritic leprosy have the tuberculoid or borderline tuberculoid subtypes of the disease. Diagnosis of leprosy has traditionally been made through skin lesion biopsy with the Fite method of acid-fast bacilli staining.938 The morphologic index (MI), a ratio of viable to nonviable organisms, has been used as a measure of treatment efficacy. The MI, which is between one and ten at treatment onset, often falls to zero within 34 months of successful therapy. More recently, polymerase chain reaction and serum antibody testing have been used for diagnosis. Histopathology. Histopathology depends on the hosts immune response (see Table 23-8).635,938,1148 Histologically, the

tuberculoid form is characterized by granulomatous centers formed by macrophages and Th1 cells, which are surrounded by Th2 cells.906 Caseation may or may not be present, and typical lesions extend throughout the dermis. Of note, bacilli cannot be demonstrated. In the lepromatous form, the lesions demonstrate large numbers of infiltrating bacilli, Th2 lymphocytes, and organism-laden, foamy macrophages with minimal granulomatous infiltration. As the name suggests, patients with borderline leprosy can have histologic features of both tuberculoid and lepromatous leprosy. Pathogenesis. The clinical and pathologic spectrum of the disease depends on the hosts immune response to M. leprae and reflects the relative balance between Th 1 (helper) and Th2 (suppressor) T cells (see Table 23-8).20,906,938,1103,1148 Tuberculoid leprosy and lepromatous leprosy represent the two extremes of disease manifestation.20 In addition, three subtypes bridge these polar extremes: the borderline tuberculoid, borderline, and borderline lepromatous forms of the disease. The tuberculoid form defines one end of the spectrum, in which the Th1 cells predominate. The Th1 cells produce interleukin-2 and gamma interferon, which in turn lead to activation of macrophages. On the other extreme, the lepromatous form is dominated by Th2 cells, which produce interleukins 4, 5, and 10, thereby downregulating cell-mediated immunity and inhibiting macrophages. The

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borderline subtypes exhibit immune responses, spanning the spectrum between the tuberculoid and lepromatous forms. Electrophysiologic Findings. Sensory evaluations demonstrate a whole spectrum of findings with a general impression that SNAPs are usually absent in the lower limb, and reduced in amplitude in the upper limb.20,642,700,1126,1246,1274 When the SNAPs are present, the latencies are usually not significantly prolonged. The SNAP conduction velocities are moderately reduced but usually not less than 60% of normal. It is not unusual for some patients to have a mononeuropathy multiplex pattern of abnormal SNAP findings. Motor nerve conduction velocities are usually reduced, with the lower limbs slightly more affected than the upper limbs. The reduction in velocity is usually 6070% of the lower limit of normal, but a few patients may demonstrate values less than 20 m/s in both upper and lower limbs.29,525,635,642,681,870,1126,1274,1349 Some patients may reveal a pattern of abnormality more consistent with a mononeuropathy multiplex as opposed to diffuse peripheral nerve involvement. Within the upper limb, the proximal segment may reveal slightly lower velocities than the forearm segment. Some reports include a suggestion of conduction block, but these notations are made only in passing; no criteria are defined and no waveform traces provided. The CMAP may be reduced in various nerves, approximating the mononeuropathy multiplex pattern, whereas in other patients a generalized lower worse than upper limb pattern is obvious. Distal motor latencies are normal or only mildly prolonged. The phrenic and facial nerves can be involved and electrophysiologic studies in these nerves, when affected, are abnormal.287,870 Needle EMG examination reveals mild to moderate degrees of positive sharp waves and fibrillation potentials, primarily in the small muscles of the hand and feet as well as the ankle dorsiflexors and evertors.58,287,652,1126,1190,1206 The MUAPs tend to be reduced in number, firing at high rates with increased amplitude and durations as well as numbers of polyphasic potentials. These findings are consistent with the pathologic observation of mild to moderate degrees of axonal loss. Treatment. Multidrug therapy with dapsone, rifampin, and clofazimine is presently the mainstay of treatment, although a number of other agents have recently demonstrated efficacy, including thalidomide, perfloxacin, ofloxacin, sparfloxacin, minocycline, and clarithromycin (see Table 23-8).20,906,938,1390 Treatment typically requires two years of therapy to achieve full eradication of the organism. A potential complication of therapy, particularly in borderline leprosy, is the reversal reaction, which can occur at any time during treatment of the disease.20,938 The reversal reaction results from a shift to the tuberculoid end of the spectrum with an increase in cellular immunity. Upregulation of the cellular response is characterized by excessive release of tumor necrosis factor-alpha, gamma-interferon, and interleukin-2 with new granuloma formation. This can result in an exacerbation of the rash and neuropathy as well as the appearance of new lesions. High-dose corticosteroids appear to blunt this adverse reaction and may be used prophylactically in high-risk patients at treatment onset. A second type of reaction to treatment is erythema nodosum leprosum (ENL), which occurs in patients at the lepromatous pole of the disease.20,938 ENL is associated with the appearance of multiple erythematous, sometimes painful, subcutaneous nodules; the neuropathy also may be exacerbated. ENL is due to the slow degradation of antigens (bacterial debris), resulting in antigen-antibody complex and complement deposition in affected tissue. ENL can be treated with corticosteroids or, if available, thalidomide.

Figure 23-8. Borderline leprosy. A patient with borderline leprosy demonstrates numerous typical skin lesions on the trunk and limbs.The lesions have a depigmented center with raised erythematous borders.

Prevention of leprosy is the ultimate goal and involves multiple strategies, starting with prompt diagnosis and treatment of suspected cases, often with brief hospitalizations to ensure understanding and compliance with multidrug regimens. Chemoprophylaxis of childhood contacts with daily rifampin for 6 months is currently recommended.20,938 Various vaccinations are available, including BCG, killed leprae, and chemically modified organism.

LYME DISEASE
Clinical Features. The organism Borrelia burgdorferi, a spirochete transmitted by ticks, is responsible Lyme disease (named for the Connecticut town where it was first detected).1010,1095 A hard-bodied tick known as Ixodes dammini (deer tick) is responsible for the disease in most cases. This disorder is not localized to the continental United States but occurs world-wide. A tick acquires the spirochete by feeding on an infected host animal and then transmits the spirochete to its next host during feeding. Approximately 1224 hours of tick attachment is required to accomplish secondary host infection. Three stages of the disease are recognized: (1) early infection (erythema migrans: localized); (2) disseminated infection; and (3) late-stage infection. Within one month after a bite from an infected tick, an expanding erythematous circular region surrounding the original tick bite is noted. It then develops a somewhat variable appearance with a clear central region (erythema migrans, also called bulls eye) and resolves spontaneously by about one month. However, the erythema migrans is not noticed by all patients. One or two weeks after the initial tick bite, systemic

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symptoms of generalized fatigue, fever, chills, localized adenopathy, headache, and painful neck motion can be observed, thus defining the second stage of the illness. Additional skin lesions may be detected about the body. The organism spreads throughout the patient with a particular preponderance for the skin, heart, nervous, and musculoskeletal systems. With neurologic involvement, symptoms and signs of peripheral neuropathy, radiculopathy, encephalitis and meningitis can be observed.542545,732,807,839,977,1010,1011,1094,1095,1175,1258,1325,1431 Pericarditis and heart block can be detected with cardiac infection. During the later portion of the second stage (weeks to years after the first inoculation), knee, wrist, or shoulder attacks of inflammatory arthritis become manifest. These symptoms may persist for years, accompanied by overt fatigue in some patients. The third stage is characterized by destructive joint changes due to the inflammatory changes in the synovium of affected joints, possibly resulting in profound loss of function. A somewhat bluish discoloration of the skin is located primarily on the distal limb regions (acrodermatitis chronica atrophians), where active spirochetes may be readily cultured. With respect to peripheral nervous system manifestations, the findings vary, depending on the stage of the disease. In stage 2 disease, cranial mononeuropathies can be documented. Facial nerve dysfunction is believed to be the most commonly observed disorder with respect to cranial neuropathies and can resemble Bells palsy, although it tends to be bilateral in about one-half of cases (rare in idiopathic Bells palsy). Additional cranial nerves can be affected but less frequently than the facial nerve. Asymmetric polyradiculoneuropathies, plexopathies or multiple mononeuropathies also can occur. Rarely, patients may be misdiagnosed with AIDP. These symptoms eventually resolve with good return of function. In stage 3, a distal glove-and-stocking distribution of altered sensation and accompanying paresthesias can be noted in roughly one-half of patients. Some patients experience muscle weakness and cramps. Reductions in proprioception and vibration are found in the feet as well as reduced deep tendon reflexes. Laboratory Features. Antibodies directed against the spirochete can be measured using immunofluorescent or enzyme-linked immunoabsorbent assay (ELISA). False-positive reactions are not uncommon. Therefore, Western blot analysis is useful to confirm a positive ELISA. Histopathology. Nerve biopsies can reveal perivascular infiltration of plasma cells and lymphocytes around small endoneurial, perineurial, and epineurial blood vessels without clear necrotizing vasculitis. Axonal degeneration and secondary demyelination can be seen. The spirochete has not been demonstrated within the peripheral nerves themselves. Pathogenesis. The pathogenic mechanism for Lyme neuropathy is unknown. The neuropathy may result from an indirect immunologic response and/or some form of vasculopathy. Electrophysiologic Findings. The peripheral nerve manifestations of the disease, with different patients demonstrating symptoms and signs that suggest a distal peripheral neuropathy, mononeuropathy multiplex, painful polyradiculitis/plexitis, entrapment neuropathy (carpal tunnel syndrome), or AIDP pattern, are rather diverse. These distinct patterns may be more apparent than real. Careful neurophysiologic testing in a relatively large group of patients with Lyme disease and the above peripheral nervous system manifestations demonstrated not only the preferential nerve dysfunction expected from the overt clinical picture, but an underlying common electrophysiologic

thread.543,544 Specifically, most patients revealed evidence consistent with a primarily axonal neuropathy. In patients with an overt clinical presentation consistent with mononeuropathy multiplex, for example, the electrophysiologic findings are usually confirmatory of the preferential nerve involvement suspected clinically; reduced CMAP and SNAP amplitudes as well as membrane instability suggest axonal loss.542,544,693a,839,977,1011,1094,1175,1258,1325,1431 The same findings generally apply for all of the above disorders, even in patients who present with preferential loss of seventh nerve function (i.e., reduced facial nerve CMAP, possibly prolonged distal motor latency, and abnormal blink reflexes).732 However, in addition to the confirmatory electrophysiologic evidence of a focal peripheral nerve lesion, all of these presentations have a number of accompanying findings, provided a careful search is made, representative of the peripheral nervous system as a whole. A reduction in both upper and in particular lower limb SNAP amplitudes is found.543,544 Various nerves are preferentially involved in different patients, but the sural nerve is typically affected. A concomitant mild reduction in sensory nerve conduction velocity is also detected. The tibial or peroneal nerve may reveal reduced CMAP amplitudes with normal or borderline distal motor latencies. F-wave latencies in the lower and occasionally upper limb nerves (peroneal/tibial and median/ulnar) are prolonged. Similarly, an absent or asymmetric tibial H-reflex can be found. All of these findings indicate a patchy axonal neuropathy in most patients with Lyme disease who present with any form of neurologic complaint affecting the peripheral nervous system.543,544 In patients with suspected Lyme disease, it is important to examine the upper and lower limbs to document a more widespread dysfunction of the peripheral nervous system than may be suspected from the clinical presentation. Rarely, a patient may present with symptoms and signs suggesting a myopathy as opposed to neuropathy.1182 The nerve conduction studies are essentially normal. Needle EMG examination demonstrates an alteration in MUAPs as characterized by short-duration, small-amplitude potentials, with increased numbers firing rapidly at low levels of force. Treatment. Adults with facial nerve palsies secondary to Lyme disease are treated with amoxicillin, 500 mg PO QID, plus probenecid, 500 mg q.i.d. for 24 weeks. If the patient is allergic to penicillin, doxycycline, 100 mg PO b.i.d., should be given for 24 weeks. Children less than 4 years of age can be treated with amoxicllin, 2040 mg/kg/day in 4 divided doses for 24 weeks. If allergic to penicillin, children can be treated with erythromycin, 30 mg/kg/day in 4 divided doses for 24 weeks. Adult patients with other types of peripheral neuropathy are treated with intravenous (IV) penicillin, 2024 million U/day for 1014 days, or ceftriaxone, 2 gm IV qd for 24 weeks. Adults who are allergic to penicillin should receive doxycycline, 100 mg PO b.i.d. for 30 days. Children with Lyme neuropathy can receive IV penicillin G 250,000 U/kg/day in divided doses for 1014 days, or ceftriaxone, 5080 mg/kg/day IV for 24 weeks.

DIPHTHERITIC NEUROPATHY
Clinical Features. A neuropathy can arise in association with the toxin produced by the organism Corynebacterium diphtheriae.419,600,665,737,807a,923,1098,1248 After exposure to the organism, immunocompromised people usually demonstrate systemic flu-like symptoms of generalized myalgias, lassitude, headache, mild fever, and possible irritability within 1 week to

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ACQUIRED NEUROPATHIES 975

10 days of exposure. A whitish, membranous exudate may be present in the throat region with or without cervical lymph node involvement. In profound disease, autonomic disturbances of heart rate and vascular tone may progress to cardiac arrhythmias and eventual death. It is also possible for the organism to produce the above symptoms after entrance through a wound in the body. About 2070% of patients develop a peripheral neuropathy. By about the third or fourth week, patients may begin to complain of difficulty in swallowing with a demonstrable reduction in palatal sensation. Hoarseness or dysarthria, along with diaphragmatic weakness, may ensue. At the same time, patients complain of blurred vision, particularly when looking at near objects. Pupils react to light but fail to accommodate. Additional cranial nerves also may become involved. In patients with a less fulminant form of the disease, a generalized peripheral neuropathy may manifest 2 or 3 months after the initial infection. The patient may note preferential loss of sensation in the distal aspects of the upper and lower limbs associated with paresthesias and weakness in the same distribution. Physical examination reveals a reduction to all sensory modalities in the distal upper and lower limbs. Manual muscle testing reveals reduced strength in the hand intrinsics and ankle dorsiflexor/plantar flexor muscles. Muscle weakness may progress over a period of weeks to the degree that the patient is unable to ambulate independently. Rarely, urethral and anal sphincters become compromised. Deep tendon reflexes are diminished or absent throughout. Laboratory Features. CSF protein can be elevated with or without lymphocytic pleocytosis.255 Histopathology. The primary sites of pathologic reaction in the nervous system are the dorsal root ganglia and the nearby ventral nerve root and spinal nerve.419 However, the more distal segments of the peripheral nerves are also affected. Segmental demyelination is the major observation with relatively good preservation of axons. Severely affected fibers are found in close proximity to well-preserved nerve fibers. A small degree of axonal loss and active degeneration also is noted. Pathogenesis. The diphtheria toxin binds to Schwann cells and inhibits synthesis of myelin proteins.1060 Demyelination is believed to result from failure to replace myelin proteins during normal metabolic turnover. Electrophysiologic Findings. In most countries, the reduction of morbidity and mortality due to diphtheria occurred before the development of sophisticated electrophysiologic techniques. As a result, there is a paucity of information about the electrodiagnostic medicine findings in patients with diphtheria. Considerable information is available from animals, because diphtheria toxin is an excellent manner in which to study demyelination experimentally. In humans, the limited number of investigations have demonstrated absent SNAPs.737 Motor nerve conduction studies reveal about a 45% reduction in the mean nerve conduction velocity expected for both upper and lower limbs.255,665,737,807a The distal motor latencies are only mildly to moderately prolonged in most cases. In a single patient, F-waves were attempted, but they were absent in the median nerve. Nerve conduction studies may be abnormal by 2 weeks after onset of symptoms suggestive of a neuropathy, but the abnormalities tend to maximize by 58 weeks, after which there is a slow and steady recovery. In most patients, the nerve conduction studies have normalized by 33 weeks after the initial clinical neurologic manifestations, but they can persist for more than 1 year in patients with profound weakness and muscle wasting. There is usually a disparity between

the severity of nerve conduction studies and clinical presentation. Although nerve conduction studies worsen by 58 weeks, the patient begins to demonstrate clinical recovery. Needle EMG in only a few patients with muscle weakness and wasting in the hand intrinsic muscles demonstrated fibrillation potentials with a reduced MUAP recruitment pattern. The above findings are certainly anticipated from the histologic demonstration of primary demyelination with some degree of axonal loss. In animal studies, a similar finding of reduced conduction velocities with prolongation of the distal motor latencies is noted.600,923,959 Although not described in humans, a considerable reduction in the CMAP amplitudes with proximal stimulation has been demonstrated in animals. The CMAPs not only are reduced in amplitude but also show significant temporal dispersion. This temporal dispersion is attributed to segmental demyelination, with an asynchronous or differential slowing of neural conduction. This finding implies that nerve conduction slowing is not uniform. The net result is an increase in the temporal dispersion of arriving motor impulses with the MUAP not summating temporally. There is a reduction in amplitude for two reasons: (1) a spreading out of the electrical activity associated with the motor units and hence not adding up in time, and (2) increased phase cancellation with positive and negative phases of motor units summating to cancel each other. Additionally, there is also a suggestion that conduction block is likely across the demyelinated segment. Computer models support the above assertions that temporal dispersion and phase cancellation result in a reduction in CMAP amplitude.708,1098 This is certainly likely, given the pathology; however, criteria have not been applied to animal studies, and this finding has not been observed in humans. Treatment. Antitoxin and antibiotics should be given within 48 hours of symptom onset to reduce the incidence and severity of complications (i.e., cardiomyopathy). However, treatment does not appear to alter the natural history of the associated peripheral neuropathy. Resolution of the symptoms may take several months in severely affected patients.

HUMAN IMMUNODEFICIENCY VIRUS

At least 20% of patients with HIV develop some form of polyneuropathy during the course of their illness.421,834,1024,1278 Six major types of peripheral neuropathy are associated with HIV infection: (1) distal symmetric polyneuropathy (DSP), (2) inflammatory demyelinating polyneuropathy (including both AIDP and CIDP); (3) mononeuropathy multiplex (e.g., vasculitis, CMV-related); (4) progressive polyradiculopathy (usually CMV-related); (5) autonomic neuropathy; and (6) sensory ganglionitis.75,244,250,278,306,438,539,764,857,1024
HIV-related Distal Symmetric Polyneuropathy Clinical Features. DSP is perhaps the most common form of peripheral neuropathy associated with HIV infection and usually is seen in patients with AIDS.421,834,897,1221 Patients often complain of numbness and painful paresthesias of the hands and feet. Some patients are asymptomatic but are found to have diminished sensation to all modalities on examination. Atrophy and mild weakness in foot intrinsic muscles may be noted. Hand intrinsic strength is commonly well preserved until the disease has progressed to affect more proximal leg muscles (i.e., relatively late in the course of the disease). Deep tendon reflexes are reduced at the ankles but are relatively preserved at the knees and in the upper limbs.

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Laboratory Features. CSF can reveal both increased protein and mild lymphocytic pleocytosis in patients with HIV infection, regardless of the stage of the infection and the presence or absence of peripheral neuropathy.77,837 Vitamin B12 deficiency has been noted in some series,82,683 but other studies have suggested that vitamin B12 metabolism does not play a significant role in the neurologic complications of HIV infection.284,1110,1347 Histopathology. Autopsy studies and nerve biopsies have demonstrated a reduction in the total number of both myelinated and demyelinated axons due to axonal degeneration.61,211,435, 436,438,1085 A loss of cell bodies in the dorsal root ganglia can be seen in addition to degeneration of the dorsal columns. Axonal regeneration and secondary demyelination are more prominent at the more proximal levels of the nerves. A small degree of perivascular inflammation (mainly macrophages and T-cells) can be observed, along with evidence of increased cytokine expression. Some degree of centrofascicular loss also can occur. Skin biopsies may demonstrate a reduced density of small myelinated nerve fibers in the epidermis.574 Pathogenesis. The pathogenic basis for DSP is unknown. It is probably not due to actual infection of the peripheral nerves. The neuropathy may be immune-mediated, perhaps caused by the release of cytokines from surrounding macrophages. As noted above, vitamin B12 deficiency may contribute to some cases but is not a major cause of most cases. Various antiretroviral agents (e.g., dideoxycytidine, dideoxyinosine, stavudine) are also neurotoxic and can cause a painful sensory neuropathy.90,338,684 However, DSP can occur in patients not previously exposed to antiretroviral agents. Electrophysiologic Findings. The electrodiagnostic medicine examination reveals evidence of a symmetric, axonal polyneuropathy that affects sensory more than motor nerves.61,212,338,421,436,570,762,1221,1237,1242,1278 Sural and superficial peroneal SNAP amplitudes are reduced with only mildly prolonged latencies. The upper limb sensory studies are normal or only mildly affected early in the course of AIDS. With disease progression, SNAPs in the lower limbs are no longer obtainable with routine techniques, and there is a reduction in upper limb SNAP amplitudes with a slight prolongation in the latency.
Table 23-9. Therapy First-line Tricyclic antidepressants (e.g., amitriptyline, nortriptyline) Gabapentin Second-line Carbamazepine Phenytoin Tramadol Third-line Mexiletine Other agents Lidocaine 2.5%/pylocaine 2.5% cream Capsaicin 0.0250.075% cream Route Oral

Motor nerve conduction velocities are usually not altered to a great degree, but the CMAP amplitude may be reduced, especially when evaluated in the foot. Needle EMG examination can reveal positive sharp waves and fibrillation potentials in the foot intrinsic muscles that progress to the leg muscles. Occasionally, the hand intrinsic muscles can demonstrate similar findings. The MUAPs are reduced in numbers and recruitment with alterations in morphology, suggesting motor unit remodeling (i.e., elevations in duration, amplitude, and phases). Treatment. Antiretroviral agents have no demonstrable affect on the course of DSP. Treatment is largely symptomatic (Table 23-9). Neurontin may be beneficial in reducing the painful symptoms.953,1323 However, a randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection demonstrated no significant benefit.685
HIV-related Inflammatory Demyelinating Polyradiculoneuropathy Clinical Features. Patients with HIV infection can present with symptoms and signs similar to those of AIDP and CIDP.897,1222 AIDP can occur at the time of seroconversion, whereas CIDP can occur at any point in the course of the infection but is more common in patient with AIDS. Laboratory Features. A helpful feature in distinguishing idiopathic AIDP or CIDP from HIV-related AIDP/CIDP is the presence of pleocytosis in the CSF, along with elevated protein levels. Histopathology. The histologic features are identical to those of AIDP and CIDP.211,242,895 There is no way to discriminate histologically idiopathic AIDP/CIDP from HIV-related AIDP/CIDP. Electrophysiologic Findings. The alterations noted for sensory and motor fibers in idiopathic AIDP and CIDP are also operational for cases associated with HIV infection.242,762,774,895,1074 Reduced motor and sensory conduction velocities are evident. Conduction block and temporal dispersion can be seen. F-waves are unobtainable or prolonged. The detailed discussions of the electrophysiologic findings in idiopathic AIDP and CIDP should be reviewed.

Treatment of Painful Sensory Neuropathies Dose 10100 mg qhs Side Effects Cognitive changes, sedation, dry eyes and mouth, urinary retention, constipation Cognitive changes, sedation Cognitive changes, dizziness, leukopenia, liver dysfunction Cognitive changes, dizziness, liver dysfunction Cognitive changes, GI upset Arrhythmias

Oral Oral Oral Oral Oral Apply cutaneously Apply cutaneously

3001200 mg tid 200400 mg q 68 hr 200400 mg qhs 50 mg qid 200300 mg tid qid qid

Painful burning skin

Chapter 23

ACQUIRED NEUROPATHIES 977

Treatment. Patients with HIV-associated AIDP or CIDP can be treated with IVIG or plasmapheresis. 242,774,825 Prednisone also can be effective, but we try to avoid steroids and other second-line immunosuppressive agents in patients with HIV-related CIDP because of the long-term implications of immunosuppression.
HIV-related Progressive Polyradiculopathy Clinical Features. Patients with advanced AIDS can develop an acute, progressive lumbosacral polyradiculopathy secondary to cytomegalovirus (CMV) infection.897,898,1222 Patients have severe numbness, pain, and weakness in the legs, which usually are asymmetric. They also note a reduction in perineal sensation with painful paresthesias. Incontinence of urine and stool are common. Occasionally, the upper limbs and cranial nerves become involved. Diminished or absent deep tendon reflexes in the legs can be found. Plantar responses are flexor. Patients may have evidence of CMV infection in other parts of the body (e.g., CMV retinitis) Laboratory Features. CSF reveals an increased protein and neutrophilic pleocytosis. CSF glucose concentration may be decreased. CMV can be cultured from the CSF, blood, and urine. Histopathology. Biopsies of the ventral and dorsal root regions demonstrate significant degrees of inflammatory infiltrates associated with varying degrees of axonal loss. These findings are most evident in the lumbar regions. Occasionally, the cranial nerve root exit from the brainstem may be involved with a minimal degree of adjacent myelitis. CMV inclusions have been demonstrated in endothelial cells and macrophages on nerve biopsy specimens.1132,1158 Pathogenesis. The polyradiculopathy is caused by the direct infection of neurons by CMV. Electrophysiologic Findings. The clinical presentation and biopsy findings suggest the type of abnormalities anticipated on electrodiagnostic medicine examination.279,898,1243 When the ventral roots are affected, a progressive decline in the CMAP amplitudes is noted, coincident with the progressive loss of axons and ensuing Wallerian degeneration. Concomitantly, needle EMG examination reveals profuse fibrillation potentials and positive sharp waves. There is a profound reduction in MUAPs (reduced recruitment) with some muscles demonstrating a complete absence of MUAPs. These abnormalities extend to essentially all muscles in the lower limbs bilaterally. The conduction velocities are normal until there is a complete absence of the motor CMAPs or sensory SNAPs, confirming the primary pathology as axonal loss with little demyelination. As expected from the lesion location, F-waves are hard to obtain and latencies can be prolonged. The above combination of findings is quite distinct from findings in both CIDP and DSP and helps to differentiate the various disorders. Treatment. There may be a limited response to ganciclovir or foscarnet in some patients.689,898,899 However, the prognosis in most patients is poor; most patients with this complication die within several weeks or months. HIV-related Multiple Mononeuropathies Clinical Features. Some patients with HIV infection, usually those with AIDS, develop multiple mononeuropathies.762,897,1222 They have weakness and reduced sensation and paresthesias in a distribution suggestive of multiple peripheral nerve involvement. Single or multiple cranial nerve dysfunction also has been described. Examination is similar to that for other causes of multiple mononeuropathies.

Laboratory Features. An elevated CSF protein with some degree of mononuclear cells is common. Histopathology. Nerve biopsies can reveal perivascular inflammation or frank necrotizing vasculitis.1159 Axonal degeneration is prominent, although secondary demyelination also may be seen. In some cases, CMV inclusions were evident in endothelial cells and macrophages on the nerve biopsy specimens.1132,1158 Pathogenesis. The pathogenic basis for this disorder is probably multifactorial. The neuropathy may be caused by deposition of HIV antigen-antibody complexes in the walls of blood vessel. Some cases may be related to vasculitis due to concomitant hepatitis B or C infection and antigenemia. In addition, CMV infection probably plays a role in some cases of multiple mononeuropathy. Electrophysiologic Findings. The electrodiagnostic medicine findings are similar to those described with other forms of multiple mononeuropathies caused by vasculitis.799,1160,1165 It is not uncommon to find electrophysiologic evidence of a generalized symmetric distal polyneuropathy due to overlapping mononeuropathies. Treatment. It is difficult to draw firm conclusions about treatment options, given the scarcity of relevant literature. Patients with multiple mononeuropathies and hepatitis B or C infection can be treated with plasma exchange, antiviral agents (e.g., vidarabine), or -interferon. Short courses of prednisone and cyclophosphamide may be used. If CMV is suspected, treatment with ganciclovir or foscarnet should be initiated.
HIV-related Autonomic Neuropathy Clinical Features. Patients with HIV infection, usually those with AIDS, also can develop an autonomic neuropathy, which manifests as orthostatic hypotension, impaired sweating, diarrhea, impotence, and bladder dysfunction.228,254,429,798 The autonomic neuropathy often occurs in patients who also have DSP. Laboratory Features. There are no distinguishing laboratory features. As with any patient with HIV infection, the CSF can reveal pleocytosis and increased protein. Histopathology. There are no reports of histopathology data in patients with autonomic neuropathy due to HIV infection. Pathogenesis. The pathogenic basis for autonomic neuropathy is unknown but probably multifactorial, as in DSP. Electrophysiologic Findings. Most patients have the electrodiagnostic features noted above for DSP. In addition, autonomic function testing is usually abnormal.218,254 Treatment. Only symptomatic treatment of autonomic problems is currently available. HIV-related Sensory Neuronopathy/Ganglionopathy Sensory ataxia due to ganglionitis is a rare complication of HIV infection.278,372,1244 The clinical features are similar to those of idiopathic sensory neuronopathy or ganglionopathy. The sensory neuronopathy may be the presenting manifestation of HIV infection. Autopsies have demonstrated degeneration of neurons and inflammatory infiltration in the dorsal root ganglia, along with the loss of myelinated nerve fibers in the peripheral nerves.278 The pathogenic mechanism is not known. Because of the rarity of the disorder, there are limited discussions of the electrophysiologic features. However, one expects to find decreased amplitudes or absence of SNAPs.

HUMAN T-LYMPHOCYTE TYPE 1 INFECTION

HTLV-1 infection can cause a peripheral neuropathy, but the most common manifestation is the tropical spastic paraparesis,

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which is discussed in detail in Chapter 16. HTLV-1 infection also can cause on inflammatory myopathy (discussed in Chapter 28).

CYTOMEGALOVIRUS
CMV can cause an acute lumbosacral polyradiculopathy or multiple mononeuropathies in patients with HIV infection, as discussed above.

EPSTEIN-BARR VIRUS
EBV has been implicated as causing some cases of AIDP, cranial neuropathies, mononeuropathy multiplex, brachial plexopathy, lumbosacral radiculoplexopathy, and sensory neuronopathies.1138

HEPATITIS VIRUSES
Hepatitis B and C can cause multiple mononeuropathies, AIDP, or CIDP.

HERPES VARICELLA ZOSTER VIRUS

Clinical Features. Herpes varicella zoster (HVZ) infection can result from reactivation of latent virus or from primary infection. Primary acquired HVZ infection is frequently associated with severe disseminated zoster in immunocompromised patients. The incidence of HVZ infection is approximately 480 persons per 100,000 population.70 The peak age of developing the disease is between 55 and 75 years of age. Two-thirds of infections are manifested by dermal zoster.24 Pain and paresthesias in the dermatome region may precede the vesicular rash by 1 week or more. Initially, the vesicular skin lesions are clear but form a crusty mass by 2 weeks and heal with dermal scar formation. A variable degree of pain is associated with the skin lesion; however, roughly 25% of affected patients have significant residual pain, called postherpetic pain, which can be quite disabling.24 This complication is more common in older patients. In a large series of patients, approximately 50% experienced the eruption in the thoracic region (T1T12) with an equal number developing skin lesions in the first division of the trigeminal (18%) and L2S4 aspects of the lumbosacral (18%) regions.1296 Cervical (C2C8) eruptions are the least frequently encountered. Of note is the rarely appreciated possibility of developing concomitant involvement of the associated motor nerves. From 530% of patients with typical cutaneous herpes zoster can develop some form of motor weakness that affects the myotomal muscles corresponding to the dermatomal distribution of skin lesions.497,524,904,1296 The weakness usually develops within the first 2 weeks of the skin eruption but can vary between several hours to 1 month. The most commonly affected region of paresis involves the cranial nerves; the facial nerve (herpes zoster oticus, Ramsay-Hunt syndrome) has the highest likelihood of being affected. Cervical and lumbosacral myotomal regions are equally likely (26% each) to be affected. Thoracic weakness is difficult to determine and most likely accounts for only 3% of patients with motor paresis. Cervical weakness, particularly with upper myotomal involvement, may be associated with phrenic nerve dysfunction. Rarely, patients with a typical skin eruption develop AIDP.298,1166 Additional neurologic manifestations of herpes zoster infection include encephalitis and stroke. Physical examination reveals the expected loss of sensation and hyperpathia in the dermatomal distribution of the disease.

With motor paresis, a loss of strength is noted in the corresponding myotomal distribution. Decreased or absent deep tendon reflexes are also expected in the appropriate regions. Unilateral phrenic nerve involvement can lead to hemidiaphragmatic paralysis.346,1034 Herpes zoster oticus begins with vesicular eruption in the ear canal, and secondary facial paralysis can appear to be Bells palsy if ear lesions are missed. When the thoracic myotomes are involved, protrusion of the abdominal wall can suggest an abdominal wall hernia.460,483 Fortunately, the prognosis for most patients with any type of focal motor involvement is relatively good.521 Laboratory Features. CSF may demonstrate a mild to moderate protein elevation with variable pleocytosis. The virus is difficult to culture from the CSF, but polymerase chain reaction can be used to confirm the presence of the virus in the CSF. Histopathology. The basic pathologic neural reaction is axonal degeneration with some degree of secondary segmental demyelination. With respect to the sensory system, severe infections can result in the destruction of dorsal root ganglion cells with secondary loss of posterior column fibers. Pathogenesis. After initial infection, HZV migrates up the sensory nerves and resides in the sensory ganglia, where it appears to be insulated from the hosts immune defense mechanisms.70 After a reduction in the immune systems capacity, the virus can be reactivated with the above symptoms. HZV travels down the sensory nerves and results in the typical skin lesions. Motor paresis is postulated to develop when the virus causes local neuritis in the spinal nerve and subsequently gains access to the motor axons. Electrophysiologic Findings. When regions of the body are affected with available peripheral nerves amenable to SNAP measurements, the potentials amplitudes may be reduced or, in severe disease, completely absent.448,1128,1149 SNAP distal sensory latencies and conduction velocities are only mildly affected, if at all. Of course, when the thoracic dermatomes are involved, it is not possible to evaluate a corresponding SNAP. However, it is possible to use somatosensory evoked potential techniques to evaluate more fully the extent of the intercostal nerve involvement as subclinical regions amenable to neural blockade may also be detected. Motor nerves affected by the infection demonstrate reduced CMAP amplitudes, which at times can be clearly abnormal or reduced toward the lower limits of normal.448,524,904,1149 Nerve conduction velocities may be mildly reduced and distal motor latencies little affected, as anticipated for a primarily axonal insult. The needle EMG examination demonstrates a reduction in the number of voluntary MUAPs in the affected myotome.448,489,526,904,1149,1296,1399 After the appropriate period, variable degrees of positive sharp waves and fibrillation potentials can be observed, depending on the extent of axonal loss in the examined muscle. Examination of the paraspinal regions also demonstrates membrane instability, confirming the impression that the lesion is at least as proximal as the spinal root level (i.e., proximal to the bifurcation of the spinal nerve into the ventral and posterior primary rami). The findings of relatively preserved nerve conductions and evoked response latencies apply equally, no matter what aspect of the peripheral nervous system is affected. For example, if the facial nerve is involved, a reduced CMAP from a facial muscle, little change in distal motor latency, reduced recruitment of MUAPs, and fibrillation potentials/positive sharp waves may be observed.673 The same findings can occur if the virus damages a

Chapter 23

ACQUIRED NEUROPATHIES 979 Diabetic Neuropathies

nerve root supplying the upper or lower limb. If a patient develops a more generalized polyradiculoneuritis, such as AIDP, the electrodiagnostic findings are commensurate with the primary demyelinating type of disease (see discussion of AIDP).298 Treatment. Large doses of IV acyclovir can be lifesaving in immunocompromised patients with severe infections. Otherwise, acyclovir is useful in improving the rate of healing and the severity of acute pain of herpes zoster, but neither acyclovir alone nor acyclovir in combination with corticosteroids reduces the frequency or severity of postherpetic neuralgia. The treatment of postherpetic neuralgia is symptomatic (see Table 23-9).445 Several options are available for treatment of postherpetic neuralgia, although none is uniformly successful. Neurontin has been noted to be effective in postherpetic neuralgia.1193 A number of placebocontrolled studies have demonstrated that tricyclic antidepressants reduce the pain in many patients.855 Carbamazepine can be helpful in some patients who have intermittent lancinating as opposed to constant burning pain.1109 Topical capsaicin ointment, applied 3 or 4 times daily for 24 weeks, is of benefit to some patients.97 Transcutaneous electrical nerve stimulation has been useful at times.937 Finally, if these therapies are not effective, short courses of narcotics may be necessary.1135

Table 23-10. 2. Autonomic neuropathy

1. Distal symmetric sensory or sensorimotor polyneuropathy 3. Diabetic neuropathic cachexia 4. Diabetic polyradiculoneuropathy Asymmetric, painful lumbosacral radiculoplexopathy (BrunsGarland syndrome, diabetic amyotrophy) Symmetric, relatively painless, polyradiculopathy (may resemble or be a variant of chronic inflammatory demyelinating polyradiculoneuropathyCIDP) Cervical radiculopathies Thoracic radiculopathies 5. Focal/multifocal mononeuropathies Cranial neuropathy Limb mononeuropathy Mononeuropathy multiplex

type 1 and type 2 DM with respect to the electrodiagnostic medicine findings in individual types of peripheral neuropathy.573
Distal Symmetric Sensory or Sensorimotor Polyneuropathy Clinical Features. The most common form of diabetic neuropathy is distal symmetric sensory polyneuropathy (DSPN). This length-dependent neuropathy manifests clinically with sensory loss beginning in the toes and gradual progression over time to involve the legs.154,365,884,1302 The sensory neuropathy can progress to affect the hands, again beginning with the fingers and progressing proximally to result in the common glove-andstocking distribution. Patients with severe disease may exhibit sensory loss over the abdominal region progressing from the midline laterally toward, but typically not affecting, the back.1392 Patients often complain of tingling, lancinating pains, burning, and deep aching pains in the feet and lower legs.134 The loss of sensation is responsible for the increased risk of ulcerations and Charcot-joints in patients with severe diabetic neuropathy. Examination is remarkable for sensory loss to all modalities in a stocking-glove distribution and reduced deep tendon reflexes, particularly at the ankles. Although there may be mild atrophy and weakness of foot intrinsics and ankle dorsiflexors, significant weakness is uncommon. Even in patients without motor symptoms or signs on clinical examination, there is often electrophysiologic evidence of subclinical motor involvement (see below). Thus, the term distal symmetric sensorimotor peripheral neuropathy is also appropriate.361 Patients with DSPN also can develop symptoms and signs of an autonomic neuropathy (discussed in detail below). Laboratory Features. The risk of developing DSPN is associated with poor control of DM and presence of nephropathy.362,1032 Nevertheless, DSPN can be the presenting manifestation of DM. Histopathology. Nerve biopsies demonstrate axonal degeneration and segmental demyelination.352,356,1303 The axonal degeneration is more pronounced distally, as expected in a length-dependent process. An asymmetric loss of axons between and within nerve fascicles can sometimes be appreciated. Clusters of small regenerated axons also can be appreciated. Microangiopathy is evident as well, with endothelial hyperplasia of epineurial and endoneurial arterioles and capillaries along with redundant basement membranes around small blood vessels. In addition, inflammatory cells sometimes can be appreciated

NEUROPATHIES ASSOCIATED WITH ENDOCRINOPATHIES

DIABETES MELLITUS
Diabetes mellitus (DM) is the most common metabolic disease with a prevalence of 14%.362,1129 DM is categorized into two major categories: (1) insulin-dependent diabetes mellitus (IDDM or type 1 DM) and noninsulin-dependent diabetes mellitus (NIDDM or type 2 DM). Several distinct types of peripheral neuropathy are associated with DM, including distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies (Table 23-10). The exact prevalence of any form of peripheral neuropathy among diabetic patients is not accurately known but has been estimated to be 566%.362,884,1032 The risk of developing peripheral neuropathy correlates with the duration of DM, control of hyperglycemia, and presence of retinopathy and nephropathy.362,884 However, diabetic neuropathy can occur in children with type 1 DM.66 A community-based study of 85,804 residents revealed that 1.3% of the population had some form of clinically recognized DM (27%, type 1 DM; 73%, type 2 DM).362 Of patients with type 1 DM, 66% had some form of neuropathy: generalized polyneuropathy, 54%; asymptomatic carpal tunnel syndrome, 22%; symptomatic carpal tunnel syndrome, 11%; visceral autonomic neuropathy, 7%; and various other mononeuropathies/multiple mononeuropathies (ulnar neuropathy, peroneal neuropathy, lateral femoral cutaneous neuropathy, diabetic amyotrophy), 3%. In patients with type 2 DM, the following percentages had neuropathy: generalized polyneuropathy, 45%; asymptomatic carpal tunnel syndrome, 29%; symptomatic carpal tunnel syndrome, 6%; autonomic neuropathy, 5%; and other mononeuropathies/multiple mononeuropathies, 3%. Considering all forms of DM, 66% of patients had some objective sign of diabetic neuropathy, but only 20% were symptomatic. The following sections discuss the different types of peripheral neuropathies associated with DM. There are no differences in

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on nerve biopsies of patients with DSPN.245,1444 These perivascular inflammatory cells consist predominantly of CD8+ T-cells. Skin biopsies demonstrate a reduction of small myelinated epidermal nerve fibers.574,676,677 Pathogenesis. The pathogenic basis for DSPN in unknown and controversial. The major theories involve a metabolic process, ischemic damage, or an immunologic disorder. Metabolic Hypothesis. Several possible mechanisms involve the role of abnormal metabolism in DSPN. Glucose and myoinositol are similar in structure, and hyperglycemia may reduce myoinositol uptake into peripheral nerves. Streptomycin-induced diabetes in animal models is associated with a reduction of myoinositol on the nerves and abnormal nerve conduction studies, which are restored by supplementing the diet with myoinositol.498 Myoinositol depletion may alter the function of Na+/K+ ATPase or cause axon damage by some other mechanism. However, nerve biopsies from human diabetic patients have not revealed reduced concentrations of myoinositol.352 Furthermore, clinical trials have failed to demonstrate efficacy of myoinositol supplementation for DSPN.501,502 DSPN also may result from altered polyol/sorbitol metabolism.458 Hyperglycemia activates the enzyme aldose reductase, which in turn causes the accumulation of sorbitol in nerves. Sorbitol is relatively impermeable and hypertonic, thereby leading to epineurial and endoneurial edema. Theoretically it can produce endoneurial hypoxia and oxidative stress. Sorbital also inhibits the uptake of myoinositol into the nerves and may impair Na+/K+ ATPase activity. However, trials have not demonstrated that various aldose reductase inhibitors prevent or significantly alter the progression of DSPN.499,1053 Hyperglycemia also may cause glycosylation of neuronal proteins, which may alter the functions of tubulin and neurofilaments.1365 This may lead to abnormal axonal transport. Perturbations in lipid metabolism associated with chronic hyperglycemia also may damage peripheral nerves.601 Vascular Hypothesis. The histopathologic features on nerve biopsy, namely microangiopathic abnormalities and asymmetric axonal degeneration support a vascular theory for DSPN. The accumulation of multifocal ischemic insults may lead to the appearance of a generalized symmetric polyneuropathy. Immunologic/Inflammatory Hypothesis. The presence of inflammatory cells and the abnormal expression of tumor necrosis factor-, interleukin (IL)-1, IL-1, IL-4, IL-6, complement and membrane attack complex in nerve biopsies of some patients with DSPN1444 supports the possibility that DSPN may be an autoimmune disorder. Electrophysiologic Findings. Sensory nerve conduction studies are the most sensitive nerve conduction test for DSPN. In asymptomatic patients with DM, as many as 50% demonstrate reduced SNAP amplitudes and conduction velocities, and up to 80% of symptomatic patients have such sensory conduction abnormalities. As expected, the abnormalities are first detected in the distal lower limbs (i.e., sural and plantar nerves).226,787,1093 The sensory alterations are noted prior to significant changes in motor conduction studies. In patients with clinical evidence of neuropathy and obtainable SNAPs, the distal latencies may be prolonged and conduction velocities slowed.66,85,155,378,615,653,966,1277,1417 H-reflex absence or latency prolongation can be expected relatively early in the course of the disease.1314 Abnormalities of central sensory conduction may be present in some patients, as demonstrated by prolonged central conduction times of brainstem and somatosensory pathways.325,738,1032,1350 Quantitative sensory testing demonstrates

reduced vibratory and thermal perception.33,366,1038 In addition, tests of autonomic function may be abnormal in patients with DSPN.366,687,940,1044 Motor nerve conduction studies reveal results similar to those of sensory nerves, although the motor nerves are less severely involved.85,155,615,654,966,1277,1322,1417 Reductions in nerve conduction velocities are similar to those for sensory nerves (i.e., 1530% below normal values). Occasionally, the slow conduction velocities fall into the demyelinating range (i.e., less than 30% below the lower limit of normal).1322,1417 Distal motor latencies are mildly to moderately prolonged, particularly in the lower limbs. It is rather common for the CMAPs to be diminished in amplitude or even absent when recorded from the intrinsic foot muscles. Despite the documentation of segmental demyelination in diabetic patients, conduction block and/or temporal dispersion occurs in only 10% or less of patients with DSPN.2,1322 F-waves studies have revealed that motor nerve slowing is rather diffuse; the proximal nerve segments are slowed but not to as great a degree as the distal portions of the nerves.413,693,936 The standard F-wave parameters of minimal latency and chronodispersion are among the most sensitive parameters and are of value in patients with subclinical peripheral neuropathy.1018 Patients with generalized neuropathy also have prolongation of facial nerve latencies.636,690 In general, the degree of sensory and motor nerve conduction abnormalities is proportional to the severity of the disease and lack of glucose control. Peroneal and median nerve conduction studies usually correlate to some degree with the severity of clinical status. Patients with long-standing disease tend to have worse electrophysiologic parameters than recently diagnosed patients. It is also possible for both clinical and electrodiagnostic evaluations to reveal peripheral nerve abnormalities in patients who have not previously been diagnosed with DM; the neuropathy is the presenting feature of the disease. Needle EMG examination of patients with DSPN may reveal varying degrees of fibrillation potentials and positive sharp waves in the distal muscles of the lower limbs and, in long-standing disease, the upper limbs. Even asymptomatic patients can have a few of these potentials in the intrinsic foot muscles. Accompanying abnormalities of reduced MUAP recruitment and increased potential amplitude and duration are frequently noted. Single-fiber EMG in patients with DSPN demonstrates both increased jitter and fiber density consistent with axonal loss.1207 Treatment. Several studies have demonstrated that tight control of glucose can reduce the risk of developing neuropathy or improve the underlying neuropathy.315,316,675,1057,1315,1385 Pancreatic transplantation (usually performed in combination with kidney tranplantation) also results in stabilization or slight improvement in sensory, motor, and autonomic function.235,675,940 Although a phase 2 trial of nerve growth factor appeared promising,33 the larger double-blind, placebo-controlled, phase 3 trial failed to demonstrate efficacy by various clinical measures, nerve conduction studies, or quantitative sensory testing.33a As noted in the discussion of pathogenesis, myoinositol supplementation and aldose reductase inhibitors have no proven benefit in DSPN. Various medications, including antiepileptic medications, antidepressants, sodium channel blockers, and other analgesics, have been used to treat painful symptoms associated with DSPN with variable success.59,173,301,548,854,922 Our approach to treating diabetic neuropathic pain is similar to that for any form of painful sensory neuropathies (see Table 23-9). Tricyclic antidepressant medications help to reduce the pain.854 The side effect

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of sedation is useful in patients who complain of severe pain at night that impairs sleep. Two recent large clinical trials have demonstrated the efficacy of gabapentin59 and tramadol in painful diabetic sensory neuropathy.548 Gabapentin is generally started at a dose of 300400 mg tid and gradually increased as tolerated and necessary up to 1200 mg tid. Tramadol also appears safe and effective and may have an additive benefit when given with gabapentin (anecdotal experience). The average effective dose of tramadol is about 200 mg/day (i.e., 50 mg qid).548 We try mexilitine when the above medications fail to offer significant benefit.301 Unfortunately, we have not found capsacian cream to be particularly useful.
Diabetic Autonomic Neuropathy Clinical Features. Another complication of DM is diabetic autonomic neuropathy.229,384,687,1391 Autonomic neuropathy typically is seen in combination with DSPN. Patients develop abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias, postural hypotension, gastrointestinal abnormalities (e.g., gastroparesis, postprandial bloating, chronic diarrhea or constipation), and genitourinary dysfunction (e.g., impotence, retrograde ejaculation, incontinence). Histopathology. Appenzellar and Richardson noted enlarged sympathetic neurons containing PAS-positive material.34 Others have demonstrated degeneration of sympathetic and parasympathetic neurons and inflammatory infiltrates in autonomic ganglia.339,817 In addition, segmental demyelination has been appreciated on teased fiber studies. Pathogenesis. The pathogenic basis for autonomic neuropathy is unknown but may be similar to that of DSPN. Electrophysiologic Findings. Electrodiagnostic studies generally demonstrate features of DSPN, which is present in most patients with severe autonomic neuropathy. Tests of autonomic function are generally abnormal, including sympathetic skin responses and QSART.229,366,687,1044,1391 To evaluate impotence or incontinence, one can perform nerve conduction studies of the pudendal nerve and needle EMG examination of the bulbocavernosus and anal sphincters.139 Treatment. Pancreatic transplantation may stabilize or slightly improve autonomic function.940,139185 In general, however, treatment of autonomic neuropathy is largely symptomatic.1391 Orthostatic hypotension can be treated with fluodrocortisone (starting at 0.1 mg bid) or midodrine (10 mg tid).625,819,1108 Nonsteroidal anti-inflammatory agents may be of benefit. Metoclopramide1238 is used to treat diabetic gastroparesis, and clonidine may help with persistent diarrhea.403 Sildenafil has gained popularity for treatment of impotence.469 Diabetic Neuropathic Cachexia Diabetic neuropathic cachexia (DNC) is an uncommon form of diabetic neuropathy.38,375,464,617 DNC is more common in males than females and generally occurs in the sixth or seventh decade of life. DNC often is the presenting manifestation of DM. Most patients do not have systemic complications of endorgan damage (i.e., retinopathy, nephropathy). In men, DNC usually occurs in the setting of type II DM, whereas the rare cases in women occur in younger type I diabetics. Patients present with an abrupt onset of severe generalized painful paresthesias involving the trunk and all four limbs in the setting of significant precipitous weight loss (not uncommonly, up to 60% of baseline body weight). Depression and impotence often occur as well. Despite the painful sensory symptoms, sensory

loss is generally mild. Deep tendon reflexes are usually symmetrically decreased. Some patients have weakness and atrophy, perhaps related to profound weight loss, whereas in others muscle strength testing is normal. The neuropathy tends to improve spontaneously, usually within 2 years. Weight gain typically precedes resolution of painful dysesthesias. Rarely, DNC can recur.617 Laboratory Features. CSF protein is increased in some patients with DNC. Histopathology. There are only a few reports of nerve histology in patients with DNC. Sural nerve biopsies in a few patients demonstrated severe loss of large myelinated nerve fibers due to axonal degeneration.38,617 Small myelinated and unmyelinated fibers were relatively spared. Pathogenesis. The pathogenic basis is not known. Electrophysiologic Findings. Detailed electrophysiologic testing has not been described. A few studies reported decreased amplitudes or absent sensory nerve action potentials.464,617 Normal or slightly diminished amplitudes of compound muscle action potentials associated with mild slowing of conduction velocities also can be observed. The limited reports of needle EMG studies have been normal.617 Treatment. As noted above, the neuropathy usually improves spontaneously over 13 years with control of DM. Symptomatic treatment of the painful paresthesias is the same as that described for DSPN and idiopathic small-fiber neuropathies.
Diabetic Polyradiculoneuropathy Diabetic polyradiculopathy is a source of recent controversy. Some authors believe that there are two or more distinct forms of diabetic polyradiculopathy,215,627,729,1033 whereas others believe that the neuropathy is a single entity.74 We believe that two categories of diabetic polyradiculopathy can be distinguished on the basis of clinical differences: (1) the more common asymmetric, painful polyradiculoneuropathy and (2) the rare symmetric, painless polyradiculoneuropathy. The latter form of polyradiculoneuropathy may represent CIDP in a patient with diabetes or a distinct form of diabetic neuropathy. Asymmetric, Painful Diabetic Polyradiculoneuropathy Clinical Features. Asymmetric, painful polyradiculoneuropahy is the most commonly appreciated form of diabetic polyradiculoneuropathy (also known as diabetic amyotrophy, Burns-Garland syndrome, diabetic lumbosacral radiculoplexopathy, and proximal diabetic neuropathy).24a,43,74,177,215,217,627,729,1033, 1161,1162,1267,1415 The polyradiculoneuropathy more commonly affects older patients with type II DM, but it can affect type I diabetics. In approximately one-third of patients, the polyradiculoneuropathy is the presenting manifestation of DM. The neuropathy usually begins unilaterally with severe pain in the low back, hip, and thigh. Within a few days or weeks, atrophy and weakness of proximal and distal muscles in the affected leg are apparent. About one-half of the patients complain of numbness and paresthesia. Because of the severe radicular pain and weakness, it is not uncommon for patients to undergo unnecessary spinal surgery. Although the onset is typically unilateral, it is not uncommon for the contralateral leg to become affected several weeks or months later. Rarely, diabetic amyotrophy begins in both legs at the same time. Nevertheless, in such cases nerve involvement is generally asymmetric. As with DNC, the polyradiculoneuropathy is often heralded by severe weight loss. The neuropathy progresses gradually or in a stepwise fashion, usually over several weeks or months, but cases of worsening over

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18 months have been documented.74 There is an erroneous misconception that only proximal muscles are affected. However, examination reveals weakness of both proximal and distal lower limb muscles.74 A mild stocking-glove sensory loss secondary to superimposed DSPN is sometimes noted. Deep tendon reflexes are reduced in the affected leg. Eventually the disorder stabilizes and slow recovery ensues. In many cases, however, residual weakness is significant. Thoracic mono- or polyradiculopathies also can present with or without involvement of the lumbosacral roots/ plexus.375,810,1026,1260,1273,1392 The pain can radiate from the posterolateral chest wall anteriorly to the abdominal region with associated loss of sensation anterolaterally. On rare occasions, it is possible to observe abdominal wall protrusion secondary to muscle weakness. Although even less common, some patients develop weakness in the upper limbs,1033 perhaps due to a superimposed cervical polyradiculoneuropathy/brachial plexopathy. Laboratory Features. CSF protein concentration usually is elevated, but cell count is normal. Erythrocyte sedimentation rates may be increased. MRI scans of the lumbosacral roots and plexus can reveal inflammatory changes.74,999 Histopathology. Sural, superficial peroneal, and lateral femoral cutaneous nerve biopsies reveal a loss of myelinated nerve fibers, which is often asymmetric between and within nerve fascicles.74,368,729,1033,1161,1162,1444 Active axonal degeneration and clusters of small, thinly myelinated, regenerating fibers can be seen. Mild perivascular inflammation of epineurial and perineurial blood vessels have been noted on some nerve biopsies. Findings suggesting microvasculitis have been described in lateral femoral cutaneous, superficial peroneal, and sural nerve biopsies.368,1033 A polymorphonuclear small-vessel vasculitis associated with IgM and complement deposition on affected epineurial vessels has also been reported.665a Pathogenesis. The histopathology and presumed response to immunomodulating therapies has led some to suggest an immune-mediated microangiopathy as the basis for diabetic amyotrophy.665a,729,1444 This may be the case, but much more information is needed. The histologic abnormalities are not specific for vasculitis or ischemia. Most biopsy specimens do not demonstrate frank vasculitis. Mild perivasuclar inflammation, which is a nonspecific abnormality, is more common. Asymmetric loss of axons between and within fibers certainly is seen with ischemic neuropathies, but it is not specific for vasculitis. The fact that patients with diabetic amyotrophy may improve with various forms of immunotherapy (see below) also does not prove that the pathogenic basis for the neuropathy is immunologic. Remember that the natural history of the disorder is spontaneous improvement. Patients with vasculitis on lateral femoral cutaneous nerve biopsies became pain-free and began to improve in strength after the biopsies without the addition of immunotherapy.1033 Such spontaneous improvement is not the natural history of other forms of true vasculitis. More studies are necessary to unravel the pathogenic nature of diabetic amyotrophy. Electrophysiologic Findings. In patients with underlying DSPN, electrophysiologic features of a generalized axonal sensorimotor polyneuropathy, as described above, are evident. The nerve conduction studies and EMG of diabetic amyotrophy reflect multifocal axonal damage to the roots and plexus.43,74,177,215,217,627,688,1033,1263,1267,1272,1415 As expected, SNAPs are absent or low in amplitude. When obtainable, the distal latencies of the SNAPs are normal or slightly prolonged. Likewise, CMAPs are diminished in amplitude in affected muscles, whereas distal latencies are normal or slightly prolonged.

F-waves are unattainable or slightly increased in latency. Conduction velocities in the affected limbs are normal or mildly slow. Autonomic studies usually reveal abnormal sudomotor, cardiovagal, and adrenergic functions.627,1033 Needle EMG demonstrates positive sharp waves and fibrillation potentials in proximal and distal muscles in the affected limbs and paraspinal muscles.43,74,177,215,217,627,688,1033,1263,1267,1272,1415 Recruitment of MUAPs is reduced in weak muscle groups. As reinnervation occurs over time, large-amplitude, long-duration, polyphasic MUAPs can be appreciated. Treatment. Small retrospective studies have reported that IVIG, prednisone, and other forms of immunosuppressive therapy are effective in patients with diabetic amyotrophy.138,627,729,1444 Anecdotally, we have been impressed that short courses of corticosteroids can help to ease the pain associated with severe polyradiculoneuropathy. This may allow patients to undergo physical therapy. However, as noted above, the natural history of this neuropathy is gradual improvement so the actual effect, if any, of these immunotherapies on the polyradiculoneuropathy is not known. Prospective, double-blinded, placebo-controlled trials are necessary to define the role of various immunotherapies.
Symmetric, Painless, Diabetic Polyradiculoneuropathy Clinical Features. This second major group of diabetic polyradiculoneuropathy presents with a progressive, relatively painless, symmetric proximal and distal weakness evolving over weeks to months.24a,241,479,627,729,1033,1106,1261,1322 This form of polyradiculoneruopathy resembles idiopathic CIDP. In fact, it is controversial whether this neuropathy represents the coincidental occurrence of CIDP in a patient with DM or is a distinct form of diabetic neuropathy. Some have suggested an increased risk of CIDP in diabetics. This type of polyradiculoneuropathy occurs in both type I and type II DM but may be more common in the latter. Weakness is most prominent distally and in the lower limbs; however, proximal leg and upper limb muscles also are affected. In addition, the arms are generally affected, particularly the distal muscles. In contrast to classic diabetic amyotrophy, patients with this form of diabetic polyradiculopathy do not usually have severe back and proximal leg pain and the motor weakness is relatively symmetric. However, distal dysesthesias, perhaps secondary to a superimposed DSPN, are occasionally present. A stocking-glove sensory loss to all modalities can be demonstrated along with reduced deep tendon reflexes. Most patients gradually improve over time regardless of treatment. Laboratory Features. As with idiopathic CIDP, CSF protein concentration usually is increased. Histopathology. Sural nerve biopsies have demonstrated a loss of large and small myelinated nerve fibers, which can be asymmetric.479,627,729,1033,1261,1322 Axonal degeneration and clusters of small regenerating fibers are seen. Occasionally, demyelinated fibers and onion-bulb formations are evident. In addition, scant perivascular mononuclear inflammatory cells may be demonstrated in the perineurium and epineurium. Nevertheless, these nerve biopsy abnormalities are not specific for symmetric diabetic polyradiculopathy or CIDP; similar findings can be seen in DSPN and diabetic amyotrophy. Pathogenesis. The pathogenic basis for this form of polyradiculoneuropathy is quite controversial.24a The neuropathy may represent the coincidental occurrence of CIDP in patients with DM. Alternatively, it may represents a spectrum of diabetic amyotrophy. Finally, the disorder may be a distinct form of diabetic neuropathy. It may be that patients with DM, especially those with autoimmune type I DM, are more prone to developing

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CIDP. The clinical features, increased CSF protein, electrophysiologic features (see below), and histopathology can be indistinguishable from idiopathic CIDP. Furthermore, some patients appear to benefit from various immunotherapies. However, the nerve histopathologic abnormalities, including immunohistochemistry, are not specific for this form of diabetic polyradiculopathy and have been noted in DSPN and diabetic amyotrophy. The apparent response to various types of immunotherapies does not imply that patients have CIDP, because they can improve spontaneously without treatment.627,1033,1322 Obviously, more work needs to be done to unravel the pathogenic nature of this form of neuropathy. The authors believe that painless, symmetric diabetic polyradiculoneruopathy is likely to be multifactorial with some cases representing CIDP; others may be unusual cases of diabetic amyotrophy or caused by a distinct metabolic neuropathy related to the DM. Electrophysiologic Findings. The electrodiagnostic medicine examination reveals a significant generalized sensorimotor polyneuropathy. The nerve conduction studies demonstrate absent or reduced SNAP and CMAP amplitudes combined with slowing of nerve conduction velocities, prolongation of distal latencies, and absent or prolonged latencies of Fwaves.80,242,479,729,1033,1261,1322,1412 Conduction block and temporal dispersion are uncommon but may be seen.479,1033 Occasionally, the electrophysiologic features fulfill research criteria for demyelination, but there are generally more axonal abnormalities than in idiopathic CIDP.479,626,1261 The needle EMG examination reveals fibrillation potentials and positive sharp waves diffusely, including multiple levels of the paraspinal musculature.80,1412 Autonomic studies demonstrate abnormalities in sudomotor, cardiovagal, and adrenergic functions.627,1033 Treatment. A number of retrospective studies have demonstrated that various forms of immunotherapy (i.e., IVIG, PE, corticosteroids, cyclophosphamide) appear to be beneficial in the symmetric, diabetic polyradiculoneuropathy.24a,242,479,627,729, 1033,1261,1322 This observation has led to the belief that this type of diabetic neuropathy is immune-mediated and perhaps represents CIDP in diabetic patients. In many instances, however, the magnitude of the response is not as robust as in idiopathic CIDP. It has been suggested that the axonal loss associated with concurrent DSPN may account for the diminished response to immunosuppressive agents.479 In addition, patients with symmetric, diabetic polyradiculoneuropathy also can improve spontaneously without treatment.627,1033 Therefore, it is by no means certain that this form of polyradiculopathy is immunemediated. Double-blind, placebo-controlled trials are needed for better assessment of treatment options.
Diabetic Mononeuropathies or Multiple Mononeuropathies Patients with DM are particularly prone to both focal neuropathies and multifocal neuropathies.12,45,637 One of the focal neuropathies likely to be observed in diabetics is a cranial mononeuropathy.894,1453 Of the cranial mononeuropathies, a seventh nerve palsy is most common. The extraocular nerves also can be affected: a focal lesion of the third nerve is the most common, followed by sixth nerve palsies and, less frequently, fourth nerve palsies. Pain in the form of a headache or located within or about the eye can precede the onset of the palsy by hours to days. There is usually complete loss of function within hours to one day; however, sparing of pupillary function is common, and resolution is noted by 35 months. Ischemia is the primary cause for the dysfunction.

Focal limb mononeuropathies are commonly observed in diabetic patients superimposed on a more mild generalized peripheral sensorimotor peripheral neuropathy. Some of the more frequently encountered isolated limb neuropathies include carpal tunnel syndrome, cubital tunnel syndrome, femoral neuropathy, peroneal neuropathy at the fibular head, and lateral femoral cutaneous neuropathies. Any of these isolated nerve insults can occur in combination within a similar time frame, creating a clinical presentation of mononeuropathy multiplex. Perhaps the most challenging form of diabetic neuropathy is the combined neuropathy in which any of the above patterns of peripheral nerve dysfunction occur in various combinations. Although this form of neuropathy is not a single disease entity, it is a useful clinical designation because it is quite descriptive of the patients symptoms and signs. The common presentation is a generalized sensorimotor peripheral neuropathy (i.e., DSPN) associated with one or more focal mononeuropathies such as carpal tunnel, cubital tunnel, foot drop, or oculomotor palsy. Clinical delineation of individual peripheral nerve insults can be difficult. Of some help in better defining all of the individual and combined peripheral nerve dysfunctions is a carefully performed electrodiagnostic medicine examination. It must be recognized, however, that at times doubt may persist as to the true nature of the patients complaints because of the limited manner in which the peripheral nervous system reacts to insult (i.e., demyelination, axonal loss, or both). The median and ulnar nerves are the most commonly affected, followed by peroneal mononeuropathy at the fibular head.426,658 Sciatic, femoral, and cranial (e.g., oculomotor, abducens, facial) nerves are affected less frequently. The electrodiagnostic medicine evaluation should include a generalized evaluation of the peripheral nervous system in addition to the focal problem. Abnormalities consistent with axonal loss (reduced or absent SNAP and CMAP amplitudes, mild reduction in conduction velocities) as well as demyelination (reduced conduction velocities, temporal dispersion, and prolonged distal latencies) can be expected out of proportion to the more generalized neuropathy, indicating a superimposed focal lesion. In profound disease, the complete absence of multiple responses can make it virtually impossible to define separate nerve lesions by electrophysiologic means. These mononeuropathies may occur with or without concomitant significant clinical or electrophysiologic evidence of a generalized peripheral neuropathy.

HYPOGLYCEMIA/HYPERINSULINEMIA
Clinical Features. Persistent hypoglycemia secondary to an islet cell tumor of the pancreas or persistent injection of elevated levels of insulin may lead to a peripheral neuropathy.286,551,566a,628,926 Patients may note progressive numbness and paresthesias in the hands and feet. Over a variable course of time, motor weakness may develop. Manual muscle testing can reveal significant muscle wasting in the distal aspects of the legs and hand intrinsic muscles, accompanied by weakness. Deep tendon reflexes are generally reduced. Correction of the hypoglycemic problem usually results in clinical improvement, especially with respect to the subjective sensory symptoms; however, patients with long-standing muscle wasting and weakness may have less than satisfactory recovery. Histopathology. Few nerve biopsies have been performed on affected patients with modern histologic techniques, thus limiting the available information. There is a suggestion, however, that the primary lesion is axonal loss primarily affecting the large myelinated fibers.628 Segmental demyelination is not a

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prominent feature, and this observation tends to be supported by electrodiagnostic findings (see below). Pathogenesis. The basis for the polyneuropathy is not known but is felt to be directly attributable to reduced glucose levels in neurons. Electrophysiologic Findings. The small number of patients reported in the past, combined with prompt recognition of the disorder, has limited the number of patients available for detailed electrodiagnostic testing. The little available information has shown a generalized reduction or absence in sensory nerve responses.628 When present, the sensory conduction velocity is reduced, but by no more than 30% of the lower limit of normal. Motor nerve conduction velocities are normal or only mildly reduced. The CMAP amplitudes are slightly decreased in the distal muscles of the hands and feet, as anticipated, given the overt muscle wasting. F-waves are prolonged in both upper and lower limbs, as are H-reflexes in the lower limbs. Needle EMG reveals reduced recruitment with MUAPs suggesting chronic motor unit remodeling in the distal limb muscles.286,551,628,926 Fibrillation potentials and positive sharp waves often accompany these changes. Some investigators have suggested an associated anterior horn cell disorder, but pathologic evidence of this supposition is lacking.551,92621 There are insufficient long-term electrophysiologic studies to define resolution after appropriate medical intervention. Treatment. Patients are treated for the underlying cause of the hyperinsulinemia.

amplitudes of SNAPs.817 When SNAPs are obtainable, the distal latencies may be prolonged and conduction velocities are slow. The amplitudes of the CMAPs are usually normal. However, there may be slightly prolonged distal latencies and slow motor conduction velocities. Treatment. Data about the response of peripheral neuropathies associated with acromegaly to treatment are insufficient.

HYPOTHYROIDISM
Clinical Features. In patients with hypothyroidism, two major forms of peripheral nerve dysfunction can be observed as well as proximal myopathy.346a,681a,956,1063 The most common form of peripheral nerve disease is carpal tunnel syndrome.346a,681a,930,1076 Less common are symptoms and signs suggestive of tarsal tunnel syndrome.1186 A few series of cases suggest that generalized peripheral neuropathies also can complicate hypothyroidism.346a,681a,880,943 Patients develop symmetric painful paresthesias and dysesthesias in both hands and feet. Reduced sensation in a glove-and-stocking distribution is noted as well as reduced or absent ankle reflexes. Documentation of frank weakness is less common despite the concurrent complaint of sensory symptoms. Histopathology. Nerve biopsy demonstrates primarily segmental demyelination with small onion-bulb formation over time in untreated patients.312,349,838,956,1062,1210 A general reduction in large myelinated fibers may be seen. Evidence of mild degrees of active axonal degeneration also can be found in some patients.321,322,817 Pathogenesis. Carpal tunnel syndrome most likely results from reduced space within the flexor retinaculum as a result of associated edematous changes. The cause of the generalized neuropathy associated with hypothyroidism is not known. Electrophysiologic Findings. Electrophysiologic evaluation demonstrates evidence consistent with carpal tunnel syndrome, mono/polyentrapment syndromes, or generalized sensorimotor polyneuropathy.312,322,346a,681a,817,838,880,943 In patients with a generalized neuropathy, the SNAP amplitudes are reduced and may have mildly prolonged latencies.349,415,1062,1210 Motor nerve conduction velocities are usually 7080% of the lower limit of normal with mild prolongation of distal motor latencies. CMAP amplitudes are relatively well preserved, with some degree of reduction compared with normal mean values in most patients. Needle EMG examination reveals variable degrees of fibrillation potentials and positive sharp waves, primarily in the intrinsic foot and hand muscles. In patients with myopathies, proximal muscle examination can demonstrate short-duration, small-amplitude potentials firing at rapid rates during low levels of force production (i.e., early recruitment). Treatment. Appropriate medical treatment usually arrests progression of the peripheral neuropathy with variable degrees of compensation, depending on the amount of peripheral nerve reserve at the time of medical intervention.

ACROMEGALY
Clinical Features. There are a number of neuromuscular manifestations of acromegaly.1056 A proximal myopathy can be readily found in acromegalic patients with long-standing disease and lack of treatment (see Chapter 28).679,1056 Several different types of peripheral neuropathies also may occur.1306 The most common mononeuropathy in acromegaly is carpal tunnel syndrome.817,1056,1181 A generalized sensorimotor peripheral neuropathy, characterized by reduced sensation and paresthesias beginning in the feet and progressing to the hands, is less frequent. Some patients develop mild distal weakness. When clinical and electrophysiologic studies are combined, evidence of carpal tunnel syndrome is noted in 82% of patients and a generalized sensorimotor peripheral neuropathy in 73% of patients.817 Finally, the bony overgrowth in or about the spinal canal and neural foramens can result in spinal cord compression, polyradiculopathies, or cauda equina compression. Histopathology. Nerve biopsies in patients with generalized polyneuropathy are abnormal,817 showing an increase in endoneurial and subperineurial connective tissue and an overall increase in the fascicular area. A reduction in myelinated and unmyelinated nerve fibers also is evident. Teased nerve fiber preparations demonstrate changes suggestive of axonal degeneration and segmental demyelination. Pathogenesis. The cause of the neuropathy in patients with acromegaly is not clear. In some cases, the neuropathy may be attributable to superimposed DM. Mitogenesis induced by increased growth hormone and upregulation of insulin-like growth factor receptors is probably responsible for the proliferation of connective tissue elements in peripheral nerves.1306 These hypertrophic changes may render the nerve fibers more susceptible to pressure and trauma. Electrophysiologic Findings. Nerve conduction studies in patients with generalized polyneuropathy demonstrate reduced

NEUROPATHIES ASSOCIATED WITH SYSTEMIC DISEASE

UREMIC NEUROPATHY
Clinical Features. Patients with renal failure develop an excess of urea and other nitrogenous waste products in the blood secondary to an inability to eliminate these substances because of failing glomeruli. Both central (encephalopathy) and

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peripheral (peripheral neuropathy) nervous system abnormalities can result from renal failure.47,118,121,1123 Approximately 60% of patients with renal failure develop a peripheral neuropathy. Patients usually complain of bilateral numbness, tingling, and feet that are extremely sensitive to normally nonpainful stimuli. Patients may note muscle cramps in the distal legs and occasional restless leg syndrome, but these symptoms are most likely not related to the neuropathy.957,958 A few patients may develop a clinical syndrome that is rapidly progressive, much like AIDP, and improves with an increase in renal dialysis or transplantation.121,1123 Physical examination demonstrates an early depression or abolition of the ankle reflexes with an accompanying reduction in the foot vibratory threshold. A small number of patients also experience a reduction in the thermal threshold, especially as the neuropathy progresses. In addition to the sensorimotor peripheral neuropathy, a number of mononeuropathies can occur. The most common mononeuropathy in patients with chronic renal failure is carpal tunnel syndrome. This syndrome is related to a particular type of hemodialysis instrument that uses a Cuprophan membrane, which may predispose patients to tissue damage. The Cuprophan membrane fails to remove completely a small 2 microglobulin, which is normally catabolized by the healthy kidney.118 This substance forms a type of amyloid deposit throughout the body, with particularly adverse consequences when deposited in the carpal tunnel about the transverse carpal ligament. Carpal tunnel syndrome is the end result of this form of amyloid accumulation. Because of their general debilitation, patients with renal failure are also prone to developing other mononeuropathies, such as ulnar neuropathy at the elbow and peroneal nerve injury about the fibular head. During renal transplant surgery, damage to the brachial plexus or peripheral nerves may result from improper limb positioning or traction. Ischemic monomelic neuropathy, affecting the median, ulnar, and radial nerves, may result from ischemia to the nerve(s) secondary to the creation of an arteriovenous shunt in the arm for dialysis.113,785,1410 Histopathology. Sural nerves in patients with generalized sensorimotor polyneuropathy demonstrate a loss of nerve fibers, particularly large myelinated nerve fibers.47,118,350,632 Evidence of active axonal degeneration is more prominent in the distal than proximal regions of the peripheral nervous system. Segmental and paranodal demyelination also can be prominent but generally is believed to be a secondary result of axonal degeneration. Evaluation of autopsy spinal cord specimens in patients with renal disease and peripheral neuropathy demonstrates anterior horn cell chromatolysis consistent with axonal loss of motor fibers. Degeneration of the fasciculus gracilis at the cervical level also has been noted. Pathogenesis. Some evidence suggests that as long as the glomerular filtration rate exceeds roughly 12 ml/minute, the adverse effects on the peripheral nervous system are minimal. At glomerular filtration rates below this value, nerve conduction studies become abnormal, and when about 6 ml/minute is reached, patients begin to demonstrate clinical signs of peripheral nerve dysfunction. Whether the Schwann cell or the axon is the primary target of the essential metabolic or toxic abnormality in uremia is still debated. The primary pathophysiology of the uremic neuropathy remains unknown, but according to one theory, some slowly dialyzable substance(s) of intermediate molecular weight alters the peripheral nerve in a manner that results in axonal and possible Schwann cell dysfunction and eventual degeneration.

Electrophysiologic Findings. In general, the electrophysiologic findings in uremic patients tend to follow the clinical symptoms and signs.4,15 The lower limbs are more involved than the upper limbs. The sural SNAPs are reduced in amplitude or, more commonly, unobtainable. When present, the distal latencies are prolonged, and sensory conduction velocities are slow. Some patients display temporally dispersed SNAPs with an increase in phases. In one study, the sural SNAPs were abnormal in 100% of patients examined.3 In the upper limbs, median and ulnar SNAP abnormalities are detectable with respect to conduction velocities, amplitudes, and distal latencies.273,630,959,962 Most patients have either prolonged or absent H-reflexes, even when the lower limb motor studies are considered normal.512,538,1057 Somatosensory evoked potential studies reveal slowing of neural conduction along both peripheral and central pathways.1130 Motor conduction studies have been the mainstay of electrodiagnostic evaluation of uremic patients for years, primarily because of ease of performance and relatively good intertrial reproducibility, provided good technique is used.227,597 However, motor nerve conductions still may vary to some degree.711 The tibial and peroneal nerves usually demonstrate some degree of slowing but typically are not reduced below 70% and 60% of the lower limit of normal for upper and lower limb nerves, respectively.1298 Median and ulnar nerve conduction velocities tend to be abnormal later in the course of the disease process compared with lower limb conductions. The mean CMAP amplitudes for uremic patients are within the low normal range, particularly early in the course of the disease. The amplitudes become abnormal and eventually disappear in the lower limbs and decrease much later in the upper limbs. F-waves are usually absent or demonstrate delayed latencies. There is some debate about whether the proximal portions of the peripheral nerves are affected to a greater degree than the distal aspects. Studies using disparate methods have arrived at opposite conclusionsi.e., no difference and more proximal than distal slowing.216,835,974,1019 This discrepancy most likely results from a more diffuse metabolic process that is not detectable over the short nerve segments that are routinely used. If mild disease is present, the proximal segments, as measured through F-waves and H-reflexes, appear to be preferentially involved. When only short segments are used in patients with obvious clinical neuropathy, the proximal nerve conduction does not appear to be as affected as the more distal segments. The concept that a metabolic derangement other than demyelination and axonal loss results in dysfunctional neural conduction is a postulated cause for improvement in nerve conduction within 1 week after renal transplantan interval too brief for remyelination or axonal regeneration. Needle EMG findings support a generalized axonopathy. Proximal and distal muscles in the upper and lower limbs should be examined, especially the foot intrinsic muscles in early disease, because the distal muscles of the lower limbs are the first to demonstrate abnormalities. Positive sharp waves and fibrillation potentials of varying degrees are evident first in the foot intrinsic muscles and later in the gastrocnemius, soleus, and tibialis anterior muscles. When the tibialis anterior demonstrates easily obtainable membrane instability, the intrinsic hand muscles begin to show the same abnormal potentials. With disease progression, reduced recruitment becomes evident in the affected muscles, again first in the lower and then with upper limb muscles. Of interest, several single-fiber investigations of uremic patients demonstrate that fiber density is relatively normal.713,1292

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Essentially normal fiber density is an important finding because it implies that the peripheral nervous systems compensatory mechanism of collateral sprouting is ineffective or inoperative. This is the likely explanation for reduced motor CMAP amplitudes relatively early in the disease process compared with other neuropathies. As axons are lost, the CMAP amplitudes drop because the remaining axons do not reinnervate the denervated fibers. For this reason, SNAP amplitudes are important indicators of axonal loss because there is no compensatory mechanism to repair the lost axons, and amplitude is a good indicator of the total number of functional axons. Furthermore, when collateral sprouting is defective, the CMAPs become a good indicator of axonal loss in the chronic phase of the disease and are noted as an abnormality relatively early in course of the disease. There are few detailed quantitative needle EMG examinations in uremic patients, but based on the presumably reduced ability of muscle fibers to be reinnervated, the MUAP parameters (amplitude and duration) should not be as abnormal as in the more commonly observed axonal loss lesions. This assumption remains to be documented. In patients with mononeuropathies, electrodiagnostic findings are compatible with focal demyelination and/or axonal loss. If the patient has sustained an ischemic monomelic neuropathy, the electrophysiologic findings are commensurate with the degree of ischemic neural insult.113,785,1310 The median, radial, and ulnar SNAPs may be absent or reduced in amplitude, depending on the degree and duration of ischemia. If CMAPs are present, the distal motor latencies are relatively normal, as are the conduction velocities. Conduction block may be seen as well. Needle EMG demonstrates a marked reduction in MUAPs with abundant positive sharp waves and fibrillation potentials along with decreased recruitment. Treatment. The sensorimotor peripheral neuropathy is usually held in check by hemodialysis and almost completely reversed if the patient receives a successful renal transplant before large numbers of axons are lost. When hemodialysis is instituted, the peripheral neuropathy and nerve conduction studies may not necessarily improve. However, hemodialysis apparently has the ability to stabilize and prevent further peripheral nerve functional deterioration.111,114,309,960 Some nerve conduction parameters may improve after hemodialysis over a short time incompatible with remyelination.1255 The peripheral neuropathy and electrodiagnostic abnormalities also improve after a successful renal transplant.110,112,961,978 Patients demonstrate an increase in both motor and sensory nerve conduction velocities, reductions in distal latencies, and increases in amplitude. Individual entrapment neuropathies also may improve. Positive sharp waves and fibrillation potentials are difficult to detect and may disappear completely. Of course, in patients with profound axonal loss and significant muscle atrophy, the ability of the peripheral neuromuscular system to repair itself is limited, and only minimal to modest gains may be made. After renal transplantation a biphasic mode of functional gains occurs. The first and more rapid return of function (weeks to months) is probably due to the above-noted metabolic effect combined with remyelination of demyelinated segments.978 Later (months to 1 year or more), improvement probably results from functional axonal regrowth and reinnervation of previously denervated muscle fibers by collateral sprouting. It is not presently possible to state definitively whether nerve conduction studies are sufficiently sensitive to determine if renal dialysis frequency and duration are adequate in individual patients.1054

Surgical release is helpful in patients with carpal tunnel syndrome. Median neuropathy at the wrist related to amyloid deposition in the form of 2 microglobulin is much less common with the newer dialysis techniques. Ischemic monomelic neuropathy is treated by revising the shunt to allow more blood flow to the nerves. If treated early enough, motor and sensory symptoms can resolve quickly, indicating an ischemia-induced conduction block rather than peripheral nerve infarction. Severe ischemia resulting in infarction leads to delayed and incomplete recovery.

GASTROINTESTINAL DISEASES
Celiac Disease (Gluten-induced Enteropathy or Nontropical Sprue) Clinical Features. Intolerance to gluten, a protein found in wheat and wheat products, results in a malabsorption syndrome (weight loss, abdominal distention, steatorrhea). Diagnosis of celiac disease is based on the documentation of (1) malabsorption, (2) blunting and flattening of jejunal villi, and (3) clinical and histologic improvement after the institution of a gluten-free diet.1046 Patients with gluten intolerance can develop neurologic complications related to vitamin B12 or vitamin E deficiencies caused by malabsorption. Patients complain of distal paresthesias and some loss of sensation associated with gait ataxia.233,239,528,528a,654,696,822a, 1046,1384 Generalized sensorimotor polyneuropathy, motor neuropathy, mononeuropathy multiplex, and neuromyotonia have been reported. Dementia can be seen in some patients. Physical examination demonstrates a distal muscle weakness, which can be in a mononeuropathy multiplex pattern or generalized, absent deep tendon reflexes, Romberg sign, and ataxic gait. Spasticity and upper motor neuron weakness can be seen in patients with subacute combined degeneration related to vitamin B12 deficiency. Laboratory Features. Anti-gliadin and anti-endomysial antibodies are often detected in the serum of patients with celiac disease.1364b Histopathology. Nerve biopsy reports are conflicting with respect to axonal loss vs. segmental demyelination. The most likely pathologic insult to the peripheral nervous system is axonal degeneration of the large myelinated fibers. Autopsy studies have revealed atrophy of the cerebellum with loss of Purkinje cells.239,528a,696 Cortical atrophy and degeneration of neurons in the thalamus, basal ganglia, and brainstem are also apparent. In addition, degeneration of the posterior columns and corticospinal tracts has been described. Pathogenesis. The neuropathy may be secondary to malabsorption of vitamins B12 and E. However, some patients have no appreciable vitamin deficiencies.1384 The pathogenic basis for the neuropathy is unclear but may be autoimmune. Electrophysiologic Findings. Limited electrophysiologic data are available for celiac disease.528,528a,654 Electrodiagnostic medicine evaluation reveals a significant reduction in the SNAP amplitude or complete absence of the SNAP. Sensory conduction velocity is only mildly reduced, even in nerves with significant amplitude reductions. Motor conduction studies demonstrate a mild reduction in the nerve conduction velocity with preservation of distal motor latencies and CMAP amplitudes. Needle EMG examination can demonstrate features typical of any other type of axonal neuropathy. One case has been described with neuromyotonia.528 Treatment. The neuropathy does not appear to be responsive to a gluten-free diet.1046 In patients with vitamin B12 or vitamin E deficiency, replacement therapy may improve or stabilize the neuropathy.

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Whipples Disease Whipples disease is a rare disorder characterized by abdominal pain, diarrhea, malabsorption weight loss, arthralgias, and other systemic involvement.266,541,1046,1229 Associated symptoms and signs include fever and peripheral lymphadenopathy, accompanied by enlargement of the celiac, mesenteric, and periaortic lymph nodes. CNS involvement can result in dementia. Supranuclear ophthalmoparesis, convergence nystagmus, myoclonus, oromandibular myorhythmia, insomnia, hyperphagia, and polydipsia have been described. Rarely, patients exhibit proximal weakness and atrophy suggestive of a myopathic process. Some patients develop a sensorimotor polyneuropathy.266 Laboratory Features. The CSF examination in patients with CNS involvement typically demonstrate inflammatory changes, including a polymorphonuclear response and periodic acid-Schiff (PAS)-positive macrophages.1046 MRI scan of the brain can reveal signal changes correlating with the sites of pathologic involvement and gadolinium enhancement suggestive of ependymitis. Histopathology. Small bowel mucosa has PAS-positive macrophages containing the bacilli Tropheryma whippeli. The organism also can be identified in the CNS. There have been no reports of peripheral nerve or muscle histopathology in patients with suspected neuropathy or myopathy. Pathogenesis. Whipples disease is caused by a gram-positive actinomycete, T. whippeli. Intestinal mucosal changes lead to malabsorption. Although the pathogenic basis of the neuropathy is not known, it may result from malabsorption of necessary vitamins. Alternatively, the neuropathy may be caused by bacterial infiltration and subsequent inflammatory involvement of the peripheral nerves. Electrophysiologic Findings. A detailed electrodiagnostic medicine report of a single patient with Whipples disease revealed evidence of a sensorimotor peripheral neuropathy, especially prominent in the lower limbs.266 Additionally, proximal muscle weakness on clinical examination suggested a superimposed myopathic process. Sensory nerve conduction revealed reduced SNAP amplitudes with mild impairment of conduction velocities. Similar findings were noted for the motor nerves with the exception of the peroneal nerve, which yielded evidence suggestive of conduction block. Needle EMG examination demonstrated a reduced recruitment pattern distally with positive sharp waves and fibrillation potentials. The proximal muscles, however, demonstrated short-duration, low-amplitude potentials consistent with a myopathic process. Single-fiber EMG failed to demonstrate significant abnormalities. Treatment. Chloramphenicol and trimethoprim-sulphamethoxazone are efficacious in the treatment of CNS disease associated with Whipples disease.1046 Because of the rarity of PNS involvement, it is not known whether antibiotic treatment improves or arrests the progression of peripheral neuropathy. Obviously, if a vitamin deficiency is documented, replacement therapy should be started. Inflammatory Bowel Disease Inflammatory bowel disease refers to ulcerative colitis and Crohns disease. Both disorders are thought to have an immunologic basis and are associated with various neurologic abnormalities, including peripheral neuropathy. In a large series of 638 patients with inflammatory bowel disease, 6 developed a peripheral neuropathy (3 AIDP, 1 mononeuropathy multiplex, 1 bibrachial plexopathy, 1 recurrent facial nerve palsy).812 All of the patients with neuropathy had ulcerative colitis. However,

polyneuropathy can complicate Crohns disease as well as ulcerative colitis and may manifest as AIDP,73,190,471,607,712,812,1450 generalized axonal sensorimotor polyneuropathy, 939 brachial plexopathy,230,812 multiple mononeuropathies,812 and cranial neuropathies.595,812 The clinical, laboratory, histologic, and electrophysiologic features of the specific types of peripheral neuropathies associated with inflammatory bowel disorders are no different from the idiopathic forms. In addition to neuropathy, patients with inflammatory bowel disease can develop weakness secondary to myasthenia gravis or myositis (including polymyositis, dermatomyositis, and granulomatous myositis).812

LIVER DISEASE
Chronic Liver Disease Patients with chronic liver disease from various causes can develop a mild, generalized sensorimotor peripheral neuropathy characterized by numbness, tingling, and minor weakness primarily in the distal aspects of the lower limbs.210,655,706,1198 Sural nerve biopsies reveal both segmental demyelination and axonal loss. Electrodiagnostic medicine evaluations have demonstrated a reduction in SNAP amplitudes as the major abnormality, with some prolongation of sensory and motor distal latencies. Motor nerve conduction studies are usually normal, although needle EMG examinations have not been well described. Quantitative sensory testing is abnormal in 62% of patients in large series, with cooling thresholds more abnormal than vibratory thresholds.210 Autonomic testing reveals dysfunction in nearly 50% of patients.210,994 Whether hepatic failure itself can cause peripheral neuropathy is unclear. Toxins that could damage peripheral nerves may accumulate as a result of liver disease. However, most patients have hepatic failure secondary to other disorders, such as alcoholism or viral hepatitis, that can cause peripheral neuropathies. Alcoholics may develop neuropathy secondary to the direct toxic effect of alcohol or because of nutritional deficiencies. Hepatitis B and C can cause mononeuropathy multiplex (secondary to vasculitis or cyroglobulinemia), AIDP, or CIDP. Furthermore, EBV-related hepatitis can be associated with AIDP. Obviously more work needs to be done before we can conclude that liver failure is the direct cause of associated peripheral neuropathies. Primary Biliary Cirrhosis Clinical Features. Primary biliary cirrhosis (PBC) is an autoimmune disorder directed against the biliary ducts in the liver. Patients develop progressive liver failure, which is often fatal. Patients with PBC can develop a peripheral neuropathy characterized by distal numbness and tingling.202,210,820 Physical examination demonstrates a reduced ability to perceive touch and vibration, along with diminished proprioception. Pain and temperature perception can be diminished to a minor degree in the most distal aspects of the limbs. Deep tendon reflexes may be reduced or absent. Muscle strength is typically normal. Although documentation is poor, it would not be surprising to find a CIDP-like neuropathy in PBC because autoimmune disorders frequently occur together. When weakness is present, other autoimmune neuromuscular disorders, such as myasthenia gravis, Lambert-Eaton syndrome, and myositis, need to be considered. Laboratory Features. Liver function tests are obviously elevated. Antimitochondrial antibodies can be detected in the sera of some patients.

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Histopathology. Nerve biopsy demonstrates a reduction in the large myelinated fibers without evidence of segmental demyelination. Pathogenesis. The cause of peripheral nerve damage is unknown. The neuropathy may have an immunological basis. Additionally, the neuropathy may be related to unknown toxins that accumulate as a result of liver failure. Electrophysiologic Features. Electrodiagnostic medicine evaluation demonstrates reduced or absent SNAPs. The motor conduction and needle EMG portions of the evaluation are normal. The electrophysiologic and histopathologic findings support the clinical impression of a primary sensory neuropathy. Treatment. PBC is treated with immunosuppressive therapy and, ultimately, liver transplantation. Whether transplantation affects the peripheral neuropathy has not been adequately addressed.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

In a single study, 87% of patients with chronic obstructive pulmonary disease had electrophysiologic evidence of a subclinical sensorimotor peripheral neuropathy.385 Only 17% of the total study population had clinical findings suggestive of a peripheral neuropathy. Similarly, 17% of patients had needle EMG evidence of axonal loss as demonstrated by a combination of positive sharp waves, fibrillation potentials, and reduced recruitment of MUAPs. Additional findings of long-duration, high-amplitude potentials suggested chronic disease with motor unit remodeling.

GOUT
Rarely, patients with gout may develop a sensorimotor peripheral neuropathy preferentially localized to the lower limbs or neural entrapments at the wrist and elbow.308 Patients with peripheral neuropathies may complain of progressive loss of sensation in the feet with difficulty in walking. Physical examination can reveal a wide-based gait with a positive Romberg sign. Deep tendon reflexes are depressed in the upper limbs and absent in the lower limbs. Despite a lack of overt muscle atrophy, a loss of about one grade of strength may be documented in the distal lower limb muscles. Decreased sensation to all modalities can be observed in the legs. Sensory nerve conductions in the lower limbs can be absent, whereas those in the upper limbs reveal reduced amplitudes with mild alterations of conduction velocity or distal latencies. Similar findings are noted for motor nerve studies. Needle EMG studies have not been detailed in patients with gouty neuropathy.

CRITICAL ILLNESS POLYNEUROPATHY

As opposed to AIDP and myasthenia gravis, which are the most common neuromuscular causes for admission to intensive care units (ICU), weakness in critically ill patients in the ICU setting121a,312a usually is secondary to critical illness polyneuropathy,115,116,117,776,1414,1424,1449a,1451 or critical illness myopathy (also known as acute quadriplegic myopathy [AQM]; see Chapter 28),310,752754,1099,1100,1452 or, much less commonly, prolonged neuromuscular blockade.76 From a clinical and electrophysiologic standpoint, it can be quite difficult to distinguish these disorders. Critical illness neuropathy was more common than critical illness myopathy in some series of ICU patients.776,1000,1424 However, other institutions and the authors

own anecdotal experiences suggest that critical illness myopathy is more common than critical illness neuropathy.754,1100 In the largest series involving 88 patients who developed weakness in the ICU, critical illness myopathy was three times as common as critical illness neuropathy (42% vs. 13%); prolonged neuromuscular blockade occurred in only one patient, who also had AQM.754 From a practical standpoint, morbidity and mortality appear to be similar in critical illness neuropathy and critical illness myopathy.754 In patients who survive the underlying sepsis and multiorgan failure, muscle strength recovers slowly over several months. Clinical Features. Critical illness polyneuropathy occurs in patients in the ICU with sepsis and multiple organ failure.115,116,117,121a,312a,776,1185,1424,1449a,1451 The peripheral neuropathy is often first suspected when the patient cannot be weaned from a ventilator. Neurologic examination can be limited by encephalopathy related to sepsis and organ failure. It is often difficult to ascertain the degree of sensory loss and modalities if the patients mental status is altered. Nevertheless, generalized weakness of the limb muscles can be appreciated. Cranial nerve musculature is usually comparatively well preserved, although mild facial weakness may occur. As noted above, respiratory muscle involvement is prominent. Deep tendon reflexes are absent or reduced. A subset of patients sustaining burn injury to 20% or more of the total body surface may develop a number of different types of neuropathies in the critical care setting.569,570,572,1164 Focal neuropathies of the median, radial, ulnar, and peroneal nerves can result from poorly applied compression dressings or malpositioning of limbs. Patients may develop a mononeuropathy multiplex (69% of patients in one series), possibly secondary to vascular insult of the vasa nervora.833 A generalized sensorimotor peripheral neuropathy that is less severe than critical illness polyneuropathy may occur in 652% of burn patients . Burn patients also may develop the complete critical illness polyneuropathy described above.174,833 Delayed paraparesis may result from electrical injuries (see Chapter 16).710 Laboratory Features. CSF is usually normal or only mildly elevated, whereas in AIDP and CIDP in CSF protein is usually significantly increased.1451 Of note, some patients have increased serum creatine kinase (CK) levels, which were attributed to myocardial infarction in some cases.1451 However, the elevated serum CKs may be secondary to critical illness myopathy rather than critical illness neuropathy. Histopathology. Nerve biopsies reveal significant axonal degeneration with little demyelination.1451 Autopsies have demonstrated chromatolysis of anterior horn cells, loss of dorsal root ganglion cells, and axonal degeneration of motor and sensory nerves.1451 Muscle biopsies show grouped atrophy and targetoid fibers suggestive of acute neurogenic process.1451 However, scattered muscle fiber necrosis and increased central nuclei, which are nonspecific myopathic features, also have been noted. AQM is usually associated with necrotic fibers and loss of myosin thick filaments. Pathogenesis. The pathogenic basis of critical illness neuropathy is not clear. One can speculate that circulating toxins and metabolic abnormalities associated with sepsis and multiorgan failure lead to axonal degeneration of the peripheral nerves, perhaps by interfering with axonal transport mechanisms or mitochondrial function.1451 Electrophysiologic Features. An electrodiagnostic medicine examination in critical care units is usually fraught with technical difficulties secondary to interference from multiple lifesaving and monitoring equipment. In addition, units are located

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on the upper floors of the hospital, thus predisposing recording of electrical signals from radio and television stations. Despite these adverse conditions, good technique can demonstrates significant abnormalities in patients with critical illness polyneuropathy.115,116,117,121a,312a,776,1185,1414,1424,1449a,1451 CMAPs are profoundly reduced in amplitude or absent. Phrenic nerve studies often reveal absence or reduction of the diaphragms CMAP amplitude. Motor nerve conduction velocity and distal motor latency are normal or only slightly abnormal. There is no conduction block or increased temporal dispersion. F-waves may be unobtainable, but when they are present, the latencies are normal or only mildly prolonged. Repetitive stimulation studies fail to reveal electrophysiologic evidence of neuromuscular junction failure. The SNAPs also should be significantly diminished in amplitude or absent. When SNAPs are recordable, the sensory conduction velocities are normal or only mildly reduced, and the distal sensory latencies are normal or only slightly prolonged. If the SNAPs amplitudes are normal or only slightly reduced in comparison with loss of CMAP amplitudes, the diagnosis of critical illness myopathy or motor axonal neuropathy must be considered. Of importance, low-amplitude SNAPs do not necessarily imply that the patients weakness is secondary to critical illness neuropathy. Patients with critical illness myopathy may have an age-related decrease in SNAP amplitudes, or the SNAPs may be abnormal secondary to an underlying condition (e.g., diabetes mellitus). Furthermore, patients may have a mixture of critical illness neuropathy and myopathy; thus SNAPs would be abnormal, but the muscle weakness may be more related to the superimposed myopathy. Needle EMG examination reveals profuse positive sharp waves and fibrillation potentials. In patients with severe weakness, it is not unusal to be unable to recruit MUAPs. When MUAPs are recruited, they are often small and polyphasic in morphology. These small units have been attributed to early reinnervation. Unfortunately, discussion of the recruitment pattern often has been neglected. One would expect to see decreased recruitment of small MUAPs in a neurogenic process. However, if one sees early recruitment of small-duration, polyphasic MUAPs, AQM should be considered. Increased jitter on single-fiber EMG has also been noted,1185 but increased jitter can be caused by remodeling of the motor terminal due to a neuropathic, myopathic, or neuromuscular junction defect. Direct muscle stimulation has been advocated to help distinguish critical illness neuropathy from myopathy.1099,1100 Direct muscle stimulation bypasses the distal motor nerve and neuromuscular junction. In a neuropathic process or prolonged neuromuscular blockade, the muscle membranes should retain excitability, and the direct muscle stimulation CMAP (dmCMAP) theoretically should be near normal despite a low or absent nerve stimulation-evoked CMAP (neCMAP). In contrast, if the muscle membrane excitability is reduced, as in AQM, both the neCMAP and dmCMAP would be expected to be very low. Rich and colleagues suggest that the ratio of neCMAP to dmCMAP should be close to 1:1 (> 0.9) in a disorder of muscle membrane inexcitability and approach zero (0.1 or less) in a neuropathy or neuromuscular junction disorder.1099,1100 However, a large control group is needed to confirm the statistical value of this ratio. Treatment. There is no specific therapy for critical illness neuropathy other than supportive care and treatment of the underlying sepsis and organ failure.

NEUROPATHIES ASSOCIATED WITH MALIGNANCY

Peripheral neuropathies can develop in a patient with malignancy as (1) a direct effect of the cancer by invasion or compression of nerves, (2) a remote or paraneoplastic effect, (3) or an iatrogenic effect of treatment (chemotherapy, immunosuppression, radiation, bone marrow transplantation).24 Estimating the frequency of peripheral neuropathies associated with malignancies is difficult because the frequency depends on a number of factors, including the type, stage, and location of the cancer, duration of disease, degree of malnutrition, and neurotoxic effects of various therapies. However, clinically evident peripheral neuropathy has been reported in 1.75.5%261,262,876,1313 of patients with malignancy, and quantitative sensory testing can detect peripheral neuropathy in 12%.801 Furthermore, nerve conduction studies have demonstrated peripheral neuropathy in 3040% of patients with cancer.876,919 Peripheral neuropathy is most common in carcinoma of the lung but also is associated with carcinoma of the breast, ovaries, stomach, colon, rectum, and other organs, including the lymphoproliferative system.191,259,261,262,493,604,784,874,1264

PARANEOPLASTIC NEUROPATHIES
The remote effects of carcinoma on the peripheral nervous system (so-called paraneoplastic neuropathies) are quite diverse.24,163,172,262,382,564,580,876,1183,1291,1313,1435 These neuropathies result from indirect carcinomatous insult to the peripheral nervous system, not from direct nerve infiltration or compression.
Paraneoplastic Sensory Neuronopathy/Ganglionopathy Clinical Features. Subacute sensory neuronopathy was the first neuropathy described as a complication of carcinoma.312 Because the site of the lesion is at the level of the sensory cell body, the disorder is also called a ganglionopathy. Small cell lungcarcinoma (SCLC) is the most commonly associated malignancy, but cases associated with carcinoma of the esophagus, breast, ovaries, and kidney and lymphoma also have been reported.24,26,261,283,491493,602,1151,1232,1324,1366 The disorder is rare and most commonly affects women in late-middle life (mean age of onset: 59 years).192,263 The predominant symptomsnumbness, dysesthesia, and paresthesiabegin distally and spread proximally. Symptoms begin in the arms in over 60% and are asymmetric in approximately 40% of cases.192 The onset can be acute or insidiously progressive. Diminished touch, pinpoint, and temperature sensation and prominent loss of vibratory and position sense result in sensory ataxia and pseudoathetosis. Deep tendon reflexes are diminished or absent. Alterations in mental status, autonomic dysfunction, and cranial nerve abnormalities occur in about twothirds of patients as a result of a superimposed paraneoplastic encephalomyelitis.602 Although most cases of sensory neuronopathy have only sensory abnormalities, mild weakness is occasionally evident and may reflect an associated sensorimotor neuropathy or a superimposed myasthenic (Lambert-Eaton) syndrome. The neuropathy generally evolves over a few months, then stabilizes. Symptoms of the neuropathy may precede symptoms of the cancer by several months or years. Discovery of a sensory neuronopathy should lead to an aggressive evaluation for an underlying malignancy. We obtain a chest CT scan, mammogram, pelvic CT, and antineuronal nuclear antibodies (anti-Hu) for all patients in addition to performing a complete physical examination.

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Laboratory Features. CSF may be normal or demonstrate mild lymphocytic pleocytosis and elevated protein.26,283,602 Type 1 antineuronal nuclear antibodies (ANNA-1), also known as anti-Hu, can be demonstrated in serum and CSF in patients with small cell carcinoma of the lung complicated by paraneoplastic sensory or sensorimotor polyneuropathy, encephalitis, and cerebellar degeneration.26,283,491,492 The antibodies are directed against a 3540 kD nuclear protein and are highly specific for SCLC.194 We advise chest radiograph every 3 months and chest CT or MRI every 6 months in patients who initially have no identifiable cancer but a sensory neuronopathy with a positive ANNA-1. Histopathology. Pathologic features of the disease include inflammation and degeneration of the dorsal root ganglia with secondary degeneration of sensory neurons and the posterior columns. Sural nerve biopsies may demonstrate perivascular inflammation.194 The inflammatory infiltrate is comprised of both B- and T-lymphocytes.629 In addition, autopsies reveal degeneration and inflammation involving neurons in the brainstem and limbic system.283,491,1366 Pathogenesis. The cause of the neuronopathy is unclear. Perhaps an antigenic similarity between proteins in tumor cells and neuron cells leads to an immune response directed against both.491,1127,1366 Electrophysiologic Findings. Nerve conduction studies in pure sensory neuronopathy reveal low-amplitude or absent SNAPs with normal CMAPs.26,283,602 A small reduction in the sensory conduction velocity may result from loss of large myelinated nerve fibers. Of importance, the SNAPs can be asymmetrically affected, reflecting clinical involvement. Furthermore, one can see abnormal SNAPs in the hand when they are normal in the legs. This feature suggests a ganglionopathy as opposed to the much more common length-dependent axonopathies, in which sural SNAPs are affected earlier and more severely than upper limb SNAPs. Blink and masseter reflexes are generally normal.51,52 Motor conduction studies are normal in pure sensory neuronopathies, but many patients have motor involvement. In particular, some patients have superimposed Lambert-Eaton syndrome. Thus, low-amplitude CMAPs, with low rates of repetitive stimulation (23 Hz), can reveal a decrement, whereas 10 seconds of exercise or fast rates of repetitive stimulation (2050 Hz) may demonstrate facilitation of CMAP amplitudes. Needle EMG findings usually are normal. Some patients with subclinical motor nerve involvement may have a few positive sharp waves and fibrillation potentials in the distal limb musculature. Furthermore, variability in MUAP morphology and increased jitter may be seen in patients with superimposed Lambert-Eaton syndrome. Treatment. Treatment of the underlying cancer may prolong survival but generally does not affect the course of the underlying neuronopathy.283 Remission after treatment of the tumor is rare.
Paraneoplastic Sensorimotor Polyneuropathy Clinical features. Sensorimotor polyneuropathies also may have an immunologic pathogenesis as part of a paraneoplastic syndrome.24 From a clinical and electrophysiologic standpoint, it is usually easy to distinguish neuropathy caused by direct tumor infiltration from a paraneoplastic or idiopathic variant by its local character, but rarelyin widespread casesthe distinction may be difficult. Although sensory symptoms predominate in the paraneoplastic anti-Hu syndrome, mild weakness is evident in many patients.283 Multiple mononeuropathies attributed

to paraneoplastic vasculitis are described in patients with lymphoma, SCLC, and adenocarcinoma of the lungs, endometrium, prostate, and kidneys.24,443,558,639,739,846,985,1307,1357,1430 Histopathology. Histologic examination of the peripheral nervous system in patients with clinical signs and symptoms of a sensorimotor peripheral neuropathy reveal a general reduction in all myelinated fibers.172,262,564,580,876,1291,1313,1435 Perivascular inflammation as well as changes due to necrotizing vasculitis have been described within peripheral nerves. Pathogenesis. The pathogenic basis of the neuropathy is not known. Perhaps an immune response is directed at both sensory and motor components of peripheral nerves. Electrophysiologic Findings. Patients with a generalized sensorimotor peripheral neuropathy demonstrate findings consistent with the above histopathologic observations.172,262,564,580, 876,1291,1313,1435 Sensory nerve conduction studies show absent or low-amplitude SNAPs with normal or borderline-slowing conduction velocities and slightly prolonged distal latencies. Motor conduction studies reveal low normal or mildly slowed velocities. The CMAP amplitudes may be reduced in the intrinsic muscles of the hands and feet. The distal motor latencies can be mildly prolonged. Needle EMG examination may reveal evidence of long-standing motor unit remodeling (increased MUAP amplitudes, durations, and phases), decreased recruitment, and fibrillation potentials and positive sharp waves of varying degrees.
Paraneoplastic Autonomic Neuropathy Autonomic dysfunction can occur as an isolated disturbance or as part of the spectrum of the anti-Huassociated encephalomyelitis-neuropathy syndrome.283 Autonomic neuropathy is most commonly described as a paraneoplastic effect of SCLC but also has been described with adenocarcinoma and carcinoid tumor of the lungs, testicular cancer, pancreatic malignancy, and Hodgkins lymphoma.214,283,453,777,1214,1245 The autonomic neuropathy may manifest as orthostatic hypotension, intestinal pseudo-obstruction, urinary retention, constipation, dry eyes and mouth, and pupillary dysfunction. In a study of 71 patients with anti-Huassociated encephalomyelitis-sensory neuronopathy syndrome, 10% presented with severe orthostatic hypotension, and 28% had varying degrees of dysautonomia during the course of the illness.283 Autopsies have demonstrated damage to neurons in the dorsal root ganglia in addition to those of the myenteric plexus in patients with intestinal pseudo-obstruction. Lennon reported autoantibodies directed against a nuclear antigen of myenteric neurons in patients with this syndrome.777

CRYPTOGENIC SENSORY OR SENSORIMOTOR POLYNEUROPATHY

Clinical Features. Cryptogenic sensory or sensorimotor polyneuropathy complicating cancer is much more common than paraneoplastic neuropathies.262,263,564 The polyneuropathy is more common in patients with SCLC but also can complicate carcinoma of the breast, ovary, uterus, testes, kidney, and gastrointestinal tract. The causes of sensorimotor neuropathy in malignancy is multifactorial. A paraneoplastic basis for the sensorimotor polyneuropathy, although often suspected, is actually uncommon. In most cases, the cause of sensory or sensorimotor polyneuropathy complicating cancer remains unknown or idiopathic. The neuropathy in most patients manifests clinically with slowly progressive, distal, symmetric numbness, beginning in

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the feet and later progressing to the hands.24,262,263,564 All sensory modalities can be affected, but the prominent sensory ataxia that is seen in sensory neuronopathies is generally not observed. Mild distal weakness of the distal lower and upper limbs may be noted. Deep tendon reflexes are diminished or absent distally. Laboratory Features. There are no specific laboratory abnormalities. Histopathology. Nerve biopsies and post-mortem tissue analysis most commonly reveal axonal degeneration and regeneration, but segmental demyelination and remyelination have been reported.261,263,312,876 Pathogenesis. The pathogenic basis is not known. Although various chemotherapies are toxic to peripheral nerves, a sensory or sensorimotor polyneuropathy can occur in untreated people with cancer. Weight loss frequently accompanies malignancies, but patients may not appear cachectic or malnourished when neuropathy initially manifests.24,876,1313 Furthermore, vitamin supplementation is of no benefit.876 The pathogenesis may be related to toxic factors released by the tumor, which may somehow result in axonal degeneration.876 Metabolic disturbances, such as an alteration in protein and fat metabolism, that occur with malignancies may be responsible for the neuropathy. Electrophysiologic Findings. Nerve conduction studies demonstrate features of a length-dependent, axonal, sensory or sensorimotor polyneuropathy.24,262,1313 Sensory studies reveal decreased or absent sensory nerve action potentials. Compound muscles action potentials are normal or only mildly reduced in amplitude. Likewise, distal latencies and conduction velocities of motor and sensory nerves are normal or only slightly prolonged or slow. EMG may reveal mild denervation changes distally. Treatment. There is no specific treatment for the neuropathy other than treating the underlying malignancy and maintaining adequate nutrition.

proliferation of large, atypical, lymphoid B-cells.786,1134,1364 The CNS and skin are the most common sites of involvement. Of note, malignant cells are absent in the peripheral blood or lymphoid tissues. Approximately 24% of patients have involvement of the spinal cord or roots, and 5% have mononeuropathies.786 Intravascular vascular and endoneurial lymphocytic infiltration (primarily B-cells) is evident on nerve biopsy. Lymphomatoid Granulomatosis. Lymphomatoid granulomatosis is an angiocentric, immunoproliferative disorder with a pleomorphic lymphoid infiltrate of blood vessels.24 The infiltrate is composed of reactive T-cells, which are driven by Epstein-Barr infected T-cells.1418 There is a predisposition for evolution into lymphoma. Distal symmetric polyneuropathy, mononeuropathy multiplex, polyradiculopathies, and cranial neuropathies occur in 1015% of patients.168,662,795 Nerve biopsies reveal perivascular lymphoplasmatoid infiltrates in the epineurium that lead to necrosis or thrombosis of the vessels and ischemic injury to the nerve fascicles. Electrophysiologic studies suggest an axonopathy.
Cranial Neuropathies and Radiculopathies Almost any type of cancer has the potential to invade the leptomeninges, cranial nerves, and nerve roots.24 Polyradiculopathy due to malignant invasion of the nerve roots manifests as radicular pain and sensory loss, weakness, and hypo- or areflexia. Widespread involvement can mimic a generalized sensorimotor polyneuropathy. Upper motor neuron dysfunction can also occur, if the spinal cord is compressed. Multiple cranial neuropathies may result from spread of a local tumor (i.e., nasopharyngioma) or by metastasis. The sixth and fifth cranial nerves are most commonly affected in nasopharyngiomas, whereas the sixth cranial nerve, followed by the third, fifth, and seventh, is most commonly affected in metastatic processes. The so-called numb chin syndrome, characterized by numbness of the lower lip and chin, is particularly worrisome for malignant invasion of the mental or alveolar branches of the mandibular nerve. MRI with gadolinium may demonstrate enhancement or compression of the nerve roots by the tumor. CSF may be abnormal, revealing increased protein, an increased cell count, and malignant cytology. It may take several weeks for evidence of active denervation to appear on EMG. Asymetrically prolonged or absent F-waves may be a sensitive early indicator of nerve root involvement. Patients with leukemia and lymphoma may respond to irradiation and intrathecal chemotherapy. However, the response rate is much lower in other types of tumors, with the possible exception of breast cancer. Brachial Plexopathy Damage to the brachial plexus usually results from metastasis, regional spread of a local tumor (e.g., Pancoast tumor), or radiation-induced injury.24 In a series of 100 patients with cancer and brachial plexopathy, metastatic tumor was responsible for the plexopathy in 78%.717 The most common tumors are lung or breast carcinomas. The cancer most often spreads via the lymphatics to the region of the lateral group of axillary lymph nodes, where divisions of the lower trunk of the brachial plexus are located. Cancers in the apices of the lungs may grow into the paravertebral space and posterior chest wall and invade the extraspinal C8T3 mixed spinal nerves, the sympathetic chain, and the stellate ganglia (see Chapter 19). The most common symptom, occuring in approximately 85% of patients, is pain in the shoulder area that radiates into the

NEUROPATHIES RELATED TO TUMOR INFILTRATION

Mononeuropathy Multiplex Occasionally, the peripheral nerves can be invaded directly by the tumor, particularly leukemia and lymphoma, resulting in mononeuropathy, mononeuropathy multiplex, polyradiculopathy, plexopathy, or even generalized symmetric distal or proximal and distal polyneuropathy.24 The onset and course of the neuropathy can be acute, subacute, or chronic progressive. Of importance, peripheral neuropathy may be the presenting clinical manifestation of leukemia or lymphoma or the heralding feature of a relapse. Leukemia. Peripheral neuropathy has been reported in up to 5.5% of cases of leukemia.725,876,1068,1269,1362,1403 Mononeuropathy or mononeuropathy multiplex may result from hemorrhage or leukemic infiltration into cranial or peripheral nerves and spinal roots. Symmetric peripheral neuropathy is unusual but has been described. Acute, subacute, and chronic sensorimotor polyneuropathies complicating chronic leukemia, especially chronic lymphocytic leukemia, are well documented.256 The neuropathy may respond to corticosteroids and treatment of the underlying leukemia. Electrophysiologic features are consistent with an axonal sensorimotor polyneuropathy. Nerve biopsies can demonstrate leukemic infiltration of the nerve, axonal degeneration, and segmental demyelination. Vasculitis also has been suggested as a cause of peripheral neuropathy in hairy cell leukemia.443,558 Angiotrophic Large-cell Lymphoma. Angiotrophic largecell lymphoma is a rare malignancy characterized by intravascular

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medial aspect of the arm and the fourth and fifth digits of the hand. Sensory loss and weakness are usually present in the distribution of the lower trunk. Horners syndrome due to involvement of the sympathetic chain or stellate ganglia is evident in most patients. A few patients have lymphedema of the affected arm. Signs and symptoms attributable to involvement of the upper and middle trunk of the brachial plexus are much less common and, when present, suggest epidural extension of the tumor. Radiation-induced brachial plexopathy usually occurs after doses greater than 6000 rads and presents 3 months to 26 years (mean: 6 years) after radiation treatment to the region.717 Unlike metatastatic plexopathy, pain occurs in only 15% of patients and usually is not as severe. Paresthesias and lymphedema are present in 55% and 45% of patients, respectively. The upper plexus is involved in 77%, and diffuse plexus involvement is seen in 23% of patients. The relative sparing of the lower trunk of the brachial plexus may relate the shorter distance that the trunk travels through the radiation port or a protective effect of the overlying clavicle. However, other studies have reported that the entire plexus is more commonly involved than just the upper trunk.916 MRI or CT scan may demonstrate malignant invasion of the plexus and perhaps extension to the epidural space. Although myokymic discharges on EMG are highly suggestive of radiation-induced damage, the absence of myokymia doses not exclude radiation plexopathy. At times noninvasive testing cannot differentiate between metastatic and radiation disease, and surgical exploration and biopsy are required for definitive diagnosis. Neoplastic invasion of the brachial plexus can be treated with radiation therapy. Although patients may experience pain relief, there is usualy no notable improvement in strength. Treatment of the pain with transcutaneuous stimulation, sympathetic blockage, or dorsal rhizotomies has been disappointing.
Lumbosacral Plexopathy Malignant invasion of the lumbosacral plexus may due to direct extension of intra-abdominal neoplasms (73%) or metastasis of a distant tumor (27%).620 The most comon tumors are colorectal, cervical, lymphoma, sarcoma, and breast cancers. The lumbar plexus is involved in 31%, the lumbosacral trunk in 51%, and the entire lumbosacral plexus in 18% of patients with malignant invasion of the plexus.383,620 Patients present with insidious onset of pain, numbness, weakness, and edema of the lower limb. Bilateral lower limbs are involved in approximately 25% of cases. Incontinence or impotence develops in less than 10% of patients. Radiation-induced lumbosacral plexopathy manifests 131 years (mean: 5 years) after completion of treatment as slowly progressive weakness.24 Unlike plexopathy secondary to tumor invasion, pain is present in only one-half of patients and typically is not as severe. Both lower limbs are typically involved, although asymmetrically, and distal muscles are affected more than proximal muscles. Bowel and bladder incontinence may result from radiation-induced proctitis or cystitis. MRI or CT of the lumbosacral spine and pelvis can demonstrate tumor invasion of the lumbosacral plexus and, at times, extension of the tumor into the epidural space. EMG reveals fibrillation potentials in the paraspinal muscles in approximately 50% of patients with radiation-induced damage, suggesting the disorder is more appropriately termed a radiation radiculoplexopathy. Myokymia is evident in over 50% of patients with radiation-induced lumbosacral radiculoplexopathy.24

NONINFILTRATIVE PERIPHERAL NEUROPATHIES ASSOCIATED WITH LYMPHOPROLIFERATIVE DISORDERS AND MONOCLONAL GAMMOPATHIES
Neuropathies associated with monoclonal gammopathies are discussed under immune-mediated neuropathies, but the relationship between neuropathy, monoclonal gammopathies, and malignancy deserves further comment. An increased incidence of monoclonal gammopathies has been observed in patients with peripheral neuropathy. About 10% of patients with idiopathic peripheral neuropathies have monoclonal gammopathies compared with 2.5% of patients with peripheral neuropathies secondary to other diseases.668,768 In addition, peripheral neuropathies may be more common in patients with monoclonal gammopathies than in the general population.1368 A causal relationship between monoclonal gammopathies and peripheral neuropathies has been suggested by studies demonstrating binding of monoclonal IgM to peripheral and periaxonal regions of nerve fibers.767,885 Antibodies directed against myelin-associated glycoprotein (anti-MAG) are present in at least 50% of patients with IgM monoclonal gammopathies and peripheral neuropathies.661,704,768 However, what role, if any, these antibodies play in the pathogenesis of peripheral neuropathies is unknown. In IgA and IgG monoclonal gammopathies, immunoglobulin deposition is generally not seen on nerve sheaths, and a causal link is much less established. All patients with peripheral neuropathies of unknown etiology should be tested for the presence of monoclonal gammopathies. Serum protein electrophoresis (SPEP) is a useful screening test, but it is not as sensitive as immunoelectrophoresis (IEP) or immunofixation (IFE). Serum IEP or IFE should be performed to identify the nature of monoclonal proteins and in patients suspected of having a myeloproliferative disorder, even with a normal SPEP, because a small monoclonal protein may not be apparent. The presence of monoclonal gammopathies should lead to an aggressive work-up for amyloidosis, multiple myeloma, osteosclerotic myeloma, Waldenstrms macroglobulinemia, cryoglobulinemia, leukemia, and lymphoma.669,671,702,744,768,1064,1361 If a monoclonal gammopathy is detected, urine protein electrophoresis and immunoelectrophoresis should be performed, along with hematologic studies, bone marrow biopsy and aspirate, and a radiographic skeletal survey. In most patients with monoclonal gammopathies, no underlying disease is found; such patients are designated as having a monoclonal gammopathies of undetermined significance (MGUS). MGUS has replaced the term benign monoclonal gammopathy because approximately 20% of patients initially classified as having MGUS eventually develop malignant disorders with long-term follow-up.747,768,1064
Lymphoma Clinical Features. Neuropathy in patients with lymphoma may be secondary to direct endoneurial infiltration or direct compression of nerves by lymphoma24,727,877,921 but more commonly occurs as a remote effect of the cancer.24,270,816,921,1381 Sensorimotor neuropathy can complicate both Hodgkins disease (HD) and nonHodgkins lymphoma (NHL).123,170,262,270,803,921,1269,1381 The incidence of peripheral neuropathy is generally thought to be lower in patients with lymphoma (approximately 12%) than in patients with SCLC.803,877 However, a prospective study reported clinically evident neuropathy in 8% and electrophysiologic evidence of neuropathy in 35% of patients with lymphoma.1381 The clinical presentation is variable. The neuropathy may be purely sensory602,1151 or motor1183

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but most commonly is sensorimotor.1381 It may be symmetric, asymmetric, or multifocal. Autonomic dysfunction also may occur. The course may be acute,170,270,921,1269 subacute,803,921,1269 chronic progressive,262,803,1381 or relapsing and remitting.123,170,262,803,921 Laboratory Features. CSF may reveal lymphocytic pleocytosis and elevated protein.727,877,921,1381 Histopathology. Nerve biopsy may reveal axonal degeneration along with segmental demyelination.170,877,1381 Inflammatory cells within the endoneurium may be demonstrated in both infiltrative and presumed paraneoplastic neuropathies complicating lymphoma (Fig. 23-9). The presence of a monoclonal population of inflammatory cells within the nerve fascicles suggests infiltration of tumor cells rather than an immunologic paraneoplastic etiology. Pathogenesis. The paraneoplastic neuropathy associated with lymphomas is presumably autoimmune, but the exact antigen(s) and triggers for the immune attack are not known. Electrophysiologic Findings. Nerve conduction studies may reveal changes compatible with an axonal sensorimotor neuropathy1381 or demonstrates features of prominent demyelination270,1269 similar to that seen in AIDP and CIDP. Treatment. The neuropathy may respond to treatment of the underlying lymphoma.727,1151,1269
Multiple Myeloma Multiple myeloma is the most common hematologic malignancy associated with a monoclonal gammopathy. The disorder typically manifests in the fifth-to-seventh decade of life with fatigue, bone pain, anemia, and hypercalcemia. Peripheral neuropathies associated with multiple myeloma are uncommon, occurring in 313% of cases.667,668,702,748,1355,1380 Electrophysiogic abnormalities, however, may be detected in 40% of cases, indicating possible subclinical peripheral neuropathy.1380 Most patients have a distal, axonal, sensory or sensorimotor neuropathy.667,1380 Less frequently, a demyelinating polyradiculoneuropathy may develop.667 A small-fiber neuropathy with painful paresthesias and loss of pinprick and temperature discrimination and autonomic dysfunction with superimposed carpal tunnel syndrome suggest amyloid neuropathy.128 Epidural cranial and spinal root compression by expanding plasmacytomas is common and may be superimposed upon and overshadow the peripheral neuropathy. Laboratory Features. Monoclonal proteins consisting of or heavy chains or light chains are usually identified in the serum or urine. Many patients are anemic, and hypercalcemia is evident on routine chemistries. Skeletal survey typically reveals osteolytic lesions. Diagnosis of multiple myeloma requires the demonstration of at least 10% plasmacytes on a bone marrow biopsy. Histopathology. Amyloid deposition may be responsible for up to two-thirds of neuropathies in patients with multiple myeloma.667 Abdominal fat pad, rectal, or sural nerve biopsy should be performed to look for amyloid deposition. In patients without amyloidosis, nerve biopsies reveal prominent axonal degeneration along with mild segmental demyelination/remyelination consistent with reinnervation.1380 Pathogenesis. The mechanism of the neuropathy in multiple myeloma is multifactorial. The most common cause is primary amyloidosis with infiltration of the nerves.667 Others may be due to the metabolic or toxic effects of the systemic consequences of multiple myeloma or amyloidosis (e.g., renal failure) Electrophysiologic Findings. Nerve conduction studies reveal low-amplitude or absent SNAPs with normal or only mildly abnormal distal latencies and conduction velocities.295,667,1380

Figure 23-9. Lymphoma. Sural nerve biopsy demonstrates marked lymphomatous infiltration of endoneurium. (Paraffin section, H&E stain).

Likewise, CMAP amplitudes are reduced in patients with weakness. The lower limbs have more profound changes than the upper limbs. The needle EMG examination demonstrates positive sharp waves and fibrillation potentials in the distal limb muscles. Recruitment of long-duration, large-amplitude polyphasic MUAPs may be reduced in the motor and sensorimotor forms of the disease but not in pure sensory neuropathy. Treatment. The treatment of the underlying multiple myeloma usually does not affect the course of the neuropathy.
Osteosclerotic Myeloma (POEMS Syndrome) Clinical Features. Osteosclerotic myeloma occurs in less than 3% of patients with myeloma. However, unlike multiple myeloma, polyneuropathy is present in almost one-half of cases of osteosclerotic myeloma.670 Systemic manifestations are common and include hepatosplenomegaly, cutaneous pigmentation, hypertrichosis, edema, ascitis, pleural effusion, leukonychia, finger clubbing, hypothyroidism, gynecomastia, testicular atrophy with impotence in men, and ammenorhea in women. This complex constitutes the Crow-Fukase or POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) (Table 23-7).69,702,749, 934,992,1355 Patients may display all or none of these features. Some patients can have POEMS syndrome without osteosclerotic myeloma. Other patients usually have Castlemans disease (angiofollicular lymphadenopathy), extramedullary plasmacytomas, or a solitary lytic plasmacytoma. In still others, no tumor is ever detected. The neuropathy manifests as tingling, numbness, and weakness of the distal lower limbs, which gradually progresses proximally in the lower limbs and upper limbs like CIDP. These alterations are bilateral and symmetric. The sensory modalities mediated by large fibers are most affected, with decreased but relative sparing of pain and temperature sensation. The cranial nerves and respiratory muscles are usually spared but can be affected. The peripheral neuropathy is usually present for several years before the correct diagnosis is established. Laboratory Features. Most patients have a IgG or IgA lambda-chain monoclonal gammopathy.702 In up to 20% of patients, the monoclonal protein is demonstrated in the urine but not in serum. In addition, various cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor-, and vascular endothelial growth factor, are elevated in the serum of patients

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with POEMS syndrome.1388 CSF protein levels are often elevated, as in CIDP.702 Skeletal survey reveals characteristic sclerotic (two-thirds of cases) or mixed sclerotic and lytic bony lesions (one-third of cases), usually in the vertebral bodies, pelvis, or ribs.702 In 50% of cases, these skeletal lesions, which represent focal plasmacytomas, are multiple. Histopathology. Sural nerve biopsy demonstrates a combination of segmental demyelination and Wallerian degeneration.992 The number of myelinated fibers is reduced, with a shift of fiber sizes toward the smaller end of the spectrum, and few inflammatory cells are noted. Pathogenesis. The pathogenesis of POEMS syndrome is not clear, but an autoimmune mechanism is likely. Immunoglobulin deposition similar to that seen in IgM-MGUS neuropathy has not been demonstrated in patients with POEMS syndrome. Electrophysiologic Findings. The electrodiagnostic medicine examination is consistent with a demyelinating or mixed axonal and demyelinative sensorimotor peripheral neuropathy.295,323,326,667,670,992 Sensory studies reveal absent or markedly reduced SNAP amplitudes with mild to moderate prolongation of the peak latencies and similar reductions in conduction velocity. Motor conduction studies demonstrate variable reductions in velocity, with some patients approaching 5060% of the lower limits of normal. The CMAP amplitudes are markedly reduced or absent in the lower limbs and mildly to moderately reduced in the upper limbs. Distal motor latencies are normal to increased. Needle EMG examination can demonstrate fibrillation potentials and positive sharp waves with reduced recruitment of MUAPs of long duration and increased amplitude. These findings are worse in lower than upper limbs and more pronounced in distal than proximal muscles. When patients are examined early in the course of the disease, only a mild generalized peripheral neuropathy may be present, with few needle EMG abnormalities. As the disease progresses, the above-noted abnormalities become manifest. Treatment. The neuropathy may respond to radiation, surgical excision of the isolated plasmacytoma, or chemotherapy. The neuropathy also may improve with the usual treatment given to patients with idiopathic CIDP (e.g., corticosteroids). In one series of 38 patients, almost 50% reported that the neuropathy responded to radiation and prednisone, with or without some other form of chemotherapy. However, the neuropathy and plasmacytoma can recur even in patients with an initial positive response to treatment.
Castlemans Disease (Angiofollicular Lymph Node Hyperplasia) Castlemans disease (angiofollicular lymph node hyperplasia) is a lymphoproliferative disorder characterized by lymphoid hyperplasia associated with capillary proliferation.181,323 Castlemans disease may be associated with POEMS syndrome (absence of the osteosclerotic lesions). The angiofollicular lymph node hyperplasia is characterized by marked vascular proliferation, which may be related to increases in serum cytokine levels and vascular endothelial growth factor.1,388 Waldenstrms Macroglobulinemia Waldenstrms macroglobulinemia is an uncommon disorder responsible for about 2% of cases of monoclonal gammopathy.481,613,702,1073,1363 The disorder is caused by a malignant proliferation of lymphoplasmacytoid cells, which produce an IgM monoclonal protein, usually with a light chain. Waldenstrms macroglobulinemia most commonly occurs in men aged 5070

years. The disease is characterized clinically by insidious onset of progressive fatigue, weight loss, lymphadenopathy, hemorrhagic diathesis (especially nosebleeds), anemia, and weakness. Hepatomegaly and splenomegaly are commonly found on physical examination. Approximately 5% of patients with Waldenstrms macroglobulinemia develop a symmetric sensory or sensorimotor peripheral neuropathy, which is similar clinically, electrophysiologically, and histologically to IgMMGUS neuropathies. Patients initially complain of numbness and paresthesias that begin in the feet, progress proximally in the lower limbs, and also affect the hands. Progressive difficulty in ambulating independently may occur, along with reduced fine motor coordination of the hands. Occasionally, a mononeuropathy multiplex pattern of involvement is seen. Laboratory Findings. Diagnosis requires demonstration of an IgM monoclonal protein in a concentration greater than 3 gm/L. Over 80% of the monoclonal proteins are associated with a light chain. The disorder is distinguished from IgMmyeloma by the absence of lytic bone lesions and hypercalcemia and by the presence of hepatosplenomegaly and lymphadenopathy. Antibodies directed against MAG can be detected in the serum in as many as 38% of patients.702,964 Histopathology. Nerve biopsies reveal findings similar to IgM-MGUS neuropathies with prominent demyelination and immunoglobulin deposition on the outer myelin membranes and occasionally in the periaxonal space, but not on the compact myelin. Pathogenesis. The mechanism of the neuropathy is unknown. As with IgM-MGUS, the neuropathy may be related to anti-MAG antibodies, although a causal relationship has not been established. Some neuropathies are caused by secondary amyloidosis or nerve fiber ischemia related to serum hyperviscosity. Electrophysiologic Findings. Nerve conduction studies most commonly reveal a demyelinating sensorimotor polyneuropathy indistinguishable from IgM-MGUS neuropathy. However, some patients have features more consistent with an axonal sensorimotor neuropathy.481,613,702,964,1073,1363 Needle EMG examination consistently reveals fibrillation potentials and positive sharp waves as well as reduced numbers of MUAPs firing at high rates during a minimal contraction. These findings are prominent in the distal muscles of the upper and lower limbs; less dramatic changes are noted in proximal muscle examination. Treatment. Some patients reportedly benefit form corticosteroids, chlorambucil, or plasma exchange.964 However, prospective, blinded, controlled trials have not been performed.

ACQUIRED AMYLOIDOSIS
Amyloidosis is a relatively nonspecific name for a heterogeneous collection of various disorders, all with amyloid deposition in different organs.575,743,750,1141 Classification of amyloidosis is based on the hereditary or acquired nature of the disease and the identification of the major protein constituent of the accumulating amyloid. Familial amyloidosis is caused by mutations in the genes for transthyretin, apolipoprotein A-1, or gelsolin. Familial amyloidosis is discussed in Chapter 22. Secondary amyloidosis (AA) is seen in patients with rheumatoid arthritis and other chronic inflammatory diseases and is associated with the accumulation of protein A. Peripheral neuropathy is uncommon in secondary amyloidosis. Primary amyloidosis (AL amyloidosis) is the designation given when the amyloid is composed of light chains; hence the term AL amyloidosis. Primary amyloidosis can occur in the setting of multiple

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myeloma, Waldenstrms macroglobulinemia, lymphoma, other plasmacytomas or lymphoproliferative disorders, or without any other identifiable disease. Amyloid is a proteinaceous substance composed of nonbranching fibrils, approximately 1020 nanometers in diameter, with a -pleated sheet structure. The fibrils are not soluble in aqueous solutions and are quite resistant to proteolytic decomposition. Amyloid eventually damages the various organs and peripheral tissues in which it is deposited. The arrangement of amyloid fibrils results in the characteristic apple-green birefringence when they are stained with Congo red and observed under conditions of polarized light. Metachromasia is seen when they are stained with methyl violet or crystal violet. The appearance of the Congo red or metachromatic staining does not distinguish among the various subtypes of amyloidosis. Immunohistochemistry using antibodies directed against light chains, protein A, gelsolin, and transthyretin are required to distinguish histologically among the various forms.
Primary Amyloidosis Clinical Features. Primary (AL) amyloidosis is a systemic disorder that typically affects men after the sixth decade of life.344,666 This later age of onset is helpful in distinguishing between AL and familial amyloidosis. Patients with AL amyloidosis may present with symptoms attributable to the major organ systems preferentially affected. Organs that commonly are rendered dysfunctional include the kidney (nephrotic syndrome), heart (congestive heart failure), skin, lungs, gastrointestinal tract (nausea, constipation, diarrhea, pain), and peripheral nervous system. Patients with peripheral nervous system involvement commonly complain of weakness, fatigue, and weight loss. The general physical examination can demonstrate limb edema, hoarse voice (amyloid deposit in vocal cords), hepatomegaly, and macroglossia. Peripheral neuropathy occurs in 1530% of patients with AL amyloidosis and may be the presenting manifestation in onesixth of cases.128,666,702,745,750 Initially small-fiber modalities are affected, resulting in painful dysesthesias along with diminished pain and temperature sensation. The neuropathy is slowly progressive, and eventually symmetric weakness develops, beginning in the distal lower limbs and accompanied by large-fiber, discriminatory sensory loss. Most patients develop autonomic involvement with postural hypertension, syncope, impotence, gastrointestinal disturbance, impaired sweating, and loss of bladder control. Carpal tunnel syndrome occurs in 25% of patients and may be the presenting manifestation.750 Enlarged peripheral nerves are a rare finding. Although the peripheral nerve symptoms are annoying, renal or cardiac failure is more serious and has lethal consequences. The clinical and electrodiagnostic findings are essentially the same in patients with primary amyloidosis and other lymphoproliferative disorders.666 Laboratory Features. The amyloid is composed of the complete or variable portion of the monoclonal light chain. Lambda () is more common than light chain (2:1) in AL amyloidosis, whereas in multiple myeloma light chains are more common.750 Histopathology. Nerve biopsies may reveal amyloid deposition in either a globular or diffuse pattern within epineurial and endoneurial connected tissue and blood vessel walls.745,750 Immunohistochemistry is helpful in demonstrating that the amyloid is composed of or, less frequently , light chains. Active axonal degeneration and severe loss of small myelinated and unmyelinated fibers are observed. Degeneration of the large

myelinated nerve fibers is less pronounced but obvious. Cranial nerves also may demonstrate significant loss of axons, with amyloid deposition the most likely cause. Amyloid deposition also can be demonstrated in the sympathetic and dorsal root ganglia. Electrophysiologic Findings. Despite the various different types of amyloidosis, similar histopathologic alterations form the foundation for the rather common electrodiagnostic medicine findings.27,348,666,1299 In patients with carpal tunnel syndrome, the electrophysiologic findings are the same as those anticipated for preferential slowing of median nerve conduction across the carpal tunnel region. The generalized sensorimotor peripheral neuropathy in all forms of amyloidosis demonstrates variable degrees of SNAP abnormalities. The SNAP amplitudes are diminished or absent. When obtainable, the distal sensory latencies are normal or only mildly prolonged, and conduction velocities are similarly normal or mildly reduced. In general, the lower limbs tend to be more severely affected than the upper limbs; in long-standing and severe disease, however, all sensory potentials may be absent. Motor nerve conduction velocities are in low normal range or slightly reduced. The distal motor latencies are normal or only moderately prolonged in the upper limbs and usually prolonged in the lower limbs. CMAP amplitudes are normal or only mildly reduced during early disease and not as severely affected as the SNAP. This finding is understandable when one considers that collateral sprouting maintains the CMAP amplitude until it can no longer compensate for lost axons, whereas the sensory system does not have this capability to a significant degree. Needle EMG usually reveals significant degrees of positive sharp waves and fibrillation potentials in the distal muscles of the lower limbs. Such findings usually are not observed in the upper limbs until late in the disease process. Reduced recruitment is noted in affected muscles. Motor unit remodeling results in the eventual demonstration of long-duration, high-amplitude, polyphasic potentials. Fasciculation potentials also may be observed in upper and lower limb muscles. Single-fiber EMG examination also demonstrates findings consistent with denervation and subsequent motor unit remodeling (i.e., elevated jitter, blocking, and fiber density). Treatment. The prognosis of patients with primary amyloidosis is poor; the median survival is 2 years.750 Death generally results from progressive congestive heart failure or renal failure. Chemotherapy with melphalan, prednisone, or colchicine, all of which reduce the concentration of monoclonal proteins, generally has been unsatisfactory.128,750

NEUROPATHIES ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE

Clinical Features. MGUS neuropathy is heterogeneic in its clinical, laboratory, and electrophysiologic features.702,746748,768 The neuropathies can be either demyelinating or axonal. As discussed in the CIDP section, neuropathies associated with an IgM monoclonal protein are typically demyelinating, whereas IgG and IgA monoclonal gammopathies may be axonal or demyelinating in nature. Patients with a demyelinating neuropathy can present with typical features of CIDP.152,661,671,672,702,969,972,1064,1168,1168a,1216,1217, 1218,1234,1235 Patients usually describe numbness and tingling in both upper and lower limbs, beginning in the distal regions and progressing proximally. Significant reductions in sensation conveyed

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by large myelinated fibers are noted, along with a reduction in the ability to perceive pain and temperature. A positive Romberg sign may be present. Weakness also can develop but usually is restricted to the distal limbs in IgM-MGUS neuropathies. Patients with IgG-MGUS and IgA-MGUS neuropathies are more likely to have symmetrical proximal and distal weakness typical of idiopathic CIDP. Deep tendon reflexes are reduced or absent throughout. Patients with an axonal neuropathy present with distal sensory loss in a length-dependent fashion. Clinical, laboratory, histopathology, and electrophysiologic features are indistinguishable from idiopathic sensory or sensorimotor polyneuropathies. The pathogenic relationship of the monoclonal protein to the neuropathy is not clear. Laboratory Features. At least 50% of the patients with IgMMGUS neuropathy have antibodies directed against myelin-associated glycoprotein (MAG).661,748,768,1064,1256 Elevated CSF levels are common in patients with a demyelinating neuropathy. Histopathology. Nerve biopsy demonstrates a reduction in the myelinated nerve fiber population with relative sparing of unmyelinated fibers.702,748,947,1234 The remaining myelinated fibers are usually of small fiber caliber. A combination of segmental demyelination and remyelination as well as axonal loss is found. In some patients, demyelination predominates, whereas in others axonal loss may be somewhat more significant. In patients with IgM-MGUS, immunohistochemistry reveals immunoglobulin deposition on the outer myelin membranes and occasionally in the periaxonal space but not on compact myelin.748,885,1256,1361 Deposition of complement (C1q, C3d, C5, and C5b-9) along the myelin sheath also has been demonstrated,911 although in some patients the presence of C5b9 deposits cannot be confirmed.699 Ultrastructurally, the myelin sheaths appear to be separated and IgM deposits can be demonstrated in zones of myelin splitting. Pathogenesis. As described earlier, IgM-MGUS is usually associated with a demyelinating neuropathy. Endoneurial injection or passive transfer of serum from patients with IgM antiMAG antibodies into animals leads to conduction block and demyelination. However, response to plasmapheresis and other immunotherapies is less satisfactory in this IgM-MGUS subgroup than in IgG/IgA demyelinating neuropathies, in which a causal link is even less well established.360 Electrophysiologic Findings. The electrophysiologic findings depend on the pathogenic basis of the neuropathy. As previously noted, IgG and IgA MGUS neuropathies can be either axonal or demyelinating. The IgM-MGUS neuropathies are typically demyelinating. When axonal loss predominates, SNAPs are reduced in amplitude or absent. CMAP amplitudes can be normal or reduced, but distal latencies and conduction velocities are normal or only mildly affected. In demyelinating MGUS neuropathies, the SNAP amplitudes are reduced or absent in most patients.275,327,329,668,942,969,972 Latencies are usually prolonged; hence conduction velocities are variably reduced. Motor nerve conduction studies reveal markedly prolonged distal latencies with moderate slowing of conduction velocities.152,661,669,942,969,972,1089,1168,1168a,1234,1235 Lower limb nerves are usually considerably more involved than upper limb nerves. Distal accentuation of demyelination and thus slowing of conductions are reflected by the lower terminal latency index (TLI) in patients with IgM-MGUS neuropathy. CMAP amplitudes are at least minimally reduced and often considerably reduced. F-wave latencies are characteristically prolonged and sometimes hard to elicit with every supramaximal stimulus.

Needle EMG quite commonly reveals positive sharp waves and fibrillation potentials in the hand and foot intrinsic muscles, with variable degrees of abnormal spontaneous activity in more proximal muscles.152,275,329,669,942,1234,1235 The location of the abnormality obviously depends on the severity of disease. MUAPs suggest extensive motor unit remodeling, with large-amplitude, long-duration potentials predominating in distal muscles and variable degrees of changes in more proximal muscles. Treatment. Patients with MGUS neuropathy who fulfill clinical and electrophysiologic criteria for CIDP can improve with immunotherapy (discussed in greater detail in the CIDP section). The demyelinating sensorimotor polyneuropathies associated with IgG-MGUS and IgA-MGUS are more amenable to treatment than the IgM-MGUS neuropathies.

NEUROPATHY ASSOCIATED WITH BONE MARROW TRANSPLANTATION AND GRAFT-VS-HOST DISEASE

Neuropathies can complicate bone marrow transplantation (BMT) secondary to the toxic effects of chemotherapy, immunosuppressive agents, radiation, or infection and perhaps to an autoimmune response directed against the peripheral nerves.21,22,24 Cranial and peripheral neuropathies1425 are most frequently related to herpes zoster infection or previous chemotherapy.293,1425 Neuropathy may be due to hemorrhage within the nerve or plexus. Other potential causes of neuropathy include carcinomatous or infectious meningitis with infiltration of nerves, toxicity from immunosuppressive medications, malnutrition, and sepsis with multiorgan failure in critically ill patients. Another important cause of peripheral neuropathy in patients with BMT is graft-versus-host disease (GVHD).21 Chronic GVHD has features associated with a variety of autoimmune disorders, and an immune-mediated response may be directed against peripheral nerves. Patients can develop a variety of cranial neuropathies, including loss of olfactory and gustatory sensation,500 sensorimotor polyneuropathy,488 multiple mononeuropathies,1425 and severe generalized peripheral neuropathies resembling GBS79,533,931,1038 or CIDP21 have been well described. Electrophysiologic studies may be consistent with a primary axonal, demyelinating, or mixed pathogenic process. Some cases of GBS have been attributed to chemotherapy, CMV, or Campylobacter jejuni infections and have improved with plasma exchange79,488 or IVIG.533 In some patients, the neuropathy responds to increased immunosuppressive therapy and resolution of GVHD.21

TOXIC NEUROPATHIES
CHEMOTHERAPY
The commonly used anticancer drugs that can cause neuropathy fall mainly into three groups: platinum agents (cisplatin), vinca alkaloids (vincristine), and taxanes (paclitaxel, docetaxel) (Table 23-11).24 The clinical manifestations of neuropathy are somewhat different for various agents. When symptoms first begin, nerve conduction studies are often normal. With further doses, abnormalities eventually occur but again may differ with the various chemotherapy drugs. These agents generally produce neuropathy in a dose-dependent relationship; the higher the dose and the longer the time of exposure, the more likely a neuropathy will occur. Age alone is probably not a major factor that predisposes patients to develop

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Table 23-11. Toxic Neuropathies Caused By Chemotherapy Drug Mechanism of Neurotoxicity Clinical Features Symmetric, S-M, large/ small fiber PN Autonomic symptoms common Infrequent cranial neuropathies Predominant large-fiber sensory neuropathy Sensory ataxia Nerve Histopathology Axonal degeneration of myelinated and unmyelinated fibers Regenerating clusters Minimal segmental demyelination Loss of large > small myelinated and unmyelinated fibers Axonal degeneration with small clusters of regenerating fibers Secondary segmental demyelination Loss of large > small myelinated and unmyelinated fibers Axonal degeneration with small clusters of regenerating fibers Secondary segmental demyelination None described EMG/NCS Axonal sensorimotor PN Distal denervation on EMG Abnormal QST, particularly vibratory perception

Vinca alkaloids Interfere with axonal microvincristine, vintubule assembly blastine, vindesine, Impairs axonal transport vinorelbine)

Cisplatin

Preferential damage to dorsal root ganglia ? Binds to and cross-links DNA ? Inhibits protein synthesis ? Impairs axonal transport

Low-amplitude or unobtainable SNAPs with normal CMAPs and EMG Abnormal QST, particularly vibratory perception

Taxanes (paclitaxel, docetaxel)

Promotes axonal microtubule assembly Interferes with axonal transport

Symmetric, predominantly sensory PN Large-fiber modalities affected more than small-fiber

Axonal sensorimotor PN Distal denervation on EMG Abnormal QST, particularly vibratory perception

Suramin Axonal PN

Demyelinating PN

Unknown ? Inhibition of neurotrophic growth factor binding ? Neuronal lysosomal storage Unknown ? Immunomodulating effects

Symmetric, lengthdependent, sensorypredominant PN Subacute S-M PN with diffuse proximal and distal weakness Areflexia Increased CSF protein

Abnormalities consistent with axonal S-M PN

Loss of large and small myeFeatures suggestive of an linated fibers with primary acquired demyelinating demyelination and secondary sensorimotor PN (e.g., axonal degeneration slow CVs, prolonged distal Occasional epi- and endoneulatencies and F-wave rial inflammatory cell latencies, conduction infiltrates block, temporal dispersion) Loss of myelinated nerve fibers Axonal degeneration Segmental demyelination No inflammation None described Axonal, demyelinating, or mixed S-M PN Denervation on EMG

Ara-C

Unknown ? Selective Schwann cell toxicity ? Immunomodulating effects Unknown ? Selective dosral root ganglia toxicity

GBS-like syndrome Pure sensory neuropathy Brachial plexopathy

Etoposide

Length-dependent, sensory predominant PN Autonomic neuropathy

Abnormalities consistent with axonal S-M PN

S-M = sensorimotor, PN = polyneuropathy, EMG = electromyography, NCS = nerve conduction studies, QST = quantitative sensory testing, GBS = Guillain-Barr syndrome From Amato AA, Collins MP: Neuropathies associated with malignancy. Semin Neurol 1998;18:125144, with permission.

a neuropathy secondary to chemotherapy. Neurotoxicity is more common and severe in patients with a preexisting neuropathy (e.g., Charcot-Marie-Tooth disease, diabetic neuropathy) and patients taking other potentially neurotoxic drugs (e.g., nitrofurantoin, isoniazid, disulfiram, pyridoxine). The mechanism by which degeneration of the ganglion cells or axons occurs is different for various agents. The pathologic process in chemotherapy-induced neuropathies is either distal axonopathy due to axonal degeneration or ganglionopathy.

It is often a difficult to decide whether to stop chemotherapy drugs in the setting of neuropathy if the tumor is responding to therapy. Occasionally, a dose reduction can ameliorate some of the neuropathy symptoms or stop them from progressing. In general, withdrawal leads to some improvement of the neuropathy. However, complete resolution of symptoms and signs is more likely if the drug is stopped in the early stages of the peripheral neuropathy. After significant cumulative doses, some symptoms and signs may persist, especially mild distal sensory

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loss and hypo- or areflexia. The neuropathy also may continue to progress for several weeks or even months after discontinuation of the offending toxic agent because of the so-called coasting-effect. Although the drug may be eliminated from the blood stream, its toxic biologic effects on the peripheral nervous system can continue. Nerve growth factor and other neurotrophins may be beneficial in the future for preventing or treating chemotherapy-induced neuropathies.24
Cisplatin Clinical Features. Cisplatin is used widely for the treatment of ovarian, testicular, and bladder cancer. Cisplatin produces a predominantly sensory neuronopathy (ganglionopathy) at cumulative doses of 225501 mg/m2.24,48,67,187,503,529,724,808,912,913,1112,1144,1304,1383 Large-fiber modalities are preferentially affected, resulting in paresthesia, hypesthesia, diminished deep tendon reflexes, loss of vibratory perception and proprioception with gait ataxia, and pseudoathetoid movements. Deep tendon reflexes are reduced or diminished throughout. Of interest, as many as 40% of patients can develop Lhermittes sign, perhaps due to demyelination and edema of the posterior columns. Weakness occurs in only 2% of patients.187 The neuropathy can appear as late as 8 weeks after the drug has been discontinued and continue to progress up to 6 months after discontinuation.24 Histopathology. Cisplatin given to rats produces changes in the dorsal root ganglion and axonal degeneration on both central and peripheral nerve processes.808 Sural nerve biopsies reveal a predominant loss of large myelinated nerve fibers.67,503,724,1112,1304 Axonal degeneration, segmental demyelination, and regenerating axonal sprouts also may be evident. Pathogenesis. Cisplatin covalently binds DNA, creating interstrand and intrastrand cross-links. Pathologic and electrophysiologic studies suggest that neuronal cell bodies in the dorsal root ganglion are preferentially affected. Binding of the drug to neuronal DNA may inhibit transcription of important proteins and impair axonal transport.24 Electrophysiologic Findings. Electrophysiologic studies reveal low-amplitude or absent sensory nerve action potentials with normal or only slightly prolonged distal latencies or slow sensory conduction velocities.290,529,724,808,912,1096,1105,1112,1304 Quantitative sensory testing has demonstrated that vibratory perception is a sensitive indicator of early cisplatin-induced neuropathy. Motor nerve conduction studies and needle EMG are usually normal.373 Vincristine Clinical Features. Vincristine, the most commonly used vinca alkaloid, produces a sensorimotor and autonomic neuropathy.24,136,179,513,592,775,869,1014,1155,1167 The earliest symptoms are paresthesias and numbness, which at times occur in the fingers before the toes. These symptoms have been reported as early as 2 weeks after a single dose of 2 mg/m2. The loss of ankle reflexes commonly precedes the subjective loss of sensation. With further dose accumulation, distal weakness of the hands and feet occurs in 2535% of patients.592,1167 Cranial neuropathies, including optic neuropathy, oculomotor palsies, facial weakness, hearing loss, and laryngeal paralysis, are rare. Autonomic nerves can become involved, leading to constipation, urinary retention, impotence, and orthostatic hypotension. Histopathology. Sural nerve biopsies reveal axonal degeneration and loss of myelinated and unmyelinated nerve fibers.136,869 Scattered clusters of regenerating axonal sprouts may be seen.

Pathogenesis. Vinca alkaloids inhibit microtubule formation by binding to tubulin. The impairment in the microtubules interferes with axoplasmic transport and subsequently causes cytoskeletal disarray and axonal degeneration.496,1155 Electrophysiologic Findings. Sensory and motor nerve conduction studies reveal diminished amplitudes or absent responses.869,1014,1105,1167 Normal or only mildly prolonged distal latencies and slow conduction velocities are evident. Stopping the drug results in improvement of SNAP and CMAP amplitudes, but they do not commonly return to pretreatment levels. Fibrillation potentials and positive sharp waves reflecting active denervation can be seen in distal muscles. The MUAP recruitment is reduced in the distal limb muscles. Over time, motor unit remodeling leads to large-amplitude, long-duration MUAPs.
Vinorelbine Clinical Features. Vinorelbine is a semisynthetic vinca alkaloid recently approved for treatment of various types of cancer. It is less neurotoxic than vincristine, but a dose-related peripheral neuropathy has been reported in 2050% of patients.24,462,1004,1009 However, the neuropathy is severe in only 1% of patients. The most common symptoms are distal sensory loss and paresthesia. Weakness can develop after 36 months of treatment. As with vincristine, autonomic neuropathy is less frequent. Deep tendon reflexes are reduced or absent at the ankles in most patients after 12 cycles of chemotherapy.1009 Histopathology. Nerve pathology has not been reported. Pathogenesis. The pathogenesis is presumably similar to that of vincristine-induced neuropathy. Electrophysiologic Findings. A prospective study using serial nerve conduction studies demonstrated a dose-dependent reduction of sensory and compound muscle action potentials.1009 Distal latencies and conduction velocities were normal. The amplitudes of the sensory and compound muscle action potentials improved after discontinuation of vinorelbine. Etoposide (VP16) Clinical Features. Etoposide, or VP16, is a semisynthetic derivative of podophyllotoxin and is used to treat patients with lymphoma, leukemia, SCLC, and testicular cancer. A moderate to severe distal, axonal, predominantly sensory polyneuropathy occurs in 410% of patients.146,390,611 Severe autonomic dysfunction can result in orthostatic hypotension and gastroparesis. The neuropathy gradually improves over several weeks or months after discontinuation. Histopathology. In mice, VP16 causes degeneration of cell bodies within the dorsal root ganglion. However, histopathology has not been described in humans with the neuropathy. Pathogenesis. Presumably, VP16 also produces its neurotoxic effects by inhibiting microtubule function, much like vincristrine. Electrophysiologic Findings. Detailed descriptions are lacking, but nerve conduction studies and needle EMG show changes consistent with an axonal sensorimotor polyneuropathy.611 Paclitaxel (Taxol) Clinical Features. Paclitaxel is used for treatment of cancer of the ovaries, breasts, lungs, bladder, and head and neck as well as lymphoma. It produces a dose-dependent, predominantly sensory neuropathy.24,206,422,802,1066,1136,1156,1328,1339 A subclinical or mild neuropathy develops in up to 85% of patients after 37 cycles at doses of 135200 mg/m2. A severe neuropathy occurs in 2% of patients at this lower dose range. However, in patients treated with doses between 250350 mg/m2, neuropathy develops after the first or second cyclesometimes within 24 hours

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of the initial infusion. As many as 70% of patients have severe neuropathy after high doses.206,1066,1136 Cumulative doses above 1500 mg/m2, preexisting neuropathy, and prior or concurrent exposure to neurotoxic agents are additional risk factors for developing a severe neuropathy.1136 The neuropathy manifests with numbness, paresthesias, and dysesthesias that begin in the feet and later involve the arms and face.206,422,802,1066,1136,1156,1328,1339 Symptoms can resolve before the next scheduled dose, but with further therapy, the sensory symptoms persist. Vibratory perception is impaired more than pain and temperature sensation, and some patients develop sensory ataxia. Distal motor weakness is uncommon, even with large cumulative doses, but weakness can occur in patients with an underlying neuropathy or other risk factors (e.g., diabetic neuropathy). Autonomic neuropathy is uncommon, unless these risk factors are present. The neuropathy can continue to progress for 1 month or more after the drug has been discontinued because of the coasting effect.1328 Histopathology. There are only a few pathologic descriptions of paclitaxel-induced neuropathy.1156,1328 Sural nerve biopsies reveal a greater loss of large- than small-diameter myelinated nerve fibers. Axonal degeneration with secondary demyelination and remyelination may be seen, but regenerating axonal sprouts are uncommon. EM has demonstrated accumulation of tubular and membranous structures within the axons.1156 Pathogenesis. Paclitaxel may have a toxic effect on the neuronal cell body, axon, or both.24 In contrast to vinca alkaloids, which disassemble microtubules, the taxanes promote microtubule assembly by increasing tubulin polymerization. This process leads to aggregation and accumulation of abnormal bundles of microtubules in dorsal root ganglia, axons, and Schwann cells.1137 Axoplasmic transport may be disrupted by the mechanical obstruction caused by the abnormal accumulation of microtubules. Electrophysiologic Findings. Paclitaxel produces both sensory and motor nerve conduction abnormalities and denervation potentials in distal muscles, reflecting an axonal neuropathy.206,422,802,1066,1136,1156,1328,1339 Reduction in amplitudes of the sensory nerve and compound muscle action potentials correlate with the cumulative dose. Distal latencies and conduction velocities are usually normal, although two cases with demyelinating features have been reported.802,1328 Quantitative sensory testing reveals impairment of vibratory perception more often than abnormal thermal thresholds.206,422,1339 The electrophysiologic motor involvement is more likely to be subclinical and occur later in the course of the neuropathy. Needle EMG may show fibrillation potentials in the distal limbs.802,1156
Docetaxel (Taxotere) Clinical Features. Docetaxel is a semisynthetic analog of paclitaxel, which is also used in the treatment of various malignancies. As with paclitaxel, a dose-dependent, predominantly sensory, peripheral neuropathy develops in 1150% of patients, although severe symptoms develop in only 4% of patients.430,581,951 Large-fiber modalities are more commonly affected, with patients complaining of distal numbness. Some patients describe pain in the hands and feet and also have Lhermittes sign. Mild proximal and distal weakness can be seen in 519% of patients. Deep tendon reflexes are absent at the ankles in one-half of patients. The neuropathy may continue to worsen for several months after discontinuation of the drug. However, most patients improve 12 months after cessation of chemotherapy.

Histopathology. Sensory nerve biopsy in one patient revealed a loss of large myelinated fibers with scattered fibers undergoing axonal degeneration.951 Pathogenesis. The pathogenic mechanism is presumably similar to that of paclitaxel (see above). Electrophysiologic Findings. Electrophysiologic studies have been reported in detail in only a few patients.430,951 Motor nerve conduction studies reveal diminished amplitudes with mild slowing of conduction velocities. Sensory nerve conduction studies demonstrate unobtainable or very low-amplitude potentials. Fibrillation potentials and large-amplitude, long-duration polyphasic MUAPs showing decreased recruitment can be appreciated in distal muscles.
Suramin Clinical Features. Suramin, a hexasulfonated naphthylurea, was used initially for treatment of trypanosomiasis and onchcerciasis and more recently for various cancers. Neurotoxicity is the dose-limiting side effect. The reported incidence of peripheral neuropathy ranges from 2590%.24,208,766,1250 Suramin appears to cause two distinct types of neuropathy: (1) a dose-dependent, distal, axonal sensorimotor polyneuropathy and (2) a subacute demyelinating polyradiculoneuropathy. The subacute demyelinating polyradiculoneuropathy is much more severe and is associated with peak plasma concentrations of over 300 g/L, exposure to greater than 200 g/L for more than 25 days per month, or cumulative dose of 40,000 mg/hr/L.24 The distal axonopathy is more common and manifests with distal numbness and paresthesias.24,208,1250 Diminished light touch, pain, and vibratory perception are noticeable on examination. Mild weakness of the distal limbs (e.g., toe extensors) and diminished ankle refelxes can be seen. The neuropathy is reversible with suramin discontinuation. A subacute sensorimotor demyelinating polyradiculoneuropathy develops in 1020% of patients after 15 months of treatment.208,766,1250 Symptoms typically begin with numbness and paresthesias of the distal limbs or face, followed by symmetric weakness (proximal > distal). The weakness progresses over 2212 months. As many as 25% of patients become bedridden and require mechanical ventilation. Patients can continue to deteriorate for 1 month after suramin discontinuation. Deep tendon reflexes are decreased or absent throughout. Recovery occurs over a few months, although some patients have residual numbness and weakness. Plasma exchange has been tried in an uncontrolled fashion with mixed results. Laboratory Features. CSF protein has been elevated in some patients with a subacute demyelinating polyradiculoneuropathy.208,1250 Histopathology. Sural nerve biopsies have been performed in a few patients with the subacute demyelinating polyradiculoneuropathy.208,766,1250 Biopsies demonstrated loss of large and small myelinated nerve fibers, demyelination and remyelination, and secondary axonal degeneration. Epineurial and endoneurial mononuclear inflammatory infiltrates were present in two biopsies.208 Pathogenesis. The mechanism of neurotoxicity is unknown. Suramin may inhibit the interaction of neurotrophic factors with peripheral nerve receptors1145,1268 or induce a form of lysosomal storage disease.457 The demyelinating neuropathy may be related to the immunomodulating effects of suramin.271 Electrophysiologic Findings. The more common distal axonopathy is associated with decreased amplitudes of sensory and compound muscle action potentials.24,208,1250 Quantitative

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sensory testing has demonstrated increased vibratory and cooling thresholds.208 Fibrillation potentials and neurogenic MUAPs may be noted in distal muscles with needle EMG. Electrodiagnostic studies in the subacute sensorimotor polyradiculoneuropathy reveal features of demyelination.208,766,1250 Prolonged distal latencies and F-waves, slow conduction velocities, temporal dispersion, and conduction block have been reported. As in the distal axonopathy, quantitative sensory testing shows increased vibratory and cooling thresholds.208 Needle EMG demonstrates decreased recruitment in proximal and distal muscles and increased insertion and spontaneous activity (fibrillation potentials and positive sharp waves) in severe cases.
Cytosine Arabinoside (ARA-C) Clinical Features. Cytosine arabinoside C is an antimetabolite used in the treatment of leukemia and lymphoma. Several types of peripheral neuropathy have been reported with cumulative doses of 6036g/m2. Cases of brachial plexopathy1179 and severe sensorimotor polyneuropathy resembling GBS124,638,949,1003,1038 have been attributed to the drug. These neuropathies may begin hours or weeks after treatment. Laboratory Features. Increased CSF protein has been demonstrated in patients with a severe neuropathy resembling GBS.1003 Histopathology. Sural nerve biopsies may reveal demyelination or axonal degeneration.124,1003,1038 Pathogenesis. The pathophysiologic mechanism for the neuropathies is not well understood. Perhaps, the antimetabolite action of cytosine arabinoside C inhibits proteins important in myelin production or axonal transport. Alternatively, its immunomodulating effects may lead to dysinhibition of autoreactive lymphocytes and an immune attack against the peripheral nerves. Electrophysiologic Findings. Electrodiagnostic studies may be compatible with a primary axonal1038 or an acquired demyelinating sensorimotor polyneuropathy.636 Needle EMG may reveal active denervation changes in distal muscles.124,638 Ifosfamide Ifosfamide is a cyclophosphamide analog. Neuropathy has been reported in patients receiving a total dose of 14 g/m2 or more. 1037 Numbness and painful paresthesias begin in the hands and feet 1014 days after treatment. Symptoms gradually resolve but recur if patients are rechallenged with chemotherapy. Electrodiagnostic and histopathologic data are lacking, but occasional symptom onset in the hands rather than the feet suggests a ganglionopathy.

affected. Cessation of the drug usually results in symptom improvement, but a number of patients continue to have residual deficits. Histopathology. Sural nerve biopsies demonstrate a reduction in the large myelinated fibers with evidence of axonal degeneration and segmental demyelination/remyelination. EM may reveal an accumulation of neurofilaments with axonal swellings. Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Sensory nerve conduction studies demonstrate a mild to moderate reduction in upper limb nerves with significant reduction to complete absence of lower limb SNAPs. The distal sensory latencies and conduction velocities are normal or mildly abnormal. Motor conduction studies reveal normal nerve conduction velocities and distal motor latencies in the upper limbs with borderline abnormal values in the lower limbs. The CMAP amplitudes are typically well preserved throughout. Needle EMG demonstrates increased amplitudes, durations, and polyphasia of MUAPs. A reduction in motor unit recruitment can be seen in weak limb muscles.
Metronidazole Clinical Features. Metronidazole is used in the treatment of various protozoan infections as well as in Crohns disease.137,253,1282 Like misonidazole, metronidazole is a member of the nitroimidazole group, and a few cases have been reported in which patients developed an axonal peripheral neuropathy with primarily sensory symptoms. The major manifestations are hyperalgesia and hypesthesia in a glove-and-stocking distribution. Deep tendon reflexes are well preserved except for a reduction at the ankles. Muscle strength is usually normal throughout. Histopathology. Nerve biopsies demonstrate evidence consistent with axonal loss. Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Nerve conduction studies reveal reduced or absent sural SNAPs with low-amplitude upper limb SNAPs. The distal sensory latencies are usually at the upper limits of normal. Compound muscle action potentials are well preserved, and motor conduction velocities are at the lower end of normal values. Needle EMG findings have not been reported. Chloroquine Clinical Features. Chloroquine is a quinoline derivative used for treating malaria, sarcoidosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis.369,381,843 Chloroquine can cause a toxic myopathy (discussed in Chapter 28). Patients with chloroquine myopathy develop slowly progressive, painless, proximal weakness and atrophy, which are worse in the legs than in the arms. Cardiomyopathy also may occur. Sensation is diminished in some patients secondary to a superimposed neuropathy. Deep tendon reflexes may be diminished particularly at the ankle. The neuromyopathy usually appears in patients taking 500 mg for 1 year or more but has been reported with doses as low as 200 mg/day. The neuromyopathy is reversible after discontinuation of the medication. Laboratory Features. Serum CK levels are usually elevated because of the superimposed myopathy. Histopathology. In addition to vacuolar myopathy, nerve biopsies also demonstrate autophagic vacuoles. Pathogenesis. Chloroquine has amphiphilic properties because it contains both hydrophobic and hydrophilic regions.

OTHER MEDICATIONS
Misonidazole Clinical Features. Misonidazole is a member of the nitroimidazole group of compounds and is used as an adjuvant agent in the treatment of various carcinomas to sensitize neoplastic cells to the effects of radiation therapy.827,882,1040 After approximately 35 weeks of administration (total dose > 18 gm), some patients may begin to complain of painful paresthesias in the feet, followed by similar symptoms in the hands. Ambulation may become impaired by a combination of sensation loss in the feet and pain. A few patients also may demonstrate evidence of a reduction in strength in the distal muscles of the lower limbs. Deep tendon reflexes are preserved, but vibration sensation and pain/temperature discrimination are significantly

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ACQUIRED NEUROPATHIES 1001

These properties account for the ability of the drugs to interact with the anionic phospholipids of cell membranes and organelles. The drug-lipid complexes are resistant to digestion by lysosomal enzymes, thus resulting in the formation of the autophagic vacuoles filled with myeloid debris. Electrophysiologic Findings. Patients with neuropathy demonstrate mild slowing of both motor and sensory nerve conduction velocities associated with a mild to moderate reduction in the amplitudes.381,843 Patients with only the myopathy usually have normal motor and sensory studies.369 EMG reveals an increase in insertional activity with significant amounts of positive sharp waves and fibrillation potentials primarily, but not exclusively, in the proximal limb muscles. Voluntary MUAPs are significantly decreased in amplitude and duration with a predominance of polyphasic MUAPs. Myotonic potentials may be seen despite a lack of clinical myotonia.
Hydroxychloroquine Hydroxychloroquine is structurally similar to chloroquine and also produces a neuromyopathy.381 Weakness and histologic abnormalities are usually not as severe as in chloroquine myopathy. Vacuoles are typically absent on biopsy, but EM usually demonstrates the abnormal accumulation of myeloid and curvilinear bodies. Amiodarone Clinical Features. Amiodarone is an antiarrhythmic medication that causes a neuromyopathy similar to chloroquine.201,425,619,840,1042 Severe proximal and distal weakness, combined with distal sensory loss, affects the legs more than the arms. The drug is known to have a number of adverse effects including tremor, thyroid dysfunction, keratitis, pigmentary skin changes, hepatitis, pulmonary fibrosis, and parotid gland hypertrophy. Peripheral neuropathy usually occurs in patients taking the medication for over 23 years. The initial complaint is reduced sensation and paresthesias in the feet with burning pains and a feeling of coldness. Within several months, difficulty in ambulation may be noted, accompanied by a tendency to fall and cramping in some leg muscles. Physical examination demonstrates a reduction in sensation to all modalities as well as absent deep tendon reflexes, especially at the ankle. Weakness is present in the distal regions of both upper and lower limbs. Histopathology. Muscle biopsies demonstrate autophagic vacuoles with myeloid inclusions. Neurogenic atrophy also can be appreciated, particularly in distal muscles. Sural nerve biopsies demonstrate a combination of segmental demyelination and axonal loss. EM reveals myeloid inclusions in muscle and nerve biopsies. These lipid membrane inclusions in muscle and nerve biopsies have persisted for as long as 2 years after discontinuation of the medication. Pathogenesis. The pathogenesis is presumably similar to other amphiphilic medications (e.g., chloroquine). Electrophysiologic Findings. Nerve conduction studies reveal variable findings among different nerves in the same patient.425,840,881,1042 The sural SNAPs are usually markedly reduced in amplitude or reduced with some degree of nerve conduction slowing. Most patients demonstrate a mild reduction (within the 7080% range of the lower limit of normal) in nerve conduction velocity throughout. Some patients, however, can have motor conduction velocities as low as 1112 m/s in the lower limb. Distal motor latencies are mildly prolonged in some patients or increased by 100% in others. Needle EMG examination usually

detects fibrillation potentials and positive sharp waves in the hand and foot intrinsic muscles with reduced recruitment.
Perhexiline Maleate Clinical Features. Perhexiline maleate has antiarrhythmic properties and was used in the past to treat angina.131,793,1189,1408 Because of its significant side effects, such as liver dysfunction, hypoglycemia, weight loss, and peripheral neuropathy with elevated CSF protein, it is now rarely used. The peripheral neuropathy is a generalized sensorimotor type manifesting with an initial reduction in sensation and paresthesias in the feet. Later weakness becomes apparent in the distal lower limb muscles, and similar sensory disturbances are noted in the hands. With time, significant weakness and muscle wasting are noted in the legs with progressive loss of strength and coordination of the hands. The neuropathy may develop over months to years. Its exact incidence is unknown. Cessation of the drug leads to significant clinical improvement in most patients, provided that profound muscle wasting has not already occurred. Histopathology. Nerve biopsies demonstrate significant segmental demyelination with variable degrees of Wallerian degeneration.391,1157 Osmiophilic inclusions are evident in Schwann cells, fibroblasts, and endothelial cells. Pathogenesis. Perhexiline is an amphiphilic drug, and the mechanism of neuropathy may be similar to other such agents (see above). Electrophysiologic Findings. Nerve conduction studies may demonstrate a reduction in both motor and sensory conduction velocities to less than 6070% of the lower limit of normal, whereas distal latencies may be increased by up to 100% of the upper limit of normal.131,793,1189,1408 The nerves are affected to different degreessome profoundly, others mildly or moderately. The SNAP and CMAP amplitudes are significantly reduced only in patients with long-standing disease of a severe nature. The H-reflex may be of help in demonstrating mild abnormalities of conduction in patients with early disease. Needle EMG reveals fibrillation potentials and positive sharp waves in patients with severe disease as well as reduced recruitment of MUAPs. Alterations of MUAP morphology suggesting motor unit remodeling can be anticipated in the distal limb muscles. Colchicine Clinical Features. Colchicine, which is used primarily to treat patients with gout, inhibits the polymerization of tubulin into microtubules. Of note, colchicine is capable of generating both a significant myopathy and a mild to moderately severe polyneuropathy.734,735,1104 Patients usually present with complaints of inability to climb stairs and arise from a low chair, with some degree of numbness and tingling in the distal lower limbs and occasionally the hands. Physical examination demonstrates significant weakness in the proximal limb muscles with a lesser degree of strength reduction in the distal limb muscles. Sensation to touch and vibration and position sense may be reduced, with some minor loss of pain and, rarely, temperature sensation in the distal limbs. Deep tendon reflexes are reduced particularly at the ankles. Histopathology. Muscle biopsies reveals a vacuolar myopathy, whereas sensory nerves demonstrate axonal degeneration. Pathogenesis. The disruption of the microtubules probably leads to defective intracellular movement or localization of lysosomes, which results in the accumulation of autophagic vacuoles in muscle and nerves.735

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Electrophysiologic Findings. Nerve conduction studies reveal low amplitude SNAPs and CMAPs.715,735,1104 The distal motor and sensory latencies may be normal or slightly prolonged. Likewise, conduction velocities are normal or mildly slow. F-waves can be expected to be significantly prolonged, and H-reflexes may be prolonged or absent. Needle EMG examination demonstrates short-duration, low-amplitude MUAPs in the proximal limb muscles accompanied by positive sharp waves and fibrillation potentials. In the distal muscles of the upper and lower limbs, the same type of abnormal membrane instability can be observed; however, the MUAPs are reduced in number with longer duration and higher amplitude than normal. This combined pattern of electrophysiologic alterations is consistent with a proximal myopathic and distal neurogenic process.
Podophyllin Clinical Features. Podophyllin resin is a topical agent used to treat condylomata acuminata. Systemic toxicity has resulted from topical exposure and oral ingestion.171,225,414,908,1228 Systemic side effects include gastrointestinal paresis, urinary retention, pancytopenia, and liver and renal dysfunction. Podophyllin toxicity can also involve the central and peripheral nervous systems, causing psychosis, altered consciousness, and peripheral neuropathy. The neuropathy is characterized by slowly progressive sensory loss, paresthesias, muscle weakness, and diminished deep tendon reflexes. The distal limbs are affected more than the proximal limbs and the legs more than the arms, as expected in length-dependent axonopathies. Nausea, vomiting, ileus, urinary retention, orthostatic hypotension, and tachycardia may result from involvement of the autonomic nervous system. The neuropathy can progress for a few months even after the medication is stopped. The neuropathy gradually improves after discontinuation of the podophyllin, but improvement can take from several months to more than 1 year. Patients may have residual deficits. Laboratory Features. CSF protein levels can be elevated. Pancytopenia, liver function abnormalities and renal insufficiency also may be noted on routine laboratory work-up. Histopathology. Nerve biopsies demonstrate axonal degeneration. Pathogenesis. Podophyllin binds to microtubules, like colchicine, and probably inhibits axoplasmic flow, leading to axonal degeneration.1039 Electrophysiologic Findings. Sensory nerve conduction studies reveal absent SNAPs or reduced amplitudes.414 The distal latencies and conduction velocities of the SNAPs are normal or only slightly impaired. Motor conduction studies are less affected, but may demonstrate reduced amplitudes. Distal latencies and conduction velocities of the CMAPs are relatively spared. Needle EMG may demonstrate fibrillation potentials and positive sharp waves in distal limb muscles along with decreased recruitment. Thalidomide Clinical Features. Thalidomide is a rarely used immunomodulating agent because of its profound teratogenic effects.439,440,756,1067 It is effective in some dermatologic conditions, such as discoid lupus erythematosus and prurigo nodularis, as well as graft-versus-host disease and leprosy and multiple myeloma.1206 One of its major dose-limiting side effects is peripheral neuropathy, which develops in 10100 % of patients. The neuropathy appears to be dose-dependent and occurs after a total dose of 4050 gm in most patients. Patients complain of

significant pain, burning, and other uncomfortable paresthesias in the feet and hands. Some particularly sensitive patients also experience proximal muscle weakness and atrophy. Loss of sensation is variable, with muscle cramping in the legs. Unfortunately, even after stopping the drug for 46 years, as many as 50% patients continue to have significant symptoms. Physical examination demonstrates an erythematous hue to the palms of the hands as well as increased fragility of the finger and toenails. Vibration and position sense usually are reduced. Muscle weakness may be noted in a proximal distribution with some wasting in severely affected patients. Deep tendon reflexes are usually diminished or absent. Histopathology. Peripheral nerve biopsy reveals axonal degeneration of the large-diameter myelinated fibers with little evidence of demyelination. A few autopsy studies also have documented degeneration of dorsal root ganglion cells. Drug cessation does not lead to a normal fiber profile. Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. The primary abnormality is a reduction or complete absence of SNAPs.439,440,756,1067 When the SNAP is present, the conduction velocity remains relatively well preserved, and SNAP latencies are not significantly affected. The lower limb SNAPs appear to be affected first and more profoundly than those in the upper limbs, although the latter follow the lower limb abnormalities rather closely. Motor nerve conduction studies are expected to reveal normal distal motor latency, conduction velocity, CMAP amplitude, and F-waves. A few patients may demonstrate absent F-waves in the lower limbs. Needle EMG is commonly normal, but a few patients with particularly profound disease reveal a small degree of positive sharp waves and fibrillation potentials in the distal lower limb muscles.
Disulfiram Clinical Features. Disulfiram (Antabuse) is used in the treatment of alcoholism. It is metabolized to carbon disulfide, which is a neurotoxin and can have adverse effects on both the peripheral and central nervous systems.28,93,126,903,909,995,1015 Patients with peripheral neuropathy can display symptoms reflective of axonal loss within 10 days to 18 months of starting the drug. Sensation is reduced primarily in a stocking distribution with later development of significant muscle weakness. Some patients present with bilateral foot drop. Fasciculations also can be observed. It is important to be aware of these neurotoxic effects because the sooner the medication is stopped, the better the prognosis for return of function. Histopathology. Sural nerve biopsy demonstrates a loss of all myelinated fibers with some preference for the large-diameter fibers, although both large and small fibers can be equally affected.28,93,126,909 Axonal degeneration is the predominant feature, but segmental demyelination also may be seen. EM reveals an accumulation of neurofilamentous material within the myelinated and unmyelinated axons, leading to axonal swelling. Pathogenesis. The neuropathy may be secondary to carbon disulfide, a metabolite of disufiram.783 A similar axonal neuropathy characterized by accumulation of neurofilaments occurs with carbon disulfide toxicity. Electrophysiologic Findings. The electrodiagnostic medicine findings are consistent with the histopathologic findings of an axonal neuropathy.28,93,909,995,1015 The SNAPs in the lower limb are usually absent or markedly reduced, whereas those in the upper limbs are reduced in amplitude. The conduction velocities

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are usually mildly reduced, although a few patients with profound disease can have reductions approaching 70% of the lower limit of normal. H-reflexes are either absent or mildly prolonged. The CMAPs are either absent or profoundly reduced in amplitude in the foot muscles. In the upper limbs, the CMAP amplitudes are usually normal or only borderline reduced. Motor nerve conduction studies demonstrate a mild prolongation in the distal motor latencies for the lower limbs with good preservation in the upper limbs. Conduction velocities are moderately reduced in severely affected patients. Needle EMG commonly reveals fibrillation potentials and positive sharp waves in the distal muscles of the lower limbs with significant reductions in recruitment. In chronic cases, motor unit remodeling results in large-amplitude, long-duration MUAPs. All abnormalities improve to varying degrees, with an occasional return to normal for the lower limbs, after cessation of the medication.
Dapsone Clinical Features. Dapsone is used world-wide in the treatment of leprosy and various dermatologic conditions. The most common side effects are anemia and methemoglobinemia, but peripheral neuropathy also may occur.7,522,939,1087,1192,1225,1376 Symptoms of a primarily motor neuropathy manifest within 5 days to as late as 5 years after starting the drug. The primary neurologic manifestation is a progressive weakness that begins in the small muscles of the hands and feet and progresses to more proximal muscles over time. The hip girdle muscles may be preferentially affected in some patients. Roughly 29% of patients note the progression of weakness first in the hands, 24% of patients first describe some form of weakness in the feet, and 41% of patients have initial motor symptoms in both hands and feet. A few patients have mainly a sensory neuropathy with minimal motor involvement. Physical examination demonstrates weakness with accompanying muscle wasting in the distal upper and lower limbs. Reflexes are usually preserved but may be diminished in some patients. Objective tests of sensation are relatively normal except for minor alterations in a few patients. Histopathology. Biopsy of the motor nerve terminal at the extensor brevis muscle has demonstrated axonal atrophy and Wallerian degeneration of the distal motor nerve terminals.1225 Segmental demyelination also is noted. Sural nerve biopsy also can reveal a loss of myelinated nerve fibers. Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Sensory nerve conduction studies usually demonstrate normal or slightly reduced amplitudes.7,522,939,1087,1192 Sensory nerve conduction velocities are normal or only mildly slow. Motor nerve conduction studies demonstrate that the distal motor latencies are prolonged by about 1030% above the upper limit of normal and that conduction velocity is normal or not less than 8090% of the lower limit of normal. The CMAP amplitude is borderline normal or reduced in the upper limb and considerably reduced or absent in the lower limb. F-wave latencies can be moderately prolonged with a number of stimuli resulting in no response. Needle EMG usually demonstrates high degrees of fibrillation potentials and positive sharp waves in association with markedly reduced recruitment, particularly in the distal limb muscles. Occasional fasciculation potentials may be observed. Over time, motor unit remodeling leads to large-amplitude, long-duration MUAPs. The nerve conduction studies usually improve to some degree after medication cessation.

Nitrofurantoin Clinical Features. Nitrofurantoin is used in the treatment of urinary tract infections because of its wide antimicrobial spectrum and ability to concentrate in the urine rather quickly. It has been reported to result in the development of an acute and profound peripheral neuropathy in which patients complain of pain, numbness, tingling, and difficulty in walking as well as manipulating objects with the hands.376,598,814,1306,1438 These symptoms can occur as early as 9 days after treatment initiation, and some patients are rendered completely quadriparetic. Patients who are elderly or have any degree of renal dysfunction are particularly sensitive to nitrofurantoin. Physical examination reveals decrease of all sensory modalities in the distal regions of the upper and lower limbs. Deep tendon reflexes are reduced or absent. Cessation of the drug usually results in recovery, but a complete return to normal may not be achieved. Histopathology. Sural nerve biopsy has demonstrated significant loss of large myelinated fibers with signs of active Wallerian degeneration. An autopsy study has shown degeneration of the spinal roots, with more severe effects on dorsal than ventral roots, and chromatolysis of the anterior horn cells.792 Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Electrodiagnostic medicine evaluation documents absent SNAPs or severely attenuated amplitude and slightly reduced conduction velocity.598,797,1306,1438 Similarly, in patients with weakness present for some time, the CMAP may be unobtainable. In patients with reduced CMAPs, the nerve conduction velocity is reduced by no more than 8090% of the lower limit of normal. Distal sensory and motor latencies may be mildly prolonged. Needle EMG examination typically reveals positive sharp waves and fibrillation potentials with marked reductions in the number of voluntary MUAPs in the distal muscles of the upper and lower limbs. In profound disease, the same findings are noted in the more proximally located limb muscles. Pyridoxine (Vitamin B6) Toxicity Clinical Features. Pyridoxine is an essential water-soluble vitamin that acts as a coenzyme for multiple transamination and decarboxylation reactions within the body.13,14,285,1176 It generally is considered quite safe with a minimum recommended daily allowance of 24 mg in adults. Pyridoxine has become a fad vitamin in that megadoses (600 mg3 or 4 gm/day) is supposed to be beneficial for all types of ailments. Unfortunately, it is not as harmless as once thought, and people can develop a rather significant peripheral neuropathy from consuming as little as 116 mg/day. The primary initial symptoms are difficulty in walking secondary to sensory ataxia. This symptom is especially problematic during eye closure or at night. Some patients note that rapid flexion of the neck results in tingling that emanates from the neck and radiates down the back and into both legs (Lhermittes sign). Physical examination reveals impairment in vibratory perception and proprioception, although all sensory modalities can be reduced. Sensory loss can begin and be more severe in the upper limbs than in the lower limbs. Fine motor control is impaired, particularly in the hands, secondary to sensory loss. Patients also may exhibit a wide-based gait secondary to sensory ataxia. Strength is normal, and deep tendon reflexes are reduced or absent, particularly at the ankles. Plantar responses are flexor.

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Histopathology. In humans, peripheral nerve biopsies reveal axonal loss of all fiber diameters.1023,1176,1432 Animal studies have demonstrated that neural damage is located primarily in the dorsal root ganglion cells with subsequent degeneration of both peripheral and central sensory processes.730,731 Pathogenesis. The pathogenic basis for the neuropathy is not known. Electrophysiologic Findings. Nerve conductions studies reveal absent or significantly reduced SNAP amplitudes.13,14,1083,1176 The sensory nerve conduction velocities are minimally reduced when they can be recorded. The CMAP amplitudes are normal or borderline small; motor conduction velocities and distal latencies are usually spared or only mildly abnormal. Needle EMG demonstrates reduced recruitment in distal muscles with occasional fibrillation potentials and positive sharp waves in some patients.
Isoniazid Clinical Features. Isoniazid (INH) is used for treatment of tuberculosis. One of its most common side effects is peripheral neuropathy.917,975,1177 Typical doses (35 mg/kg/day) are associated with a 2% incidence of neuropathy; neuropathy develops in at least 17% of patients taking in excess of 6 mg/kg/day.1177 The neuropathy is more likely in the elderly and malnourished patients and so-called slow acetylators. It can be prevented by coadministration of pyridoxine, 100 mg/day. The initial symptoms are numbness and tingling in the distal upper and lower limbs, which usually occur after 6 months of treatment with smaller doses but may begin within a few weeks with large doses. If the INH is stopped early, the symptoms resolve after a few days or weeks. However, if the medication is continued, the sensory loss spreads proximally and dysesthesias occur. Furthermore, distal weakness and aching of the calves may develop. Recovery at this stage can take months and may be incomplete. Examination reveals loss of all sensory modalities, distal muscle atrophy and weakness, diminished deep tendon reflexes, and occasionally ataxia. Histopathology. Sural nerve biopsies reveal axonal degeneration and loss of both myelinated and unmyelinated nerve fibers.975 Autopsy studies have demonstrated degeneration of the dorsal columns.1177 Pathogenesis. INH inhibits pyridoxal phosphokinase resulting in pyridoxine deficiency. The neuropathy is thought to be related directly to INH-induced pyridoxine deficiency. INH is metabolized by acetylation. People with slow acetylation (an autosomal recessive trait) maintain a higher serum concentration of INH and are more susceptible to developing the neuropathy than people with rapid acetylation.1177 Slower acetylation also can occur with age. Electrophysiologic Findings. Insufficient data are available. Ethambutol Clinical Features. Ethambutol is another antituberculous medication that can cause a toxic peripheral neuropathy as well as severe optic neuropathy.933,1177 The neuropathy usually occurs in patients receiving prolonged doses in excess of 20 mg/kg/day. Patients describe mild numbness in the hands and feet. Examination reveals a loss of large fiber modalities and reduced reflexes distally. Weakness is uncommon. The peripheral neuropathy gradually improves after discontinuation of the medication, but recovery of the optic neuropathy is more variable. Histopathology. A decreased number of myelinated nerve fibers due to axonal degeneration has been noted in human and animal studies.847

Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Nerve conduction studies are remarkable for diminished amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities. Motor conduction studies are usually normal.847
Nucleosides Clinical Features. The nucleoside analogs zalcitabine (dideoxycytidine [ddC]), didanosine (dideoxyinosine [ddI]), stavudine (d4T), lamivudine (3TC), and antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) are used in the treatment of HIV infection. One of their major dose-limiting side-effects is a predominantly sensory, length-dependent, symmetric, painful neuropathy.90,106,338,1352 Zalcitabine is the most extensively studied nucleoside analog. High doses of ddC (> 0.18 mg/kg/day) are associated with a subacute onset of severe burning and lancinating pains in the feet and hands. The neuropathy occurs in most patients even at lower doses (0.06 mg/kg/day), although it is less severe. As many as 34% of patients taking even lower doses of ddC (0.03 mg/kg/day) develop a toxic neuropathy after 151 weeks (mean: 16 weeks) after starting the medication. Examination reveals hyperpathia, diminished pinprick and temperature sensation, and, to a lesser degree, impaired touch and vibratory perception. Deep tendon reflexes are diminished distally. Mild weakness at the ankles and in foot intrinsic muscles is seen in a few patients. Of importance, a coasting effect can be demonstrated; patients may continue to worsen even 23 weeks after stopping the medication. Nevertheless, a reduction of the dose leads to improvement in most patients after several months (mean time: about 10 weeks). Histopathology. Detailed histopathologic descriptions in humans with nucleoside-induced toxic neuropathies are lacking. Pathogenesis. Nucleoside analogs inhibit reverse transcriptase, impairing HIV replication. They also inhibit mitochondrial DNA polymerase, which is the suspected pathogenic basis for the neuropathy. Acetyl-carnitine deficiency may contribute to the neurotoxicity. Electrophysiologic Findings. Impaired temperature and vibratory thresholds have been noted on QST.90,106 The QST abnormalities, particularly vibratory perception, precede clinical symptoms or standard nerve conduction abnormalities. Sensory nerve conductions reveal decreased amplitudes or absent responses.90,338,1352 Distal latencies and conduction velocities of the SNAPs are normal. Motor conduction studies are usually normal, although unobtainable CMAPs have been described.1346 EMG demonstrates fibrillation potentials and positive sharp waves in distal muscles along with decreased recruitment of large, polyphasic MUAPs.338 Chloramphenicol This antibiotic also can cause a distal sensory polyneuropathy and optic neuropathy.643,1083 The neurotoxicity is now rare but occurred more commonly in the past with prolonged courses and large doses. The neuropathy is characterized by numbness and paresthesias in the feet. Hyperpathia and calf tenderness can be noted. Sensory examination reveals a mild loss of all modalities, and deep tendon reflexes are reduced in the legs. The upper limbs usually are spared. There are no detailed descriptions of the histologic or electrophysiologic findings. Phenytoin Clinical Features. Phenytoin is a commonly used antiepileptic medication.103,997,1084 Most patients treated with

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phenytoin do not complain of symptoms suggestive of peripheral nerve compromise. However, rare patients develop symptoms and signs of a mild, primarily sensory neuropathy. In patients who are clinically toxic with elevated blood levels, overt symptoms of numbness and tingling as well as difficulty in ambulating may be present. There is usually a loss of touch, position sense, and vibration as well as diminished or absent deep tendon reflexes at the ankles. Such patients may demonstrate a mild degree of weakness in the distal muscles of the upper and lower limbs. Fortunately, most patients respond well to lowering the phenytoin levels, with some normalization of the nerve conduction studies and needle EMG abnormalities. Phenobarbital can result in a peripheral neuropathy with similar findings.1212,1275 Histopathology. Sural nerve biopsy may reveal loss of the large myelinated axons with some accompanying segmental demyelination and subsequent evidence of remyelination.1084 Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. Electrodiagnostic medicine findings may reveal alterations suggestive of a mild peripheral neuropathy, affecting primarily the sensory fibers, in about 20% of patients taking only phenytoin.780,829,925,1212 In patients with definite symptoms and signs of a peripheral neuropathy, the SNAP amplitudes are reduced in both upper and lower limbs with mildly to moderately reduced conduction velocities. Motor conduction velocities are low normal or mildly reduced, and the distal motor latencies are normal or only mildly prolonged. The CMAP amplitudes in most patients are normal. Similar findings have been demonstrated in animal studies. Needle EMG in most patients is normal; however, in persons with significant toxicity, fibrillation potentials and positive sharp waves are found in the distal muscles of the upper and lower limbs. Recruitment of large-amplitude, long-duration, polyphasic MUAPs is reduced.
Lithium Clinical Features. Lithium can result in central nervous system toxicity with findings of tremor, dysarthria, confusion, obtundation, sweating, and seizures, as well as electrocardiographic and electroencephalographic abnormalities. A few patients have developed significant sensorimotor peripheral neuropathies after lithium administration.160,952,1317 Usually they present with central nervous system toxicity. After drug withdrawal, symptoms related to central nervous system toxicity resolve, but patients may demonstrate weakness, loss of sensation distally, and depressed or absent deep tendon reflexes. Histopathology. Nerve biopsy demonstrates a loss of large myelinated fibers with little demyelination. Pathogenesis. The pathogenic basis of the neuropathy is not known. Electrophysiologic Findings. The few reported electrodiagnostic medicine studies demonstrated absent SNAP and CMAP responses in the lower limbs with reduced amplitudes, but relatively normal conduction velocities in the upper limbs. Needle EMG examination revealed positive sharp waves and fibrillation potentials as well as complex repetitive discharges. The numbers of voluntary MUAPs were markedly reduced in the distal limb muscles. Eosinophilia-Myalgia Syndrome Clinical Features. This interesting disorder arose from the ingestion of contaminated L-tryptophan in the latter part of the 1980s and early 1990s. 330,567,1131 After identification and

removal of the contaminant, the disorder has all but disappeared. Some patients consuming the offending L-tryptophan presented with progressive symptoms of fever, skin rash, myalgia, arthralgia, peripheral edema, cough, and occasional alopecia. About 30% of patients also had symptoms and signs suggestive of a progressive sensorimotor peripheral neuropathy.567,1152,1195,1231,1316 Other patients developed a severe peripheral neuropathy simulating Guillain-Barr syndrome567,1231 or mononeuropathy multiplex.1195 In addition, a number of patients also had a primary myopathy or combination of myopathy and peripheral neuropathy. Patients demonstrate a progressive loss of strength in a proximal, distal, or proximal and distal distribution with accompanying myalgias. Deep tendon reflexes usually were depressed in the upper limbs and absent in the lower limbs. Multimodality stocking-and-glove sensory loss was worse in the lower limbs. Laboratory Features. The serum CK level may be normal or elevated. Autoantibodies are absent and ESR usually is normal. The absolute eosinophil count is elevated (>1 109 cells/L). Histopathology. Nerve biopsies reveal inflammatory infiltrate, mainly mononuclear with occasional eosinophils and often perivascular, in the epineurium, endoneurium, and/or perineurium, accompanied by evidence of vasculopathy and angioneogenesis.567,1152,1195,1231,1316 Significant axonal degeneration is also appreciated. Pathogenesis. Two trace adulterants have been identified as the possible toxins: 3-phenylamino alanine (PAA) and 1,1'-ethylidenebis tryptophan (EBT).856 The mechanism by which the contaminant resulted in the disorder is unknown, but eosinophilia and eosinophilic infiltrate in tissues suggest some form of allergic reaction. Electrophysiologic Findings. Electrodiagnostic medicine evaluation reveals reduced or absent SNAPs in the lower limbs with diminished-amplitude SNAPs in the upper limbs.567,1152,1195,1231,1316 The distal sensory latencies usually are normal. The CMAPs amplitudes may be profoundly reduced or absent in the lower limbs with mild to moderate amplitude reduction in the upper limbs. Conduction block is also evident in some cases. Distal motor latency usually is well preserved, but conduction velocities may be normal or significantly slow, suggesting a major demyelinating component. F-waves are either present but prolonged and not present after each stimulus, or simply absent. Needle EMG demonstrates positive sharp waves and fibrillation potentials in the distal limb muscles with reduced MUAP recruitment and increased potential amplitude and duration. Some patients have MUAP parameter alterations consistent with a myopathic process when proximal girdle muscles are examined (i.e., early recruitment of MUAPs with reduced durations and amplitudes). Treatment. Discontinuation of L-trytophan and treatment with high-dose corticosteroids usually are effective. Some patients experience relapses after withdrawal of steroids.

INDUSTRIAL AND ENVIRONMENTAL AGENTS

A number of known toxic substances are used in the manufacturing process of multiple materials. Once they are identified, appropriate precautionary measures can be instituted to protect workers. Unfortunately, multiple people all too often become impaired before a substance is recognized as hazardous to human health. Several industrial agents are known to affect the peripheral nervous system adversely, primarily through the production of a distal axonopathy.

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Acrylamide Clinical Features. Acrylamide, a vinyl monomer, is an important industrial agent in the form of a white crystalline substance. The polymerized form of the monomer produces a substance used as flocculators and in grouting agents. The monomer is a white powder that can be absorbed through the skin or inhaled.53,449 A few patients have been reported to become ill after exposure to water contaminated by acrylamide grouting of wells.609 After exposure, patients develop contact dermititis with excessive sweating and peeling of erythematous skin over the same regions. Shortly thereafter, a distal sensorimotor polyneuropathy develops.441,609,782 Patients have a loss primarily of large fiber function. Pain and paresthesia are uncommon. Ataxia, dysarthria, and increasing irritability can be seen. Chronic low-level exposure may present with mental confusion and hallucinations in addition to weakness, gait difficulties, and occasionally urinary incontinence. Physical examination reveals distal muscle weakness and wasting with a loss of vibration in the distal upper and lower limbs but relatively good preservation of touch, pain, and temperature sensation. Patients may be ataxic and demonstrate a positive Romberg sign. Deep tendon reflexes are depressed in the upper limbs and markedly diminished or absent in the lower limbs. Distal weakness of the hands and feet is noted. A course tremor may be noted in the hands. After elimination of acrylamide exposure, function gradually returns. Patients with low levels of exposure usually do quite well. However, in patients exposed to large amounts, significant improvement may require a year or more, and patients may not recover completely. Histopathology. A few sural nerve biopsies reveal primarily axonal degeneration with loss of large myelinated fibers.441 Experimental studies in animals demonstrate that the earliest histologic abnormality is paranodal accumulation of 10-nm neurofilaments at the distal ends of the peripheral nerves.1170,1177 Enlargement of the distal axons with subsequent axonal degeneration and segmental remyelination can be seen. Unmyelinated fibers as well as degeneration of the posterior columns, spinocerebellar tracts, optic tracts, mamillary bodies, and the corticospinal tracts also can be found. Pathogenesis. The exact pathogenic basis is unknown, but it is believed that acrylamide impairs fast bidirectional axonal transport as well as slow antegrade transport.1177 Electrophysiologic Findings. Only a small number of electrodiagnostic medicine examinations have been reported in humans, and none has included needle EMG.441,609,782 Sensory nerve conduction velocities are normal or only slightly reduced, but SNAPs are usually markedly reduced in amplitude. Motor nerve conduction studies demonstrate well-preserved distal motor latencies and only an occasional mild reduction in conduction velocities. CMAP amplitudes are at the lower range of normal. Some degree of temporal dispersion of the CMAPs can be observed in patients exposed to high levels of the substance. These modest abnormalities are usually observed only in patients suffering from acute intoxication. In patients chronically exposed to low levels, nerve conduction studies are relatively normal, despite clinical symptoms and signs. After elimination of exposure to acrylamide, electrophysiologic studies return to normal values. Animal studies have verified a number of the above-noted clinical, histologic, and electrophysiologic findings.1170,1252 Carbon Disulfide Clinical Features. Carbon disulfide is used in the manufacture of viscose Rayon products and sheets of cellophane.1177,1354

The primary route of entry is through inhalation, but carbon disulfide can also be absorbed through the skin. Acute exposure to high levels produces various psychotic disturbances, which resolve with elimination of exposure. Chronic low-level exposure can result in a peripheral neuropathy.1177,1356 Patients complain of distal numbness and tingling, usually beginning in the lower limbs and progressing to involve the upper limbs. Reductions in all sensory modalities can be demonstrated and accompanied by a diminution in deep tendon reflexes. Distal muscle atrophy and weakness may be evident. Histopathology. Detailed descriptions of the histopathology in humans are lacking. However, experimental studies in animals have shown accumulation of 10-nm neurofilaments and axonal swellings, similar to that seen in acrylamide and hexocarbon toxicity.1177 Pathogenesis. The exact pathogenic basis for the neuropathy is not known, but theories include (1) a chelating effect on enzyme function, (2) direct inhibition of various enzymes, and (3) release of free radicals after cleavage of the carbon-sulfur bond with secondary axonal damage.1177 Electrophysiologic Findings. Nerve conduction studies demonstrate a reduction in the SNAP conduction velocities and may be the only abnormality noted early in the disease.252,1343 The amplitudes of the SNAPs have not been addressed in detail. Motor conduction studies demonstrate comparatively less pronounced slowing of conduction. The distal motor latencies may be normal or slightly prolonged. No comments have been made about the CMAP amplitude during the disease process. Needle EMG examination may reveal fibrillation potentials and positive sharp waves in the distal limb muscles, especially in the lower limbs. After cessation of the toxic exposure, electrophysiologic data may improve in a few patients, but many simply no longer progress and maintain a new steady state of neural conduction slowing.
Ethylene Oxide Clinical Features. Ethylene oxide is one of the most widely used industrial substances. It is used for sterilizing heat-sensitive materials, particularly in the health care setting. The primary manifestations of human exposure are dermatologic lesions, mucosal membrane irritation, nausea, vomiting, and altered mentation. People exposed to high levels can develop a severe sensorimotor peripheral neuropathy.269,1184 Patients usually complain of acral hypesthesia and paresthesias accompanied by difficulty in walking and increased fatigability. Examination demonstrates a reduction in sensory modalities, primarily in the distal aspects of the lower limbs, with some evidence of intrinsic foot muscle wasting and a wide-based gait. A mild reduction in muscle strength can be detected in the intrinsic foot and distal lower limb muscles. Heel-to-shin ataxia, slow and clumsy alternating hand motions, and diminished deep tendon reflexes are present. Histopathology. Sensory nerve biopsies reveal the loss of primarily, but not exclusively, large myelinated fibers. Pathogenesis. The pathogenic basis of the neuropathy is not known. Ethylene oxide can act as an alkyating agent and bind with many organic molecules, including DNA. Electrophysiologic Findings. Electrodiagnostic medicine evaluation reveals reduced amplitudes or absence of sensory responses, especially in the lower limb.418,509,742 Sensory conduction velocities are diminished but usually not below 80% of the lower limit of normal. H-reflexes in the lower limbs are commonly absent. Motor conduction studies demonstrate reduced

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amplitudes or absent CMAP responses. Motor nerve conduction velocities also are slightly decreased. Needle EMG demonstrates fibrillation potentials, positive sharp waves, and reduced recruitment of MUAPs. The MUAPs are increased in duration and amplitude as well as number of phases.
Organophosphates Clinical Features. The organophosphorous esters are used primarily in the production of insecticides, plastics, and petroleum products and as toxic nerve agents in biologic warfare. Multiple instances of accidental and intentional intoxication by types of organophosphorus compounds have resulted in neurologic complications.583,1196,1197,1233,1373 These compounds inhibit acetylcholinesterase and result in the accumulation of acetylcholine at cholinergic synapses (see Chapter 25). Toxic exposure to organophosphate esters can result in muscarinic, nicotinic, and central effects, thus producing the acute clinical symptoms and signs. The muscarinic effects can cause nausea, vomiting, abdominal cramping, diarrhea, pulmonary edema, and bradycardia. Central effects can produce anxiety, emotional lability, ataxia, altered mental status, unconsciousness, and seizures. Nicotinic actions result in generalized weakness and fasciculations. Acute intervention is directed at maintaining ventilation and circulation through the administration of atropine to counteract the muscarinic effects. Within 1296 hours a so-called intermediate syndrome may become evident after the onset of acute muscarinic actions. During this period, proximal muscle and cranial nerve weakness can develop, along with respiratory compromise. Supportive care is of primary importance to see the patient through the several weeks of crisis. Death can result from respiratory failure and cardiovascular collapse. Some patients with acute organophosphate toxicity later develop a distal sensorimotor peripheral neuropathy (organophosphate-induced delayed polyneuropathy [OPIDP]).98,300,583,813,1197,1344,1374 OPIDP evolves several weeks after exposure and maximizes within several weeks. Patients may note cramping in the calf muscles followed by burning or tingling in the feet. Weakness is also an early finding. Symptoms and signs may progress to involve the hands. Weeks after the development of the peripheral neuropathy, superimposed signs of central nervous system dysfunction with increased tone and hyperreflexia may be seen. In patients with mild peripheral neuropathy, the prognosis is good. However, patients with significant peripheral and central nervous system insult generally are left with reduced abilities to perform activities of daily living. Histopathology. Autopsy studies of ginger jake-related OPIDP in Jamaica from 1930 revealed abnormalities suggestive of a distal axonopathy along with degeneration of the gracile fasciculus and corticospinal tract.1177 In addition, autopsy of a patient who died 15 months after intoxication by sarin gas revealed marked loss of both myelinated and unmyelinated nerve fibers in the sural nerve and a moderate loss of nerve fibers in the sciatic nerve.583 The posterior columns and dorsal root ganglia appeared to be spared. Pathogenesis. Organophosphates do not cause the toxic neuropathy by inhibiting acetylcholinesterase. Rather, specific organophosphates cause OPIDP by binding to and inhibiting an enzyme called neuropathy target esterase (NTE).813 The function of NTE is not known, but it is present throughout the CNS and PNS. Inhibition of NTE is not sufficient for the development of OPIDP. The organophosphate-NTE complex must age, whereby a lateral side-chain of NTE is cleaved, before the toxic neuropathy develops.

Electrophysiologic Findings. Electrodiagnostic findings in the acute and subacute stages of the disease are consistent with neuromuscular dysfunction secondary to compromise of acetylcholinesterase.98,578,1344,1376 Sensory and motor nerve studies are normal. Of note, however, is the demonstration of repetitive firing of the CMAPs after a single neural stimulus. A decrement can be observed in response to low rates of repetitive stimulation and persists for about 411 days. In some patients an interesting decrement-increment phenomenon can be detected after a mild exposure or in the recovery phase. At both low (25 Hz) and high (20 Hz) rates of repetitive stimulation, the CMAP amplitudes initially decrement but then recover, approaching the baseline amplitudes. Needle EMG reveals a reduction in voluntary MUAPs. The electrodiagnostic examination in OPIDP reveals findings consistent with an axonal sensorimotor polyneuropathy. Sensory and motor evoked response amplitudes are reduced with only mild prolongation of the distal latencies. Likewise, the sensory and motor conduction velocities are usually at the lower limits of normal or mildly reduced. Needle EMG reveals significant reduction in voluntary MUAPs with attempts at muscle contraction and positive sharp waves and fibrillation potentials at rest.
Hexacarbons (Glue Sniffers Neuropathy) Clinical Features. Both n-hexane and methyl n-butyl ketone are classified as hexacarbons and are metabolized in the body to 2,5-hexanedione, the substance believed to be responsible for the toxic neuropathy. Hexacarbons are water-insoluble industrial organic solvents with a high vapor pressure. Accidental exposure in factories and intentional glue sniffing account for most peripheral neuropathies associated with these compounds. The clinical manifestations can result from inhaling vapors or through skin absorption. A profound subacute sensorimotor polyneuropathy progressing over the course of 46 weeks can develop secondary to hexacarbon toxicity.482,719,1177,1253,1309 Initially, most patients note numbness and tingling in the feet. A progressive loss of sensation in the proximal leg may occur, at which time the upper limbs become numb. Progressive loss of motor function ensues, with impaired ambulation and decreased fine motor coordination skills. Sphincter function usually is preserved, as are swallowing and respiratory functioning. Physical examination is commensurate with the above symptoms. A flaccid weakness is accompanied by loss of deep tendon reflexes and position/vibration sense. Pain and temperature sensation are only mildly reduced. Exuberant perspiration may be noted on the soles of the feet. Histopathology. The nerve biopsy can demonstrate evidence of profound loss of myelinated as well as giant axons (Fig. 23-10).482,1177,1309 Some degree of demyelination also is noted, but axonal loss is clearly the dominant finding. There are no onion-bulb formations or inflammation. EM reveals that the swollen axons are filled with 10-nm neurofilaments. Pathogenesis. The exact mechanism by which hexacarbons cause a toxic neuropathy is not known. It has been speculated that the neuropathy is due to hexacarbon interactions that lead to covalent cross-linking between axonal neurofilaments.1177 Impaired transportation of cross-linked neurofilaments leads to aggregation, swelling of the axons, and eventual axonal degeneration. Electrophysiologic Findings. The electrodiagnostic evaluation demonstrates decreased amplitude of the SNAPs with normal or only mild slowing of sensory conduction velocities or prolonged distal latencies.18,197,224,472,576,608,695 Lower limb SNAPs are preferentially affected, but in profound disease upper limb SNAP responses also may be markedly reduced or absent. The

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neuropathies in humans.1420 The severity of the neuropathy is usually related to the amount of metal that enters the patients system either acutely or chronically. Clinical improvement depends on cessation of exposure and supportive measures. Unfortunately, a number of the heavy metals can enter various storage zones in the body, from which they are slowly released, producing a chronic low-level, continual-dosing phenomenon. Most patients are exposed to heavy metals as a result of workrelated activities, although a few patients may have attempted suicide or are the victims of attempted homicide. Multiple organ systems can be involved in addition to the peripheral nervous system. The combination of systemic effects and peripheral nerve dysfunction at times helps to distinguish the type of metal involved, although laboratory determination of serum and urine metal levels is the definitive method of diagnosis.
Figure 23-10. Hexane neuropathy. Sural nerve biopsy reveals thinly myelinated, markedly swollen axons. (Epoxy-embedded, toluidine blue stain).

CMAP amplitudes are decreased in the upper and lower limbs. However, mild cases of neuropathy may be associated with normal CMAPs. Nerve conduction velocities are usually reduced to about 7080% of the lower limit of normal. In some patients, a few nerves in both upper and lower limbs may demonstrate conduction velocities approaching 50% of the lower limit of normal.695 Needle EMG examination reveals a reduced number of MUAPs firing at rapid rates in distal muscles. These findings usually are accompanied by fibrillation potentials and positive sharp waves. Some patients also have readily detectable fasciculation potentials.
Vinyl Benzene (Styrene) Vinyl benzene or styrene is an industrial liquid used in the manufacture of some plastics and synthetic rubber materials. Exposed workers can develop a peripheral neuropathy that is primarily sensory.83 Burning paresthesias begin in the feet and progress up the legs. Usually strength is preserved and patients can ambulate without difficulty aside from pain in the feet. Physical examination demonstrates a reduction in pain and temperature with relatively good preservation of proprioception and vibration. Deep tendon reflexes are well preserved. Limited electrophysiologic testing demonstrates a mild reduction in motor conduction velocities in the lower limbs. Additional Agents Other agents reported to result in a preferential axonal sensorimotor peripheral neuropathy include dichlorophenoxyacetic acid and carbon monoxide.470,1241 Such cases are extremely rare, and only a few patients have been cited in the literature. Briefly noted electrodiagnostic medicine examinations have described findings suggestive of a primarily axonal neuropathy with little in the way of nerve conduction velocity alterations but large amounts of fibrillation potentials and positive sharp waves associated with reduced MUAP recruitment. Further studies are required to characterize the peripheral neuropathy in greater detail.

HEAVY METAL INTOXICATION

A number of metals, especially those with high atomic weights (so-called heavy metals), can produce primarily axonal

Lead Clinical Features. Lead neuropathy is an increasingly rare cause of peripheral nerve disease because of the realization of its harmful effects.94,1420 It occasionally can be seen in children who consume lead-based paints in older buildings and in industrial workers dealing with metals, batteries, or paints containing lead products. Both organic and inorganic lead substances can gain access to the human body from environmental sources and result in central and peripheral nervous system dysfunction. In children, the most common presentation of lead poisoning is encephalopathy. Patients usually have some abdominal discomfort, accompanied by varying degrees of constipation. However, children and adults can present with symptoms and signs of a primarily motor peripheral neuropathy.123,408,409,633,1199,1223,1420 A so-called lead line can be seen in some patients. It manifests as a bluish-black coloration of gums near the teeth. With respect to the neuropathy, patients may note the insidious and progressive onset of upper limb weakness. There are few or no sensory complaints, and sensory examination to all modalities is usually well preserved. The classic sign is noticeable motor involvement of the radial nerve with a wrist/finger extensor weakness. When the lower limbs are involved, an asymmetric foot drop is likely. Deep tendon reflexes are diminished, and plantar responses are flexor. Laboratory Features. Laboratory investigation can reveal an elevated serum coproporphyrin level, basophilic stippling of erythrocytes, and reduced hemoglobin content, suggesting a microcytic/hypochromic anemia. A 24-hour urine collection demonstrates elevated levels of lead excretion, which can be magnified by the addition of a chelating agent in suspicious cases. Histopathology. There is generally a reduction in the number of large myelinated axons with little, if any, segmental demyelination.164 Pathogenesis. It is unclear whether the primary target of the toxic insult is the anterior horn cell or, more distally, the peripheral or motor nerve.1420 Nor is the exact pathogenic mechanism by which lead causes axonal degeneration known. It has been speculated that lead may interfere with mitochondrial function.1420 Electrophysiologic Findings. In motor and sensory nerve conduction studies, distal latency, amplitude, and velocity have been reported to be mildly abnormal in studies of relatively large numbers of patients exposed to various forms of lead.123,164,183,408,409,1199,1200,1202,1223 When these values are compared with values after treatment, an improvement is noted.36,927 On needle EMG, the most common finding is an increase in the MUAP amplitude, duration, and number of phases. Alterations

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ACQUIRED NEUROPATHIES 1009

in recruitment usually are not noted until there is moderate loss of axons. Fibrillation potentials and positive sharp waves can be seen in the affected muscles. Treatment. The most important treatment is removing the source of the exposure. Chelation therapy with calcium disodium ethylenediamine tetraacetate (EDTA), British anti-Lewisite (BAL), and pencillamine demonstrates variable efficacy.1420
Mercury Clinical Features. Intoxication results from exposure to either organic or inorganic mercurials.656,836,1211,1420 The organic form is usually found in methyl or ethyl mercury. Perhaps the most infamous case of organic mercury poisoning resulted from dumping mercuric chloride into Minimata Bay, where sea life converted the substance into methyl mercury. The population dependent on the fish and crustaceans for food developed mercury poisoning. An initial manifestation of organic mercury poisoning is paresthesias in the distal regions of the limbs. Over time, the paresthesias progress proximally, eventually involving the tongue. Patients may display ataxia, reduced mentation, visual and hearing loss, and dysarthria. The inorganic mercury compounds, which are used primarily for industrial purposes, consist of various mercury salts. The gastrointestinal system is believed to be the major source of entry into the human body. Mercury vapors in poorly ventilated industrial areas also can be a significant health hazard. The actual mercury metal or fluid at room temperature is reported to be nonhazardous because it is apparently poorly absorbed from the gastrointestinal tract. In acute poisonings with mercury salts, gastrointestinal symptoms predominate, although nephrotic syndrome may be a major problem. Mercury vapors exert their toxic effect through their high lipid solubility and thus result in central nervous system effects such as loss of appetite, mental confusion, weight loss, and fatigue. Some degree of peripheral neuropathy may be manifest in particularly sensitive patients. Laboratory Features. Organic mercury intoxication can be extremely difficult to prove. Little of the metal may be excreted in the urine because it is highly lipid-soluble and thus remains in the body. Inorganic mercury, on the other hand, is readily excreted in the urine, and 24-hour urine collection can reveal an increased concentration. Histopathology. Histopathologic evaluation of patients exposed at Minimata Bay demonstrated significant degeneration of the calcarine aspect of the cerebral cortex and cerebellum, hence accounting for ataxia and visual complaints.1420 Prominent degeneration of axons in the sural nerves and lumbar dorsal roots was also observed. Segmental demyelination was absent. Pathogenesis. It is hypothesized that mercury exerts its toxic effect on neurons by combining with sulfhidryl groups of enzymatic or structural proteins, thereby impairing their proper function and leading to degeneration of the neurons.1420 The primary site of pathology appears to be the dorsal root ganglia. Electrophysiologic Findings. Only a few electrodiagnostic medicine evaluations have been reported in patients with ongoing mercury exposure.1146 Several investigations have noted a distinct lack of electrophysiologic abnormalities in patients with proven mercury exposure; however, these conclusions are of little value because they were performed 7 months or more after cessation of exposure.779,1367Electrodiagnostic findings in patients exposed to organic mercury and mercury vapors may be abnormal.5,8,614,1205,1224,1305 In patients with low blood levels

despite clinical symptoms, sensory studies may yield low normal values for amplitude and conduction velocity. Although this may be statistically significant when patients are compared with a control population, the absolute value in individual patients is within normal limits and, therefore, of little diagnostic use. When patients with high serum or urine levels are examined, a number of abnormalities may be found. The sural and superficial peroneal nerves may reveal reduced SNAP amplitudes and normal or slightly reduced (> 80% of lower limit of normal) conduction velocities. In patients with long-standing exposure, somatosensory evoked potentials of the median nerve demonstrate peripheral potentials but no cortical potentials.1305 Motor conduction velocities are usually normal or borderline slow with normal CMAP amplitudes. Distal motor latencies are normal in most patients. F-wave and H-reflex latencies can be normal or slightly prolonged. The needle EMG examination may reveal positive sharp waves and fibrillation potentials in some patients, but there is usually a lack of abnormal spontaneous activity. Occasionally, patients exposed to mercury present with abnormalities suggestive of motor neuron disease.5 Quantitative motor unit analysis typically demonstrates MUAPs with increased duration and amplitude, but recruitment is normal. Such findings in patients with low-level exposure over years suggests a slow loss of axons with subsequent motor unit remodeling. Treatment. Chelating agents such as penicillamine have been used, but the number of treated cases is too small to allow comment on efficacy.1420 The mainstay of treatment is removing the source of exposure.
Thallium Clinical Features. Thallium is a heavy metal that can exist as a monovalent or trivalent species.342,1069,1420 Monovalent thallium ions are present in multiple tasteless, and odorless salts (sulfate, acetate, and carbonate) that are highly soluble in aqueous solutions. These solutions are both colorless and highly toxic. Initially thallium salts were used to treat a variety of conditions, such as tuberculosis, venereal disease, syphilis, and ringworm. Therapeutic use was abolished after full recognition of its toxic effects. Subsequently thallium was used primarily as a rodenticide. Accidental and intentional poisonings resulted in the banning of thallium for any purpose in the United States in 1965. It is, however, still available worldwide as a rodenticide and from time to time may be recognized in victims of homicide attempts. The lethal dose of thallium in humans is rather variable but averages about 1 gram or 815 mg/kg body weight. Death can result in less than 48 hours after a particularly large dose. Most patients present initially with complaints of burning paresthesias of the plantar surfaces of the feet bilaterally as well as abdominal distress and occasional vomiting.342,1069,1420 The burning pain in the feet may be severe enough to limit ambulation. Pain and temperature sensation is reduced, and vibratory perception and proprioception are mildly decreased. Deep tendon reflexes are reduced distally but generally preserved proximally. Distal muscle atrophy and weakness gradually ensue. With severe intoxication, proximal weakness and involvement of the cranial nerves can occur. Some patients require mechanical ventilation as a result of respiratory muscle involvement. In addition to nausea and abdominal pain, retrosternal pain, thirst, sleep disturbances, and psychotic behavior may be noted.

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Within the first week, patients may display continued vomiting, hair root pigmentation, an acne/malar rash, and possible hyperreflexia. By the second and third weeks, mild tachycardia and hypertension are noted as well as hyporeflexia about the ankles and the beginning of alopecia. The hallmark of thallium poisoning is alopecia, but it may not be evident until the third or fourth week after exposure and can be rather mild in some patients. Of importance, alopecia is not pathognomonic for thallium intoxication because exposure to vincristine, chloroprene, and mercaptopurine also can result in hair loss. Laboratory Features. Serum and urine levels of thallium are increased. Routine laboratory testing can reveal anemia, azotemia, and liver function abnormalities. CSF protein levels also are elevated. Histopathology. The primary pathologic reaction of the peripheral nervous system to thallium intoxication is axonal loss.185,296,342 Chromatolysis of cranial and spinal motor nuclei and dorsal spinal ganglia has been demonstrated. Wallerian degeneration is the prominent feature noted on peripheral nerve biopsy, with little or no segmental demyelination. There is a general reduction in nerve fibers of all diameters. Mitochondria can appear swollen in experimental cultured neuronal tissue.1420 Pathogenesis. It is not known whether the primary insult is to the neuronal cell body or the axons. The pathogenic basis for the toxicity is also unknown. Electrophysiologic Findings. An electrodiagnostic examination of the patient within the first few days of intoxication reveals no significant abnormalities.65,342,796 By 10 days after thallium exposure, it is possible to note an absence of the medial and lateral plantar mixed nerve action potentials with preserved sural nerve SNAPs. This finding is important because the most distal aspects of the peripheral nervous system are preferentially affected first. Limiting the sensory examination to the sural nerve can result in disappointingly normal studies despite profound symptoms.Because patients usually complain of plantar foot pain, these nerves should be examined. Over the ensuing weeks, the more proximal lower limb sensory nerves are affected. When present, the SNAP is usually reduced in amplitude, and the distal sensory latencies or conduction velocities are mildly abnormal. H-reflexes may be present within the first 10 days after exposure but then disappear and may not return for some time. Motor conduction studies in the lower limbs can reveal absent CMAPs in the foot intrinsic muscles. When these responses are present, the conduction velocity is mildly reduced, but the CMAP is markedly reduced. Serial studies demonstrate an initial reduction in amplitude in both upper and lower limb CMAPs with a gradual increase over the ensuing years. The distal motor latencies are normal or mildly prolonged. Needle EMG examination within the first few days of exposure may reveal only a reduced recruitment of motor units. Within the next 10 days intrinsic foot muscles reveal evidence of denervation by way of positive sharp waves and fibrillation potentials. These abnormalities progress to affect the more proximal muscles in the lower limbs. With time the denervated muscle fibers are reinnervated, thus reducing the number of observed abnormal spontaneous potentials. Motor unit remodeling generates MUAPs with elevated amplitudes and durations. Treatment. With acute intoxication, potassium ferric ferrocyanide II may prevent absorption of thallium from the gut.1420 However, it is not clear whether the medication is effective once thallium has been absorbed. Unfortunately, chelating agents are not particularly useful. Maintaining adequate diuresis helps to

eliminate thallium from the body without increasing tissue availability from the serum.1420
Arsenic Clinical Features. Arsenic is another heavy metal that can cause a toxic sensorimotor polyneuropathy.221,440,497a,631,928,981, 1420,1447 The neuropathy begins 510 days after ingestion of arsenic and progresses for several weeks. Most patients with acute arsenic poisoning complain of abrupt onset of abdominal discomfort, nausea, vomiting, pain, and diarrhea, followed within several days by a burning sensation in the feet and hands. Soon thereafter, progressive loss of muscle strength develops distally. With severe intoxication, weakness progresses to the proximal muscles and cranial nerves. Some patients may require mechanical ventilation. Diminished deep tendon reflexes are also noted commensurate with the degree of strength loss. Such symptoms and signs can be suggestive of AIDP; hence, acute arsenic intoxication should be kept in mind when evaluating patients with an acute onset of sensory and motor loss. Some patients display slow mentation and confusion, suggesting central nervous system toxicity. If the ingested dosage is large enough, CNS symptoms may predominate with rapid progression to death due to vascular collapse. Clinical skin changes may be helpful in raising the suspicion of arsenic intoxication. There can be loss of the superficial epidermal layer several weeks after the initial exposure or with chronic low levels of ingestion. Variations in skin coloration create patchy regions with various degrees of increased or decreased pigmentation. Mees lines, which are transverse lines at the base of the fingernails and toenails, may become evident by 1 or 2 months. They correlate with arsenic exposure. In patients with both long fingernails and repeated intoxication, in time one can observe multiple Mees lines on examination. Of note, such nail abnormalities can be seen in disorders other than arsenic poisoning (e.g., thallium poisoning). Laboratory Features. Clearance from blood is rapid; therefore, serum concentration of arsenic is not diagnostically helpful. Arsenic levels are increased in the urine, hair, or fingernails of affected patients. As in lead intoxication, basophilic stippling of erythrocytes occasionally is observed as well as an aplastic anemia with pancytopenia. Increased CSF protein levels without pleocytosis, as seen in AIDP, also can be demonstrated. Histopathology. Peripheral nerve biopsies in patients with arsenic poisoning demonstrate an increase in interstitial fibrosis as well as increased endoneurial cells. A reduction in total numbers of large- and small-diameter myelinated fibers results from axonal degeneration. Segmental demyelination is rare, but occasional onion-bulb formations are evident. Autopsy studies have revealed a loss of anterior horn cells. Pathogenesis. The pathogenic basis of arsenic toxicity is not known. It is believed that arsenic reacts with sulfhydryl groups of enzymatic and structural proteins in the neurons. In particular, arsenic may inhibit the pyruvate dehydrogenase complex.1420 The resulting impairment of cellular metabolism may lead to neuronal degeneration. Electrophysiologic Findings. The traditional electrophysiologic abnormalities are consistent with a primarily axonal sensorimotor polyneuropathy.221,410,497a,631,928,981,984,1420 Specifically, sensory studies commonly reveal complete absence of the SNAPs, especially in the lower limb. The upper limb SNAPs are also absent or markedly reduced in amplitude. Not uncommonly, the CMAPs may be absent, particularly in the lower limb. When obtainable, motor nerve conduction studies are

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mildly to moderately reduced (i.e., 8090% of the lower limit of normal). Distal motor latencies are not especially affected. Maximum abnormalities in motor nerve conduction studies occur approximately 35 weeks after exposure. Return to normal requires several years, and in some patients normal neural conduction may not be restored. Needle EMG examination reveals positive sharp waves and fibrillation potentials with reduced numbers of motor units in the distal muscles, progressing proximally in patients exposed to significant amounts of arsenic. The important point about the studies defining the above abnormalities is that they were performed somewhat late in the disease. Of interest are a number of reports documenting arsenic intoxication of significant degree after single or limited doses with electrophysiologic studies performed soon after or before diagnosis.320,328,463,781,1411 Such patients customarily are exposed to a single large dose and present clinically with AIDP. The electrophysiologic studies demonstrate absent or markedly reduced sensory responses. Motor conduction studies may reveal evidence suggestive of conduction block and prolongation of Fwave latencies. Serial studies demonstrate progressive deterioration of the CMAP amplitudes to distal stimulation, associated with progressive conduction block and reductions in the conduction velocities. Initially, needle EMG examination reveals an increase in insertional activity and reduced MUAP recruitment, but by 23 weeks marked fibrillation potentials and positive sharp waves are found with reduced number of MUAPs. Early in the disease, membrane instability may be noted only in the paraspinal muscles, which always should be examined. Treatment. Chelation therapy with BAL has yielded inconsistent results in small retrospective studies. Nevertheless, the beneficial effect of BAL, if any, is not dramatic; therefore, its use is not recommended.1420
Gold Clinical Features. Gold therapy (e.g., sodium aurothiomalate) is sometimes used to treat rheumatoid arthritis. Some patients treated with gold salts develop a sensorimotor peripheral neuropathy several months after drug initiation.1420 Most patients complain first of paresthesias in the distal aspects of the lower and sometimes upper limbs. These sensations usually progress over the ensuing weeks with accompanying weakness primarily, but not exclusively in the distal muscles of the lower limbs. Not uncommonly, a systemic reaction (e.g., rash and pruritus) to gold is also noted. Examination reveals diminution of deep tendon reflexes with plantarflexor responses and reductions in all sensory modalities in the distal lower limbs and occasionally upper limbs. A few patients display spontaneous and vermicular movements of some limb muscles (i.e., myokymia). Patients with connective tissue diseases who do not take gold therapy also can develop peripheral neuropathies. Stopping the gold usually results in remission of most if not all symptoms over the course of several weeks. This does not occur if connective tissue disease is the primary cause of the peripheral nerve symptoms. It is wise to stop gold therapy in patients with peripheral nerve symptoms to evaluate the respective roles of gold and connective tissue disease. Histopathology. The few studies that have been performed in humans found a number of peripheral nerve alterations, indicating both axonal degeneration and segmental demyelination of varying degrees. Pathogenesis. The pathogenic basis for the neuropathy is not known. It may be related to an immunologic reaction triggered by gold therapy.1420

Electrophysiologic Findings. Electrodiagnostic medicine findings are somewhat variable, depending on the degree of peripheral neuropathy at the time of examination.659,900,1379 Mild cases may demonstrate few abnormalities. For example, a slight prolongation in the SNAPs or mild reduction in amplitudes and conduction velocities may be noted. Motor studies and needle EMG are normal. On the other hand, patients with significant neuropathy may show complete absence of SNAPs in the lower limbs with significant reductions in amplitude of upper limb SNAPs. The distal sensory latencies may be mildly to moderately prolonged with slowing of conduction velocities into the abnormal range (usually not exceeding 70% of the lower limit of normal). The CMAPs are well preserved in most patients, but the motor conduction velocity can be mildly reduced in addition to a slight prolongation in the distal motor latency. Needle EMG examination demonstrates reduced recruitment with occasional positive sharp waves and fibrillation potentials in the distal muscles of the lower limb. Myokymia may be noted in both upper and lower limb muscles in some patients, with or without accompanying positive sharp waves and fibrillation potentials. Treatment. Treatment consists of stopping the gold therapy. BAL has been tried in a few patients, but its efficacy is unclear.1420

NEUROPATHIES RELATED TO NUTRITIONAL DEFICIENCIES

THIAMINE (VITAMIN B1)
Clinical Features. Thiamine deficiency is rare except in people who consume alcohol as their major source of nutrition. This section, however, focuses on patients with a primary thiamine deficiency unrelated to excessive alcohol ingestion. Symptoms due to insufficient dietary intake of thiamine are known as beriberi and may present in two forms: dry and wet. The difference is simply the presence (wet beriberi) or absence (dry beriberi) of congestive heart failure and lower limb edema. Both forms are associated with neurologic symptoms. Beriberi primarily results from a diet high in processed foods without appropriate vitamin supplements. Prisoners of war and people consuming milled rice, from which the outer coating is removed, are at risk for developing beriberi. Patients usually present with complaints of numbness and tingling or burning in the soles of the feet.288,599,1279 Within several days, weakness may be noted in the distal muscles of the lower limbs, accompanied by similar sensory symptoms in the fingertips. Physical examination may reveal lower limb edema with cardiac enlargement and an apical systolic cardiac murmur (wet beriberi). Sinus tachycardia is present, and cardiac conduction blocks may be identified. Deep tendon reflexes are absent at the ankles and occasionally at the knees, with depressed upper limb reflexes. A mild to moderate reduction in all sensory modalities is noted in a stocking distribution, with some patients displaying similar sensory findings in the hands. Calf tenderness may be noted in some patients. Histopathology. Sural nerve biopsies reveal significant axonal loss primarily of large myelinated fibers with little segmental demyelination. Chromatolysis of the anterior horn cells and dorsal root ganglia cells, along with axonal degeneration and secondary demyelination of the posterior columns, has been noted on autopsies.

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Pathogenesis. The pathogenic basis for neuropathy in patients with thiamine deficiency is not known. Thiamine is a coenzyme required for oxidative decarboxylation of ketoacids and transketolation in the pentose phosphate shunt. Impaired energy metabolism due to thiamine deficiency may result in impairment of axonal transport and other high energy-dependent intracellular processes. Electrophysiologic Findings. The electrodiagnostic evaluation demonstrates findings consistent with the histopathologic loss of large myelinated axons. Sensory nerve conduction studies document that the distal sensory latencies and conduction velocities are normal or only mildly impaired, whereas the SNAP amplitudes are either absent or significantly reduced.599 The CMAP is normal or slightly reduced in the upper limbs and reduced or absent in the lower limbs. Distal motor latencies are at the upper limits of normal or slightly prolonged. Motor conduction velocities are normal or reduced to not less than 7580% of the lower limit of normal. Needle EMG demonstrates positive sharp waves and fibrillation potentials, mainly in the distal lower limbs. Occasionally, abnormal spontaneous activity is noted in the hand intrinsic muscles. A few patients may demonstrate complex repetitive discharges and fasciculation potentials. The MUAPs display increased durations, large amplitudes, and decreased recruitment. Treatment. Thiamine (50 mg) is injected intramuscularly daily for 2 weeks, followed by 5 mg/day orally. Administration of thiamine improves the symptoms and signs of beriberi.

PYRIDOXINE (VITAMIN B6)

Pyridoxine is not only neurotoxic in large dosages (see above) but may be associated with a sensorimotor polyneuropathy in patients with deficiencies. Pryridoxine deficiency has been associated with isoniazid and hydralazine treatment.

COBALAMIN (VITAMIN B12)

Clinical Features. Patients can present with hematologic (megaloblastic anemia), gastrointestinal, and neurologic manifestations of vitamin B12 deficiency. Neurologic symptoms result from both peripheral and central nervous system insult.416,417,534,571,641,664,720,733,804,861 Either the central or peripheral nervous system may be perferentially affected, and a number of patients have combined peripheral and central nervous system dysfunction. In patients with a primarily central nervous system disorder, altered mentation combined with primarily posterior column and occasionally pyramidal fiber insult (subacute combined degeneration) can result. Such patients not only have decreased cognitive abilities but also display gait ataxia with primarily lower limb weakness in association with extensor plantar responses, hyperreflexia, and a positive Romberg sign. On the other hand, a preferential alteration of the peripheral nervous system manifests with complaints of numbness and tingling. Examination demonstrates decreased or absent deep tendon reflexes in the lower and occasionally upper limbs, flexor plantar responses, reduced vibration, and some diminution in pain and temperature sensation in the distal aspects of the limbs as well as muscle wasting and weakness in the distal lower limb muscles. A combination of central and peripheral neural insults is essentially a peripheral neuropathy superimposed on a central nervous system insult. Patients complain of the distal limb paresthesias with significant difficulty in ambulating, particularly in the dark. Muscle wasting in the foot intrinsic

muscles is observed as well as reduced lower limb reflexes. In the upper limbs, normal deep tendon reflexes or hyperreflexia can be found in addition to upper limb hypertonicity accompanied by lower limb extensor plantar responses. Laboratory Features. Serum cobalamine levels are decreased or in the low range of normal. In patients with B12 levels in the low normal range and symptoms and signs suggestive of cobalamine deficiency, it is important to assess serum or urine levels of methylmalonic acid and homocysteine. These metabolites are increased in patients with cobalamine deficiency and can precede abnormalities in serum B12 concentrations. A complete blood count and smear can reveal megaloblastic anemia. Of importance, the neurologic complications of cobalamine deficiency can be evident before the hematologic abnormalities are appreciated. Patients with an autoimmune basis for B12 deficiency may demonstrate autoantibodies directed against gastric parietal cells. Histopathology. Histopathologic examination reveals degeneration of the posterior columns in patients with central nervous system disorders, whereas axonal degeneration with secondary segmental demyelination is noted in peripheral nerve dysfunction. Pathogenesis. The cobalamin molecule is a heme-like compound that is water-soluble but lipid-insoluble. It is found in meat, fish, and dairy products; fruits, vegetables, and grains do not contain this vitamin.1021 The molecule is far too large to diffuse readily across the intestinal mucosa; therefore, it requires a transport molecule known as intrinsic factor, which is synthesized by the gastric parietal cells. Vitamin B12-deficient states thus result from dietary deficiency (strict vegetarian diet: lactovegetarian), lack of intrinsic factor (pernicious anemia with autoimmune destruction of parietal cells or gastrectomy), malabsorption syndromes (sprue or lower ileum resection), genetic defects in methionine synthetase, and bacteria (blind-loop syndrome) or parasites (Diphyllobothrium latum [fish tapeworm]) that consume the vitamin before it is absorbed. Cobalamin is necessary for demethylation of methyltetrahydrofolate. Tetrahydrofolate, in turn, is important in the production of folate coenzymes, which are required for DNA synthesis. The pathogenic mechanism for the neuropathy associated with cobalamin deficiency is not known. The neuropathy may result from impairment in DNA synthesis or some other biochemical defect. Electrophysiologic Findings. The electrodiagnostic evaluation reveals abnormalities consistent with a sensory or sensorimotor axonopathy in patients with peripheral neuropathy.416,417, 534,571,641,664,720,733,804,861 The SNAP amplitudes are reduced or absent, whereas the distal sensory latencies and conduction velocities are essentially normal or only mildly abnormal. Motor conduction studies may be normal or demonstrate low-amplitude CMAPs. The motor conduction velocities and distal motor latencies are usually normal. However, F-waves and H-reflexes may be prolonged in latency, and there may be an increase in Fwave chronodispersion. Somatosensory evoked potentials of both upper and lower limb nerves demonstrate findings consistent with prolongation of central conduction time in patients with central nervous system dysfunction.571 Magnetic stimulation also may demonstrate slow central motor conduction.571 Needle EMG reveals fibrillation potentials and positive sharp waves in the distal lower limb muscles with significant reductions in motor unit recruitment. The administration of cobalamin usually reverses, at least in part, most electrophysiologic abnormalities. Treatment. Cobalamin deficiency is treated with intramuscular injections of vitamin B12.

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Vitamin B12 Deficiency Secondary to Nitrous Oxide Inhalation Nitrous oxide has been abused because of its ability to cause a euphoric state. Nitrous oxide can inactivate methylcobalamine, giving rise to clinical and laboratory features described above with vitamin B12 deficiency. Several patients have developed neuropathy and subacute combined degeneration related to nitrous oxide inhalation.577,771,1153,1358 Physical examination reveals reduced sensation to touch and vibration with relatively good preservation of pain, temperature, and proprioception throughout. Deep tendon reflexes are diminished at the ankles, but are normal in other body regions. Sural nerve biopsy can reveal a reduction in the total number of myelinated fibers and evidence consistent with axonal loss. Electrodiagnostic studies demonstrate occasional low-amplitude SNAP responses with normal latencies and conduction velocities. H-reflexes are typically absent in the lower limbs. Similarly, the CMAPs for both upper and lower limb nerves are well preserved for distal motor latency with a minor reduction in conduction velocity. The amplitude may be borderline low. F-waves are usually prolonged in the upper limb and absent in the lower limbs. Needle EMG of the distal muscles may be normal or reveal a reduced number of MUAPs. Some patients have positive sharp waves and fibrillation potentials.

potentials, positive sharp waves, and occasional fasciculation potentials may be observed. Treatment. Administration of folic acid usually results in good clinical recovery.

VITAMIN E
Clinical Features. Vitamin E or alpha-tocopherol is a lipidsoluble antioxidant vitamin considered essential for humans. It is present in minute amounts in the lipid bilayer constituting the cell membrane. There is a close relationship between the metabolism of lipids and that of vitamin E. Three major conditions are associated with vitamin E deficiency: (1) deficient fat absorption (e.g., cystic fibrosis, chronic cholestasis, short-bowel syndrome, and intestinal lymphangiectasia); (2) deficient fat transport (abetalipoproteinemia, hypobetalipoproteinemia, normotriglyeridemic abetalipoproteinemia, and chylomicron retention disease), and (3) a genetically based abnormality of vitamin E metabolism.511,549,550,616a Any of the preceding disorders can result in vitamin E deficiency with neurologic consequences. Patients usually note progressive difficulty in ambulating, especially in the dark, secondary to lack of control of the legs and trouble with sensing there position in space. Ability to perform fine-motor activities with the hands may be markedly reduced . Even with gross movement the upper limbs are described as not going where the patient desires them to go. Some patients report difficulty in arising from a low chair or placing objects overhead. Some patients note a loss of sensation in the feet. Progressive loss of speech control also may be noted. Physical examination reveals an unsteady gait with an inability to walk in tandem as well as a positive Romberg test. Marked upper and lower limb ataxia is noted; truncal ataxia is prominent in some patients. A marked reduction or absence of deep tendon reflexes is a prominent finding, as is loss of position and vibration in the lower and upper limbs. Manual muscle testing is difficult because of the loss of proprioception makes it difficult for some patients to control their musculature adequately. Preferential proximal muscle weakness in some patients suggests a superimposed myopathic process. Ocular examination reveals ophthalmoplegia and retinopathy in patients with significant disease. Histopathology. Peripheral nerve biopsy reveals loss of the large-diameter myelinated fibers, demonstrating that the dorsal root ganglion cell bodies are a major focus of neural loss. Relative sparing of the small-fiber population is noted. Occasional vacuoles in the myelin sheath and break-up of the Schmidt-Lanterman incisures are found. Segmental demyelination is not a feature of vitamin E deficiency. Autopsy has demonstrated profound loss of fibers in the dorsal columns and reductions in the cells of the gracile and cuneate nuclei. Pathogenesis. The pathogenic basis for vitamin E deficiency is not known. Vitamin E has antioxidant properties and may serve to modulate glutamate excitotoxicity. The dorsal root ganglia and the posterior column nuclei have the lowest concentrations in the nervous system and therefore may be particularly sensitive to diminishing concentrations of vitamin E and its possible neuroprotective effects. Electrophysiologic Findings. The most consistent finding in vitamin E deficiencies is reduced amplitudes or absent SNAPs.149,511,549,550,616a,1171 The sensory nerve conduction velocities are normal or only borderline reduced. Somatosensory evoked potentials demonstrate normal peripheral nerve potentials, and marked slowing and attenuation of central responses

FOLIC ACID
Clinical Features. Neurologic disorders are similar to those encountered with vitamin B12 deficiency (see above).129,379,404,1229 Subacute combined degeneration, a sensorimotor peripheral neuropathy, or both can be present in patients with folic acid deficiency. Patients with a peripheral neuropathy usually complain of numbness and tingling in the hands and feet with difficulty in ambulating. Distal muscle atrophy usually is observed on physical examination, as is the absence or significant reduction in deep tendon reflexes. A reduction to vibration, touch, and pain and temperature sensation is present in the lower limbs. It is necessary to measure both serum folic acid and vitamin B12 levels to define a pure folic acid deficiency. Histopathology. No histopathologic analysis has been done in the limited number of patients reported with folic acid deficiency. Pathogenesis. Folic acid is found in fruit and vegetables; liver has particularly high concentrations.1229 Dietary sources of folic acid contain primarily the conjugated compound, but optimal absorption requires deconjugation through specific enzymes at a pH of 5.0. Humans absorb folic acid primarily in the proximal jejunum, but only after the deconjugated form is bound to a specific carrier molecule. Folic acid is required in DNA synthesis. The first signs of deficiency are megaloblastic erythrocyte alterations. Pure folic acid deficiencies are extremely rare but may occur in elderly people on poor diets, alcoholics, young people consuming only snack foods, and patients with partial gastrectomies, duodenojejunal resections, celiac disease, or disorders of the jejunal mucosa.129,379,404,1229 A number of drugs (phenytoin, phenobarbitol, sulfasalazine, colchicine) also interfere with optimal utilization of folic acid. Electrophysiologic Findings. Electrodiagnostic evaluations have been sparse in the few reported patients. The sensory and motor nerve conduction velocities are usually normal or mildly reduced, whereas SNAP and CMAP amplitudes may be slightly diminished. Distal motor and sensory latencies are marginally affected. Needle EMG examinations are normal in most patients, but reduced recruitment associated with fibrillation

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document slowing of central conduction with loss of posterior column fibers. Motor conduction studies are normal with no alterations in conduction velocity, distal motor latency, or CMAP amplitude in either upper or lower limbs. Needle EMG is also typically normal. A few patients may demonstrate rare fibrillation potentials in distal muscles with some MUAP parameter alterations, suggesting a neurogenic type of motor unit remodeling. A rare patient may demonstrate an abundance of short-duration, lowamplitude, polyphasic MUAPs with early recruitment, implying the presence of a superimposed myopathic process. Treatment. Early recognition is imperative because treatment can arrest and sometimes reverse the neurologic symptoms. Treatment is initiated with 400 mg twice daily and gradually increased up to 100 mg/kg/day until vitamin E levels normalize. Patients with malabsorption syndromes require water-miscible vitamin E preparations or intramuscular injections in doses of 100 mg/week.

JAMAICAN NEUROPATHY
Clinical Features. Jamaican neuropathy occurs in two forms: (1) ataxic neuropathy or tropical ataxic neuropathy and (2) spastic or tropical spastic paraparesis.71,1008,1113,1114 The spastic form of the disease may be more common and involves primarily the pyramidal tracts at or about the lumbosacral region. Slow progression of leg weakness, numbness, dysesthesias, back pain, impotence, and urinary incontinence usually are noted. Examination reveals spastic paraparesis with hyperreflexia in the lower limbs and extensor plantar responses. Patients ambulate with a scissors gait. In Jamaica, as opposed to other parts of the world, retrobulbar neuritis and deafness are rather common. The ataxic form of the disease is characterized by the onset of burning feet, with profound loss of posterior column modalities and fewer alterations in pain and temperature sensation. Lower limb absence of deep tendon reflexes is the rule, but strength is well preserved. Histopathology. Sural nerve biopsies reveal axonal loss of both myelinated and unmyelinated fibers. The sensory ganglia also are involved, with both peripheral and central degeneration of sensory nerve fibers. Pathogenesis. The exact cause is unknown but may be associated with some form of toxin or malnutrition. Some cases of tropical spastic paraparesis probably are caused by human Tcell lymphotropic virus type I (HTLV-1; see above).100 Electrophysiologic Findings. There is only one electrodiagnostic medicine report of a patient with the ataxic form of Jamaican neuropathy.71 The upper and lower limb SNAP responses were reduced in amplitude with mild prolongation of the distal sensory latencies. Lower limb CMAP amplitudes were reduced, whereas those in the upper limb were preserved. The distal motor latencies and conduction velocities demonstrated no significant abnormalities. Upper and lower limb Fwave minimal latencies were normal. Needle EMG was consistent with chronic axonal loss in that reduced numbers of MUAPs had prolonged durations and increased amplitudes.

POSTGASTRECTOMY SYNDROMES
Patients who undergo gastrectomies for various medical reasons or gastric restriction operations for morbid obesity can have a sensorimotor peripheral neuropathy or central nervous system dysfunction similar to that found in pernicious anemia.1,63,405,1416 The peripheral nerve manifestations may present in an acute fashion, resembling AIDP, or, more commonly, as a distal sensorimotor peripheral neuropathy. The disorder is usually a result of vitamin B12 malabsorption; hence the neurogenic disorder is understandable. The few reported electrodiagnostic medicine studies have been reported only in brief and describe a mild slowing (within 80% of the lower limit of normal) for both motor and sensory nerve conduction velocities. Needle EMG may only reveal reduced recruitment, and a few patients may have electrical myotonia. Abnormal membrane instability in the form of fibrillation potentials and positive sharp waves is apparently not particularly common.

ALCOHOLIC NEUROPATHY HYPOPHOSPHATEMIA

Patients undergoing hyperalimentation can develop hypophosphatemia if insufficient phosphate is included.95,1396,1433 A rare complication of this electrolyte imbalance is the development of a subacute and severe sensorimotor peripheral neuropathy that at times presents clinically as AIDP. Patients complain of paresthesias that begin in the feet and progress to the upper limbs and remainder of the body. Difficulty in ambulating secondary to weakness and poor appreciation of and inability to control the limbs in space develops over the course of hours to days. Weakness, ataxia, depressed deep tendon reflexes, and reduced perception of all sensory modalities are noted on physical examination. Weakness also may involve the respiratory muscles, requiring assisted ventilation. Electrodiagnostic evaluation reveals an absence of SNAPs. Motor conduction studies reveal slowed lower limb conduction velocities. The lower limb CMAPs are reduced in amplitude and temporally dispersed. F-waves can be difficult to elicit or completely absent. Needle EMG examination shows reduced MUAP recruitment with fibrillation potentials and positive sharp waves in the distal limb muscles. Correction of the hypophosphatemia results in clinical and electrophysiologic improvement. Clinical Features. People who have consumed alcohol for many years, especially to the exclusion of adequate nutritional intake, can develop a generalized sensorimotor primarily axonal peripheral neuropathy.6,84,104,178,,180,853,1204,1208,1413 Some patients present with acute or subacute onset of paresthesias, numbness, areflexia, and weakness, which can resemble GBS.1035,1276,1426 Cranial nerves are spared, but autonomic dysfunction is common. Nutritional deficiency with prominent weight loss 23 months before onset of the acute neuropathy is common. Unlike GBS, CSF protein in alcohol-related acute axonal polyneuropathy is usually normal or only slightly elevated. Much more common in alcoholics is insidious onset of a slowly progressive sensorimotor polyneuropathy. Patients present mainly with numbness, paresthesia, and burning pain. Weakness, if evident, is mild. In acute and chronic forms of alcohol-related polyneuropathy, examination demonstrates reduction to all sensory modalities in a glove-and-stocking distribution; findings are worse in the lower than in the upper limbs. Deep tendon reflexes at the ankles are usually absent, whereas those at the knee and upper limbs are diminished. Distal lower limb weakness is common, but distal upper limb weakness and occasionally proximal lower limb weakness can be demonstrated. An occasional patient presents with symptoms and signs suggestive of myopathy as opposed to neuropathy.

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Histopathology. Reductions in the total number of largeand small-caliber myelinated fibers maintain the bimodal fiber distribution.84,1378,1426 Wallerian degeneration is the primary abnormality, with small degrees of secondary segmental demyelination. In the acute form of peripheral neuropathy, significant degrees of axonal degeneration can be observed, whereas the more slowly progressive form results in only a few degenerated axons despite documentation of an overall loss of fibers. Pathogenesis. The exact cause of peripheral nerve insult in alcoholism is unknown, but it may be related in part to nutritional deficiency (e.g., B vitamin group, folate) or a direct toxic effect of alcohol on peripheral nerves. A dose-dependent toxic effect of alcohol on sensorimotor and autonomic nerves was noted in a case-controlled study.918 Electrophysiologic Findings. Electrodiagnostic evaluation reveals a sensory or sensorimotor polyneuropathy.6,84,104,178, 180,272,853,1204,1378,1413,1426 Evaluation of the sensory fibers demonstrates that the lower limb sensory nerves are altered early in the disease even before the development of overt symptoms of peripheral neuropathy. For example, the sural nerve conduction velocity is mildly to moderately reduced, as is the SNAP amplitude. Over time, the conduction velocity worsens mildly, but the SNAP amplitude eventually may become unobtainable. As the condition progresses, the H-reflex latencies can become prolonged until they also disappear. With marked reduction in the lower limb sensory responses, the upper limb sensory responses begin to demonstrate a reduction in velocity (no greater than 7080% of the lower limit of normal) as well as a reduction in SNAP amplitude. Brainstem and visual evoked potentials may be abnormal in alcoholic patients, suggesting that the central portions of the cranial nerves also are affected.198,199 Motor conduction studies in the lower and upper limbs follow a pattern similar to that of the sensory nerves. The peroneal and tibial nerve conductions demonstrate a mild to moderate reduction in velocities as well as a mild prolongation of the distal motor latencies. Of importance is the progressive reduction in CMAP amplitudes. The F-waves are only mildly prolonged in latency but become harder to obtain as the corresponding CMAP amplitudes decline. Motor conduction studies in the upper limb usually are less affected early in the disease, but in chronic alcoholics, upper limb nerves may be markedly abnormal. The relative refractory period can be used to detect early abnormalities in patients without clinical evidence of peripheral neuropathy.16 Needle EMG of the distal lower limb muscles characteristically reveals positive sharp waves and fibrillation potentials. A reduced number of MUAPs is detected with increased durations and numbers of polyphasic MUAPs. Similar findings are noted in time when the upper limb muscles are investigated. Singlefiber EMG shows an increase in fiber density accompanied by increased jitter and blocking.1292 All of these findings are consistent with a primarily axonal neuropathy accompanied by motor unit remodeling. Treatment. Abstaining from alcohol and consuming an optimal diet can improve the peripheral neuropathy.582,1426

CHRONIC IDIOPATHIC SENSORY OR SENSORIMOTOR POLYNEUROPATHY

Clinical Features. Chronic acquired sensory or sensory motor polyneuropathies occur in approximately 3% of middleaged to older adults. Despite extensive evaluation, the cause of 1035% of all polyneuropathies cannot be determined. Such

cases are categorized as chronic idiopathic polyneuropathy.387,474,594,851,873,968,1045,1070,1428,1429 The diagnosis of chronic idiopathic polyneuropathy is one of exclusion. Laboratory tests for fasting blood glucose, ANA, ESR, SPEP, vitamin B12, thyroid, liver, and renal functions should be normal. Most patients present with sensory symptoms between the ages of 45 and 70 years. Patients may complain of numbness, tingling, or pain (e.g., sharp stabbing paresthesias, burning, or deep aching sensation) in the feet. In fact, discomfort or pain is quite common (6580% of patients).445,486,968,970 In a large series of 93 patients with idiopathic sensory polyneuropathy, the presenting symptoms were numbness and tingling with pain in 63%, numbness or tingling without pain in 24%, and pain alone in 10%.1429 These sensory symptoms begin in the toes, slowly progress up the legs, and eventually reach the distal upper limbs. In about 50% of patients, sensory symptoms are confined to the lower limbs.968,970,1429 The average time to involvement of the upper limbs is about 5 years.968 Physical examination reveals a stocking-glove pattern of sensory loss. Vibratory perception is the sensory modality most commonly impaired (80100% of patients).968,970,1045,1429 Proprioception is impaired in only 2030% of patients, and fewer than 25% have a positive Romberg sign. Pinprick is reduced in 7585% of patients, whereas light touch is impaired in 5492%. Mild distal weakness and atrophy involving foot intrinsic muscles and the ankle dorsiflexors and evertors are evident in as many as 4075% of cases.969,970,1429 Less than 20% of patients have hand intrinsic weakness. However, the mild weakness is not clinically significant and is not the primary symptom or sign of the neuropathy in which sensory abnormalities predominate. Deep tendon reflexes are usually absent at the ankle and diminished at the knees and upper limbs.968,970,1429 Approximately 1525% of patients have generalized areflexia. Classified in the category of idiopathic sensory or sensorimotor polyneuropathies are patients who appear to have pure small-fiber sensory neuropathies.474,594,1045,1429 Such patients have normal sensory nerve conduction studies, and nerve biopsies demonstrate a relatively normal density of large myelinated nerve fibers. Approximately 80% of patients complain of burning pain in the feet. Sharp, lancinating pain, numbness, or paresthesias occur in 4060% of patients. The hands often become affected over time. Symptoms restricted to the upper limbs, cranial nerve involvement, and superimposed autonomic neuropathy are exceptional.474,594 Reduced pinprick or temperature sensation is noted in almost all patients, and vibratory perception is reduced in over 50% of patients. Fewer than 14% of patients have a reduction in proprioception. Motor examination is normal in patients with small-fiber sensory neuropathies. Deep tendon reflexes are usually normal; fewer than 10% of patients have reduced reflexes at the ankles. Symptoms and signs of autonomic impairment (e.g., dry eyes or mouth, facial flushing, reduced or increased sweating, impotence, incontinence, constipation, diarrhea) are seen in the majority of patients with painful sensory neuropathies.972a Laboratory Features. Although patients have normal fasting blood glucose and hemaglobin A1C levels, oral glucose tolerance tests are abnormal in approximately one-third of patients.1224a,1271a About 510% of patients with chronic idiopathic sensory or sensorimotor polyneuropathy have a monoclonal protein.723,970 The overall incidence of monoclonal proteins in older populations is approximately 5%.746 Therefore, the relationship between monoclonal proteins and pathogenesis of the neuropathies is unclear. A strong pathogenic relationship

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has been demonstrated only in patients with demyelinating sensorimotor polyneuropathies and IgM monoclonal proteins, most of whom have anti-MAG antibodies. Most patients with chronic idiopathic sensory or sensorimotor polyneuropathy have axonal neuropathies histologically and electrophysiologically (see below). PCR amplification of the variable T-cell receptor -chain gene reveals the frequent occurrence of dominant T-cell clones of unknown significance.455 Some authors have reported that as many as 30% of patients with chronic idiopathic sensory neuropathy demonstrate antisulfatide antibodies.948,1051 However, other large studies, even by the original group of investigators, have failed to show increased titers of antisulfatide antibodies.968,811,1045,1427,1429 Panels screening for various antiganglioside and other antinerve antibodies (e.g., anti-GM1, anti-Hu antibodies) have no role in screening patients with chronic idiopathic sensory neuropathy.703,1045,14271429 CSF examination is usually normal and thus unwarranted. Histopathology. Sural nerve biopsies confirm the axonal nature of chronic idiopathic sensory polyneuropathies. Axonal degeneration and regeneration with secondary demyelination are often evident on biopsy.873,968,970,1045,1429 Loss of large- and small-diameter myelinated fibers and small unmyelinated fibers can be seen on quantitative morphometry. Demyelination is not a prominent feature. Scattered T-cells may be seen on nerve biopsy although neither significant inflammation of the nerves nor vasculitis is present. The findings on nerve biopsy are rather nonspecific and not helpful in finding the cause of the neuropathy. Thus, we do not routinely perform nerve biopsies on patients with chronic idiopathic sensory polyneuropathies. We consider biopsy in patients with autonomic signs or monoclonal gammopathies to assess for amyloidosis and in patients with underlying diseases at risk for vasculitis (e.g., connective tissue disorders, hepatitis B or C). As expected, patients with small-fiber neuropathies display a selective loss of small myelinated nerves and unmyelinated nerve fibers.474,574,1045 However, even with quantitative analysis, nerve biopsies are normal. The measurement of intraepidermal nerve fiber density on skin biopsies appears to be more sensitive in identifying patients with small-fiber neuropathies than sural nerve biopsies, nerve conduction studies, or quantitative sensory testing (QST).574,593,596,859,1045 After a punch biopsy of the skin in the distal lower limb (foot, calf, or thigh), immunologic staining (e.g., protein gene product 9.5 or PGP 9.5) can be used to measure density of small intraepidermal fibers. Antibodies directed against vasoactive intestinal polypeptide, substance P, and calcitonin gene-related proteins can be used to measure the density of sudomotor axons innervating sweat glands, piloerector nerves to hair follicles, and nerves to small arterioles. Intraepidermal nerve fibers arise entirely from the dorsal root ganglia and are believed to represent the terminals of C and A nociceptors. The density of these nerve fibers is reduced in patients with small-fiber neuropathies, in which nerve conduction studies, QST, and routine nerve biopsies are often normal. In more than one-third of patients with painful sensory neuropathies, intraepidermal nerve fiber density on skin biopsies represent the only objective abnormality even after extensive evaluation.1045 Pathogenesis. The pathogenesis probably is multifactorial. With advances in molecular genetics, some cases probably will be determined to be genetic; others may have a degenerative or immunologic basis. Recent studies suggest that glucose intolerance alone without frank diabetes may be the cause of neuropathy in as many as one-third of patients.407a,1224a,1271a.

Electrophysiologic Findings. Sensory nerve conduction studies demonstrate either absent or reduced amplitudes, particularly of the sural SNAPs.387,594,851,968,970,1045,1070,1428,1429 Sensory nerve conduction velocities, when obtainable, are normal or only mildly slow, whereas distal sensory latencies are normal or slightly prolonged. QST demonstrates abnormal thermal and vibratory perception in as many as 85% of patients.1045,1429 In addition, autonomic testing (e.g., QSART) is abnormal in some patients. Despite the fact that sensory symptoms are much more prominent and weakness, if present, is mild, motor nerve conduction studies are often abnormal. In the large series of patients with idiopathic sensory polyneuropathy reported by Wolfe and colleagues, 60% had motor conduction abnormalities.1429 The most common motor findings are reduced peroneal and posterior tibial CMAP amplitudes. Distal latencies and conduction velocities of the peroneal and posterior tibial CMAPs are normal or only slightly impaired. Abnormalities of median and ulnar CMAPs are much less common. Occasionally both tibial and peroneal nerve responses to the foot intrinsic muscles are absent. The needle EMG examination is consistent with an axonal neuropathy. Positive sharp waves, fibrillation potentials, and reduced recruitment usually are detected in the foot intrinsic and distal lower limb muscles. In profound disease, similar but less severe findings are noted in the upper limbs. MUAP changes of long-duration and increased-amplitude potentials also can be detected. These findings are consistent with a long-standing peripheral neuropathy, causing axonal loss with compensatory motor unit remodeling through collateral sprouting. In patients with pure small fiber neuropathies, motor and sensory nerve conduction studies as well as needle EMG are, by definition, normal.474,574,594,1045 However, QST may reveal abnormal thermal and vibratory perception.594,972a,1045,1429 Furthermore, autonomic testing demonstrates abnormalities in some patients.972a,1045,1260 Treatment. No treatment slows the progression or reverses the numbness or lack of sensation. The disturbing neuropathic pain often can be eased with various medications.445,1428,1429 Our approach to treating the painful paresthesias and burning sensation is similar to the treatment of neuropathic pain, regardless of its cause (e.g., painful sensory neuropathies related to diabetes mellitus, HIV infection, herpes zoster infection) (Table 23-9). Antiepileptic medications (e.g., gabapentin, carbamazepine, phenytoin) and antidepressant medications (e.g., amitriptyline, nortriptyline, desipramine) are most commonly used. The nonnarcotic analgesic, tramadol, also may be tried.

ILLUSTRATIVE CASES
CASE 1:ACUTE ONSET OF LIMB WEAKNESS
Reason for Referral. Acute onset of weakness and sensory complaints. History. A 40-year-old male physician is seen in the hospital with a 4-week complaint of diminished sensation and mild weakness. Approximately 3 weeks before this examination he noted the onset of numbness and tingling in the left and right toes, followed in 2 days by prominent numbness and tingling in the hands. These sensations slowly progressed proximally along both upper and lower limbs over the next 2 weeks to involve all 4 limbs and the trunk. During this same period, progression of reduction in muscle strength was noted throughout, but the weakness in the proximal limb muscles was slightly greater than in the distal ones. He also had difficulty in climbing stairs,

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not because of weakness, but because of a decreased ability to sense where his limbs were. He also noted that he could no longer walk with a narrow base gait or perform a heel-to-toe gait. Running was rather difficult, again not because of overt weakness, but secondary to coordination of the legs. Approximately 5 days before hospital admission, he noted loss of the nasolabial fold bilaterally, worse on the right than on the left. Over the course of the next several days it became increasingly difficult to close his eyes, purse the lips, or retain fluids in the mouth. The patient denies any history of illness over the past 3 months, but approximately 6 weeks before the onset of symptoms, he had received the second dose of a hepatitis immunization. Physical Examination. During physical examination 3 weeks after the onset of abnormal sensations and weakness, the patient is alert and oriented. Deep tendon reflexes are absent throughout, and the patient states that previously they were easy to obtain and symmetric. A reduction in position and vibration sensation is noted in the toes only. Pinprick and temperature are reduced in the distal regions of the upper and lower limbs bilaterally. Manual muscle testing demonstrates a reduction in neck flexor and extensor strength. The proximal upper and lower limb muscles are approximately 4/5 and the distal muscles are 4+/5. Shoulder shrugging is approximately 4/5 bilaterally. Of note, the patient states that the reduction in strength is significant since he participated noncompetitively in weight-lifting activities. An obvious bilateral facial palsy is noted with an inability to bury the eyelids or hold air in the mouth on compressing the cheeks. The patient cannot tandem walk and ambulates with a mildly wide-based gait. A reduction in sensation in the cutaneous distribution of the trigeminal nerve is observed as well as a diminished degree of sensation in the oral cavity. Extraocular muscle movements are intact. His blood pressure, normally 108/70 mmHg, is 160/90 mmHg and is verified at the elevated level by the patient in the resting state. His resting heart rate is approximately 90 beats/minute compared with a previous level of 60 beats/minute. Cerebrospinal fluid analysis revealed an elevated protein level and no cells. By the time of the examination the patient has received two doses of intravenous immunoglobulin (IVIG). Nerve Conduction Studies. Nerve conduction studies are performed in the right upper and lower limbs. The mid-palm temperature is 32.5C on the right and 31.5C posterior to the right lateral malleolus. DSL S Amp DML M Amp NCV Nerve (ms) (V) (ms) (mV) (m/s) F-wave R median 4.1 15.7 4.6 7.8 55.0 38.2 R median 1.9 25.5 (7.0 cm) R ulnar 3.9 10.1 3.8 5.9 57.0 34.2 R peroneal 4.1 8.8 10.4 4.9 39.0 59.2 R tibial 11.5 5.1 37.0 58.7 R sural 4.4 10.1 R facial 5.4 3.1 Note. No evidence suggests conduction block in any of the motor nerves studies in comparing CMAP duration and proximal vs. distal amplitudes. The F-wave latencies are reported as the shortest in a series of 15. Supramaximal stimulation alone produced approximately one-half as many responses as stimuli delivered. DSL, distal sensory latency; S Amp, sensory amplitude; DML, distal motor latency; M Amp, motor amplitude; NCV, nerve conduction velocity; ms, milliseconds; V, microvolts; mV, millivolts; m/s, meter/second. Motor and sensory amplitudes are

measured baseline to peak. Sensory latencies are measured to peak and motor latencies to initial negative onset. Needle Electromyography. A needle EMG investigation is performed on the right upper and lower limb, using a disposable monopolar needle. Muscle Rest Activity Recruitment Supraspinatus Silent Normal Deltoid Silent Normal Biceps brachii Silent Normal Triceps Silent Normal Pronator teres Silent Normal Extensor carpi radialis Silent Normal Extensor digitorum Silent Normal communis Abductor pollicis brevis Silent Normal First dorsal interosseous Silent Normal Abductor digiti quinti Silent Normal Paraspinal C4T1 Silent Normal Tensor fascia lata Silent Normal Gluteus maximus Silent Normal Vastus medialis Silent Normal Tibialis anterior Silent Normal Gastrocnemius Silent Normal Abductor hallucis Silent Normal Comment. The morphology of motor unit action potentials appeared normal.
Summary of Findings 1. The nerve conduction velocities in the lower limb are mildly slowed. 2. All F-waves are abnormally prolonged and reduced in number compared with the number of stimuli delivered. 3. Sensory and motor evoked response amplitudes are at the lower spectrum of normal for this patient. 4. Distal motor latencies are prolonged for lower limb nerves and the median nerve. 5. Needle EMG examination reveals no abnormalities in any of the muscles tested. Electrodiagnostic Medicine Impression 1. The patient demonstrates electrophysiologic evidence of a mild degree, suggesting a widespread demyelinating neural process. The markedly abnormal F-waves suggest that a significant degree of the pathology is located proximally and not amenable to routine nerve conduction testing. The combination of nerve conduction abnormalities and cerebrospinal/clinical findings suggests that the patient may have a slightly atypical presentation of acute inflammatory demyelinating polyradiculoneuropathy. Comment The patient has comparatively less pronounced motor weakness than objective sensory loss. In general, the history and physical findings suggest a mild to moderate degree of peripheral nervous system dysfunction. The distinct lack of mentation difficulties excludes an overt central nervous system disorder. A combination of elevated CSF protein with no cells and physical findings suggesting a peripheral nerve disorder progressing over several weeks is certainly suspicious of AIDP. Reduced numbers and prolongation of F-waves with essentially normal limb conduction velocities are somewhat confirmatory of a preferentially proximal peripheral nerve disorder. Mildly abnormal distal motor latencies, normal nerve conduction velocities in the

1018 PART IV

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upper limbs, and borderline abnormalities in the lower limbs document a mild slowing of nerve conduction in both upper and lower limbs. Needle EMG abnormalities are absent and support the lack of significant axonal loss or conduction block. The electrophysiologic findings are rather nonspecific but certainly compatible with the clinical impression of AIDP. Although conduction block was not demonstrated by this patient, it is important to document its presence by careful recording the CMAP amplitude subsequent to multiple stimulation sites along the course of different nerves. A dramatic reduction in amplitude not accompanied by an abnormal increase in CMAP duration certainly suggests neural blockade. Localizing the CMAP to a short segment is further substantiation of the focal nature of the lesion and helps to confirm the impression of conduction block. In the upper limb, the axilla-to-elbow and forearm-to-wrist segments can be readily assessed for conduction block. In examining the lower limb, it is rather difficult, although not impossible, to examine the portions of the peroneal and tibial nerves that traverse the thigh by stimulating the sciatic nerve just inferior to the gluteal fold. Multiple sensory nerves should be examined because the patient may have preferential involvement of upper limb sensory nerves with relative sparing of nerves in the lower limb, particularly during the early stage of the disease. Needle EMG is of minimal help in formulating a diagnosis in the above patient; however, the absence of membrane instability is certainly expected, given the lack of muscle wasting, minimal strength reduction, and good preservation of CMAP amplitudes to distal stimulation. In some patients with profound disease, it is possible to detect positive sharp waves and fibrillation potentials, which define the presence of axonal loss. The preservation of CMAP amplitudes, lack of significant conduction block distal to the forearm, and absent abnormal spontaneous activity suggest a good clinical prognosis with eventual motor return. Indeed, the patient recovered relatively close to his previous level of functioning over the ensuing 8 months.

CASE 2: PROGRESSIVE LOWER LIMB NUMBNESS AND WEAKNESS

Reason for Referral. Progressive lower limb numbness and weakness. History. A 45-year-old, cachectic-appearing woman is referred for an electrodiagnostic medicine evaluation of progressive lower limb numbness and weakness. Approximately 8 months ago the patient noted the development of numbness and tingling in the plantar surfaces of both feet and a mild degree of a burning sensation in the same distribution. Over the past 8 months the burning has intensified, making ambulation increasingly difficult. Over the same period the patient noted an extension of the numbness and tingling to the lower limb just distal to the knee region. About 1 month ago similar symptoms began in the fingertips and now involves both hands. The patient also states that walking is becoming difficult because of more frequent tripping on pavement. She admits to drinking about a fifth of whatever hard liquor she can obtain per day for the past several years and is rather vague about the exact time frame. There is some suggestion of at least a 25-pound weight loss over the past year. The patient admits to smoking approximately 23 packs of cigarettes per day for the past 1520 years. Physical Examination. The patient appears older than her stated age and is quite thin, presently weighing 100 pounds. Previous medical records indicate a weight of 140 pounds 18 months ago. She is alert and cooperative with a definite odor of alcohol about

her. Cranial nerves are intact. Deep tendon reflexes are absent at the ankle and knee with diminished reflexes for the biceps and triceps. Plantar responses are neutral. The jaw jerk is present but diminished. Manual muscle testing demonstrates 3+/5 for the toe extensors/flexors and ankle dorsiflexors/plantarflexors. Knee flexors and extensors are 4/5, as are the hip flexors and extensors. The upper limb demonstrates a 3+/5 grade of strength for the hand intrinsic muscles with a 4/5 strength for the remainder of the upper limb musculature. Sensation is decreased to all modalities in a typical glove-andstocking distribution. Mild hepatomegaly is noted on abdominal examination, and the skin demonstrate numerous spider angiomata. Nerve Conduction Studies. Nerve conduction studies are performed in the right upper and lower limbs. The mid-palm temperature is 33.5C on the right and 32.5C posterior to the right lateral malleolus. DSL S Amp DML M Amp NCV Nerve (ms) (V) (ms) (mV) (m/s) F-wave R median 4.4 4.0 5.2 3.8 44.0 35.2 R median 2.9 5.5 (7.0 cm) R ulnar 4.2 3.1 4.6 2.9 47.0 34.2 R peroneal Absent Absent R tibial 6.9 0.5 36.0 R sural Absent L sural Absent L peroneal Absent L tibial 6.6 0.6 35.0 DSL, distal sensory latency; S Amp, sensory amplitude; DML, distal motor latency; M Amp, motor amplitude; NCV, nerve conduction velocity; ms, milliseconds; V, microvolts; mV, millivolts; m/s, meter/second. Motor and sensory amplitudes are measured baseline to peak. Sensory latencies are measured to peak and motor latencies to initial negative onset. Needle Electromyography. A needle EMG investigation is performed on the right upper and lower limb, using a disposable monopolar needle. Muscle Rest Activity Recruitment Supraspinatus Silent Normal Deltoid Silent Normal Biceps brachii Silent Normal Triceps Silent Normal Pronator teres 1+ Fibs/PSW Normal Extensor carpi radialis Silent Normal Extensor digitorum 1+ Fibs/PSW Normal communis Abductor pollicis brevis 2 Fibs/PSW Reduced First dorsal interosseous 2+Fibs/PSW Reduced Abductor digiti minimi 2+ Fibs/PSW Reduced Paraspinal C4T1 Silent Normal Abductor pollicis brevis* 2+Fibs/PSW Reduced First dorsal interosseous* 2+ Fibs/PSW Reduced Tensor fascia lata Silent Normal Gluteus maximus Silent Normal Vastus medialis 1+ Fibs/PSW Normal Tibialis anterior 2+ Fibs/PSW Reduced Gastrocnemius 2+ Fibs/PSW Reduced Abductor hallucis 3+ Fibs/PSW Markedly reduced Paraspinals L1S1 Silent Normal Tibialis anterior* 2+ Fibs/PSW Reduced Gastrocnemius* 2+ Fibs/PSW Reduced Abductor hallucis* 3+ Fibs/PSW Markedly * Also performed on the left side.

Chapter 23

ACQUIRED NEUROPATHIES 1019

Summary of Findings 1. The nerve conduction studies in the lower limbs are absent, whereas those in the upper limb reveal reduced motor and sensory amplitudes with mild prolongation of distal latencies and reductions in conduction velocity. 2. All F-waves that can be obtained are mildly prolonged. 3. Needle EMG examination demonstrates a loss of MUAPs in the distal upper and lower limb muscles with a concomitant documentation of positive sharp waves and fibrillation potentials in the same muscular distribution. Electrodiagnostic Medicine Impression The patient demonstrates electrophysiologic evidence consistent with a generalized sensorimotor peripheral neuropathy resulting in primarily loss of axons, as demonstrated by reduced or absent sensory and motor responses with only mild reductions in conduction velocity. The needle EMG examination reveals a reduced number of motor units with denervation in the distal upper and lower limb musculature. These findings are compatible with the history of reduced nutrition and increased alcohol intake. A thorough medical evaluation should be pursued to investigate the possibility of a coexistent occult process. Comment The patient provides a history compatible with significant alcohol intake for a prolonged period, coupled with reduced nutritional intake. A prolonged history of smoking also is noted. A complaint of progressive numbness, tingling, and burning beginning in the feet and progressing not only proximally in the lower limbs but also in the hands, accompanied by weakness, is certainly suspicious for a generalized sensorimotor peripheral neuropathy. The physical examination is compatible with the history: a glove-and-stocking distribution of sensory loss is objectively found as well as absent or reduced deep tendon reflexes and distal muscle weakness. The clinical impression of a generalized sensorimotor peripheral neuropathy is appropriate. An electrodiagnostic medicine evaluation reveals a number of confirmatory electrophysiologic findings. Both motor and sensory responses are absent in the lower limbs, and distal motor latency and conduction velocity are relatively preserved in a single nerve, given the CMAP amplitude. These findings suggest profound axonal loss. In the upper limbs, the distal motor latencies are mildly prolonged and the conduction velocities reduced, but the major abnormality is a reduction in all CMAP amplitudes. The reduced CMAPs are out of proportion to the neural conduction parameters, again supporting the impression of preferential axonal loss as the major disease process. Reduced MUAPs, accompanied by positive sharp waves and fibrillation potentials in the distal regions of the limbs, with the lower limbs more affected than the upper limbs, are compatible with the impression of a distal axonal generalized polyneuropathy affecting both motor and sensory fibers. Despite the obvious clinical history and physical examination as well as the electrodiagnostic findings, all of which support a diagnosis of an alcohol-induced generalized sensorimotor axonal polyneuropathy, a number of metabolic (nutritional, diabetes mellitus) and occult disorders (carcinoma of the lung) should be pursued to some degree, given the patients poor nutrition, weight loss, and smoking history.

for the clinician. The clinical history and examination are the most important aspects of evaluating patients with neuropathy. However, electrodiagnostic techniques are extremely valuable in helping to define the underlying pathophysiologic process (e.g., axonal or demyelinating), its distribution (e.g., multifocal or generalized), and the functional subtypes of the nerves involved (e.g., motor, autonomic, large-fiber sensory, small-fiber sensory). Clinical and electrophysiolgic features of a demyelinating polyneuropathy or multifocal/multiple mononeuropathies are extremely important findings because these types of acquired peripheral neuropathies are often treatable. Based on clinical and electrodiagnostic studies, the appropriate laboratory work-up should be ordered, eliminating the costly and inefficient shotgun approach to evaluating patients with neuropathy. Again, the authors emphasize that electrodiagnostic medicine specialists must be knowledgeable about the underlying pathophysiology and treatment of the different types of acquired peripheral neuropathy.299,482

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CONCLUSION
Because of the vast number of acquired peripheral neuropathies, evaluation and accurate diagnosis can be challenging

1020 PART IV

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Chapter 23
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122. Bonomo L, Casato M, Afeltra A, Caccavo D: Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 1987;83:7266730. 122a. Boonyapisit K, Katirji B: Multifocal motor neuropathy presenting with respiratory failure. Muscle Nerve 2000;23:18871890. 123. Boothby JA, de Jesus PV, Rowland LP: Reversible forms of motor neuron disease. Arch Neurol 1974;31:1823. 124. Borgeat A, De Muralt B, Stalder M: Peripheral neuropathy associated with high-dose Ara-C therapy. Cancer 1986;58:852853. 125. Borit A, Altrocchi PH: Recurrent polyneuropathy and neurolymphomatosis. Arch Neurol 1971; 24:4049. 126. Borrett D, Ashby P, Bilbao J, Carlen P: Reversible late onset disulfiram induced neuropathy and encephalopathy. Ann Neurol 1985;17:396399. 127. Bosboom WMJ, Van den Berg LH, De Boer L, et al: The diagnostic value of sural nerve T cells in chronic inflammatory demyelinating polyneuropathy. Neurology 1999;53;837845. 128. Bosch EP, Smith BE: Peripheral neuropathies associated with monoclonal proteins. Med Clin North Am 1993; 77:125139. 129. Botez MI, Peyronnard J-M, Bachevalier J, Charron L: Polyneuropathy and folate deficiency. Arch Neurol 1978;35:581584. 130. Bouchard C, Lacroix C, Plante V, et al: Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy. Neurology 1999;52:498503. 131. Bouch P, Bousser M-G, Peytour MA, Cathala HP: Perhexiline maleate and peripheral neuropathy. Neurology 1979;29:739743. 132. Bouch P, Leger JM, Travers MA, et al: Peripheral neuropathy in systemic vasculitis: Clinical and electrophysiologic study of 22 patients. Neurology 1986;36:15981602. 133. Bouch P, Moulonguet A, Younes-Chennoufi AB, et al: Multifocal motor neuropathy with conduction block: A study of 24 patients. J Neurol Neurosurg Psychiatry 1995;59:3844. 134. Boulton AJM, Knight G, Drury J, Ward JD: The prevalence of symptomatic diabetic neuropathy in an insulin-treated population. Diabetes Care 1985;8: 125128. 135. Bourque CN, Anderson BA, del Campo MC, Sima AAF: Sensorimotor perineuritisan autoimmune disease? Can J Neurol Sci 1985;12:129133. 136. Bradley WG, Lassman LP, Pearce GW, Walton JN: The neuromyopathy of vincristine in man. J Neurol Sci 1970;10:107131. 137. Bradley WG, Karlsson IJ, Rassol CG: Metronidazole neuropathy. Br Med J 1977;1:610611. 138. Bradley WG, Chad D, Verghese JP, et al: Painful lumbosacral plexopathy with elevated erythrocyte sedimentation rate: A treatable inflammatory syndrome. Ann Neurol 1984;15:457464. 139. Bradley WG, Lin JT: Assessment of diabetic sexual dysfunction and cystopathy. In Dyck PJ, Thomas PK, Asbury AK (eds): Diabetic Neuropathy. Philadelphia, W.B. Saunders, 1987, pp 146161. 140. Bradley WG, Bennett RK, Good P, Little B: Proximal chronic inflammatory polyneuropathy with multifocal conduction block. Arch Neurol 1988;45: 451455. 141. Bradley WG, Verma A: Painful vasculitic neuropathy in HIV-1 infection: Relief of pain with prednisone therapy. Neurology 1996;47:11461151. 142. Bradley WG, Shapshak P, Delgado S, et al: Morphometric analysis of the peripheral neuropathy of AIDS. Muscle Nerve 1998;21:11881195. 143. Bradshaw DY, Jones HR: Guillain-Barr syndrome in children: Clinical course, electrodiagnosis, and prognosis. Muscle Nerve 1992;15:500506. 144. Brannagan TH, Nagle KJ, Lange DJ, Rowland LP: Complications of intravenous immune globulin treatment in neurologic patients. Neurology 1996;47: 674677. 145. Brannagan TH: Retroviral-associated vasculitis of the nervous system. Neurol 1997;15:927944. 146. Bregman CL, Buroker RA, Hirth RS, et al: Etopside- and BMY-40481-induced sensory neuropathy in mice. Toxicol Pathol 1994;22:528535. 147. Briani C, Brannagan TH III, Trojaborg W, Latov N: Chronic inflammatory demyelinating polyneuropathy. Neuromuscul Disord 1996;6:311325. 148. Bril V, Ilse WK, Pearse R, et al: Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barr syndrome. Neurology 1996;46: 100103. 149. Brin MF, Fetell MR, Green PHA, et al: Blind loop syndrome, vitamin E malabsorption, and spinocerebellar degeneration. Neurology 1985;35:338342. 150. Bromberg MB: Comparison of electrodiagnostic criteria for primary demyelination in chronic polyneuropathy. Muscle Nerve 1991;14:968976. 151. Bromberg MB, Feldman EL, Jaradeh S, Albers JW: Prognosis in long-term immunosuppressive treatment of refractory chronic inflammatory demyelinating polyradiculoneuropathy. J Clin Epidemiol 1992;45:4752. 152. Bromberg MB, Feldman EL, Albers JW: Chronic inflammatory demyelinating polyradiculoneuropathy: Comparison of patients with and without an associated monoclonal gammopathy. Neurology 1992;42:11571163. 153. Bromberg MB, Albers JW: Patterns of sensory nerve conduction abnormalities in demyelinating and axonal peripheral nerve disorders. Muscle Nerve 1993;16:262266. 154. Brown MJ, Martin JR, Asbury AK: Painful diabetic neuropathy: A morphometric study. Arch Neurol 1976;33:164171.

1022 PART IV

CLINICAL APPLICATIONS
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Chapter 23
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256. Crange A, Theodorou I, Sabourin J-C, et al: Inflammatory neuromuscular disorders associated with chronic lymphoid leukemia: evidence for clonal B cells within muscle and nerve. J Neurol Sci 1996;137:3541. 257. Crange A, Sharshar T, Plancenault T, et al: Matrix metalloproteinase-9 is increased and correlates with severity in Guillain-Barr syndrome. Neurology 1999;53:16831691. 258. Crisafulli CM, Saadeh PB, Wolf E: Phrenic nerve conduction studies and needle electromyography of the diaphragm in acute inflammatory demyelinating neuropathy. Muscle Nerve 1991;14:893. 259. Croft PB, Wilkinson M: Carcinomatous neuromyopathy. Its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lancet 1963; 1:184188. 260. Croft PB, Henson RA, Urich H, Wilkinson PC: Sensory neuropathy with bronchial carcinoma: A study of four cases showing serologic abnormalities. Brain 1965; 88:501514. 261. Croft PB, Wilkinson M: The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. Brain 1965; 88:427448. 262. Croft PB, Urich H, Wilkinson M: Peripheral neuropathy of sensorimotor type associated with malignant disease. Brain 1967; 90:3166. 263. Croft PB, Wilkinson M: The course and prognosis in some types of carcinomatous neuromyopathy. Brain 1969; 92:18. 264. Cros D, Chiappa KH, Patel S, Gominak S: Acquired pure sensory demyelinating polyneuropathy: A chronic inflammatory polyradiculoneuropathy variant? Ann Neurol 1992;32:280. 265. Cruickshank B: The arteritis of rheumatoid arthritis. Ann Rheum Dis 1954;13: 136146. 266. Cruz Martinez A, Gonzalez P, Garza E, et al: Electrophysiologic follow-up in Whipples disease. Muscle Nerve 1987;10:616620. 267. Cruz Martinez A, Rabano J, Villoslada Ccabello A: Chronic inflammatory demyelinating polyneuropathy as first manifestation of human immunodeficiency virus infection. Electromyogr Clin Neurophysiol 1990;30:379383. 268. Cruz Martinez A, Arpa J, Lara M: Electrophysiological improvement after intravenous immunoglobulin in motor neuropathy with multifocal conduction block. J Neurol Neurosurg Psychiatry 1993;56:12361237. 269. Crystal HA, Schaumburg HH, Grober E, et al: Cognitive impairment and sensory loss associated with chronic low-level ethylene oxide exposure. Neurology 1988;38:567569. 270. Currie S, Henson RA, Morgan HG, Poole AJ: The incidence of non-metastatic neurological syndromes of obscure origin in the reticuloses. Brain 1970;93: 629640. 271. Czernin S, Gessl A, Wilfing A, et al: Suramin affects human peripheral blood mononuclear cells in vitro: Inhibition of Y cell growth and modulation of cytokine secretion. Int Arch Allergy Immunol 1993;101:240246. 272. DAmour ML, Shahani BT, Young RR, Bird KT: The importance of studying sural nerve conduction and late responses in the evaluation of alcoholic subjects. Neurology 1979;29:16001604. 273. DAmour ML, Dufresne LR, Morin C, Slaughter D: Sensory nerve conduction in chronic uremic patients during the first six months of hemodialysis. Can J Neurol Sci 1984;11:269271. 274. Dalakas MC, Houff SA, Engel WK, et al: CSF monoclonal bands in chronic relapsing polyneuropathy. Neurology 1980;30:864867. 275. Dalakas MC, Engel WK: Polyneuropathy with monoclonal gammopathy: Studies of 11 patients. Ann Neurol 1981;10:4552. 276. Dalakas MC, Engel WK: Chronic relapsing (dysimmune) polyneuropathy: Pathogenesis and treatment. Ann Neurol 1981;9(Suppl):134145. 277. Dalakas MC: Chronic idiopathic ataxic neuropathy. Ann Neurol 1986;19:545554. 278. Dalakas MC, Pezeshkpour GH: Neuromuscular diseases associated with human immunodeficiency virus infection. Ann Neurol 1988;23(Suppl): S38S48. 279. Dalakas MC, Yarchoan R, Spitzer R, et al: Treatment of human immunodeficiency virus-related polyneuropathy with 3'-azido-2',3'-dideoxythymidine. Ann Neurol 1988;23(Suppl)S92S94. 280. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: Risk of precipitating thromboembolic events. Neurology 1994;44:223226. 281. Dalakas MC: Autoimmune ataxic neuropathies (sensory ganglinopathies): Are glycolipids the responsible autoantigens? Ann Neurol 1996;39:41942. 282. Dalakas MC, Quarles RH, Farrer RG, et al: A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996;40:792795. 283. Dalmau J, Graus F, Rosenlum MK, Posner JB: Anti-Hu associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992;71:5972. 284. Dal Pan GJ, Allen RH, Glass JD: Cobalamin (vitamin B12)-dependent metabolism is not altered in HIV-1-associated vacuolar myelopathy. Ann Neurol 1993;34:281282. 285. Dalton K, Dalton JT: Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand 1987;76:811. 286. Danta G: Hypoglycemic peripheral neuropathy. Arch Neurol 1969;21: 121132. 287. Dastur DK, Antia NH, Divekar SC: The facial nerve in leprosy. Int J Leprosy 1966;34:118138.

1024 PART IV

CLINICAL APPLICATIONS
322. Dinn JJ, Dinn EI: Natural history of acromegalic peripheral neuropathy. Quart J Med 1985;57:833842. 323. Donaghy M, Hall P, Gawler J, et al: Peripheral neuropathy associated with Castlemans disease. J Neurol Sci 1989;89:253267. 324. Donaghy M, Mills KR, Boniface SJ, et al: Pure motor demyelinating neuropathy: Deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778783. 325. Donald MW, Bird CE, Lawson JS, et al: Delayed auditory brainstem responses in diabetes mellitus. J Neurol Neurosurg Psychiatry 1981;44:641644. 326. Donofrio PD, Albers JW, Greenberg HS, Mitchell BS: Peripheral neuropathy in osteosclerotic myeloma: Clinical and electrodiagnostic improvement with chemotherapy. Muscle Nerve 1984;7:137141. 327. Donofrio PD, Alessi AG, Burke JM: Polyneuropathy in benign monoclonal gammopathy of undetermined significance. Muscle Nerve 1984;7:564. 328. 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288. Dastur DK, Manhgani DK, Osuntokun BO, et al: Neuromuscular and related changes in malnutrition. J Neurol Sci 1982;55:207230. 289. Daube JR, Kelly JJ, Martin RA: Facial myokymia with polyradiculoneuropathy. Neurology 1979;29:662669. 290. Daugaard GK, Petrera J, Trojaborg W: Electrophysiological study of the peripheral and central neurotoxic effect of cis-platin. Acta Neurol Scand 1987; 76:8693. 291. David WS, Peine C, Schlesinger P, Smith SA: Nonsystemic vasculitic mononeuropathy multiplex, cryoglobulinemia, and hepatitis C. Muscle Nerve 1996;19:15961602. 292. Davies L, Spies JM, Pollard JD, McLeod JG: Vasculitis confined to peripheral nerves. Brain 1996;119:14411448. 293. Davis DG, Patchell RA: Neurologic complications of bone marrow transplantation. Neurol Clin 1988;6:377387. 294. Davis GL, Balart LA, Schiff ER, et al: Treatment of chronic hepatitis C with recombinant interferon alpha. A multicenter randomized controlled trial. N Engl J Med 1989;321:15011506. 295. Davis LE, Drachman DB: Myeloma Neuropathy. Arch Neurol 1972;27: 507511. 296. Davis LE, Standefer JC, Kornfel M, et al: Acute thallium poisoning: Toxicological and morphological studies of the nervous system. Ann Neurol 1981;10:3844. 297. Dawson DM, Samuels MA, Morris J: Sensory form of acute polyneuritis. Neurology 1988;38:17281731. 298. Dayan AD, Ogul E, Graveson GS: Polyneuritis and herpes zoster. J Neurol Neurosurg Psychiatry 1972;35:170175. 299. Dehaine I, Martin JJ, Geens K, Cras P: Guillain-Barr syndrome with ophthalmoplegia: Clinicopathological study of the central and peripheral nervous systems, including the oculomotor nerves 1986;36Z:851854. 300. de Jager AEJ, van Weerden TW, Houthoff HJ, de Monchy JG: Polyneuropathy after massive exposure to parathion. Neurology 1981;31:603605. 301. Dejard A, Petersen P, Kastrup J: Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet 1988;1:911. 302. DeJesus PV: Landry-Guillain-Barr-Strohl syndrome: Neuronal disorder and clinico-electrophysiological correlation. Electromyogr Clin Neurophysiol 1974;14:115132. 303. De Jong RN: The Guillain-Barr syndrome. Polyradiculoneuritis with albuminocytologic dissociation. Arch Neurol Pyschiatr 1940;44:10441068. 304. De Pablos C, Calleja J, Fernandez F, Berciano J: Miller Fisher syndrome: An electrophysiologic study. Electromyogr Clin Neurophysiol 1988;28:2125. 305. De Pablos C, Berciano J, Calleja J: Brain-stem auditory evoked potentials and blink reflex in Friedreichs ataxia. J Neurol 1991;238:212216. 306. de la Monte SM, Gabuzda DH, Ho DD, et al: Peripheral neuropathy in the acquired immunodeficiency syndrome. Ann Neurol 1988;23:485492. 307. Delaney P: Neurologic manifestations of sarcoidosis. Ann Intern Med 1977; 87:336345. 308. Delaney P: Gouty neuropathy. Arch Neurol 1983;40:823824. 309. Del Campo M, Bolton CF, Lindsay RM: The value of electrophysiologic studies in assessing peripheral nerve function during optimal hemodialysis. Muscle Nerve 1983;6:533534. 310. Deconinck N, Van Parijs V, Beckers-Bleukx G, Van den Bergh P: Critical illness myopathy unrelated to corticosteroids or neuromuscular blocking agents. Neuromuscul Disord 1998;8:186192. 311. Delanoe C, Sebire G, Landrieu P, et al: Acute inflammatory demyelinating polyneuropathy in children: Clinical and electrodiagnostic studies. Ann Neurol 1998;44:350356. 312. Denny-Brown D: Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry 1948; 11:7387. 312a. deSeze M, Petit H, Wiart L, et al: Critical illness polyneuropathy. A 2-year follow-up with 19 severe cases. Eur Neurol 2000;43:6169. 313. De Silva RN, Willison HJ, Doyle D, et al: Nerve root hypertrophy in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 1994;17:168170. 314. De Vivo D, Engel WK: Remarkable recovery of a steroid-responsive recurrent polyneuropathy. J Neurol Neurosurg Psychiatry 1970;33:6269. 315. Diabetes Control and Complications Trial Research Group: The effect of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977986. 316. Diabetes Control and Complications Trial: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869880. 317. DiBisceglie AM, Martin P, Kassianides CK, et al: Recombinant interferon alpha therapy for chronic hepatitis C. A randomized, double-blind, placebo controlled trial. N Engl J Med 1989;321:15011506. 318. Dick DJ, Lane RJM, Nogues MA, Fawcett PR: Polyneuropathy in occult hypothyroidism. Postgrad Med J 1983;59:518519. 319. Dierckx RA, Aichner F, Gerstenbrand F, Fritsch P: Progressive systemic sclerosis and nervous system involvement. Eur Neurol 1987;26:134140. 320. Difini JA, Santos JF, Barton B: Misdiagnosis of acute arsenical neuropathy. Muscle Nerve 1990;13:854. 321. Dinn JJ: Schwann cell dysfunction in acromegaly. J Clin Endocrinol 1970; 31:140143.

Chapter 23
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1026 PART IV

CLINICAL APPLICATIONS
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Chapter 23
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Chapter 23
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Chapter 23
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Chapter 23
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1034 PART IV

CLINICAL APPLICATIONS
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Chapter 23
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Pachner AR, Steere AC: The triad of neurologic manifestations of Lyme disease: Meningitis, cranial neuritis, and radiculoneuritis. Neurology 1985;35:4753. 1012. Pakalnis A, Drake ME, Barohn RJ, et al: Evoked potentials in chronic inflammatory demyelinating polyneuropathy. Arch Neurol 1988;45:10141016. 1013. Pakiam ASI, Parry GJ: Multifocal motor neuropathy without overt conduction block. Muscle Nerve 1998;21:243245. 1014. Pal PK: Clinical and electrophysiological studies in vincristine induced neuropathy. Electromyogr Clin Neurophysiol 1999;39:323330. 1015. Palliyath SK, Schwartz BD, Gant L: Peripheral nerve functions in chronic alcoholic patients on disulfiram: A six month follow-up. J Neurol Neurosurg Psychiatry 1990;53:227230. 1016. Palmer KNY: Polyradiculoneuropathy treated with cytotoxic drugs. Lancet 1966;1:265. 1017. Pamphlett RS, Mackenzie RA: Severe peripheral neuropathy due to lithium intoxication. J Neurol Neurosurg Psychiatry 1982;45:656. 1018. 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1033. Pascoe MK, Windebank AJ, Litchy WJ: Subacute diabetic proximal neuropathy. Mayo Clin Proc 1997;72:11231132. 1034. Passerini L, Cosio MG, Newman SL: Respiratory muscle dysfunction after herpes zoster. Am Rev Resp Dis 1985;132:13661367. 1035. Pastena L, Chiodo F, Ceddia A: Guillain-Barr syndrome in chronic alcoholism. Drug Alcohol Depend 1988;21:153156. 1036. Pasternak JF, Fulling K, Nelson J, Prensky AL: An infant with chronic, relapsing polyneuropathy responsive to steroids. Dev Med Child Neurol 1982;24: 504510. 1037. Patel SR, Forman AD, Bejamin RS: High dose ifosfamide-induced exacerbation of peripheral neuropathy. J Natl Cancer Inst 1994;86:305306. 1038. Paul M, Joshua D, Rehme N, et al: Fatal peripheral neuropathy associated with high-dose cytosine arabinoside in acute leukemia. Br J Haematol 1991;79: 521423. 1039. Paulson JC, McClure WO: Microtubules and axoplasmic transport: inhibition of transport by podophyllotoxin: An interaction with microtuble protein. 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1036 PART IV

CLINICAL APPLICATIONS
1101. Richter C, Schanbel E, Csernok E: Treatment of ANCA-associated vasculitis with high-dose intravenous immunoglobulin. Arthritis Rheum 1994;37:S353. 1102. Ricker K, Hertel G: Electrophysiological findings in the syndrome of acute ocular muscle palsy with ataxia (Fisher syndrome). J Neurol 1976;214:35 44. 1103. Ridley DS, Jopling WH: Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis 1966;34:255276. 1104. Riggs JE, Schochet SS, Gutman L, et al: Chronic human colchicine neuropathy and myopathy. Arch Neurol 1986;43:521523. 1105. Riggs JE, Ashraf M, Snyder RD, Gutmann L: Prospective nerve conduction studies in Cisplatin therapy. Ann Neurol 1988;23:9294. 1106. Riley DE, Shields RE: Diabetic amyotrophy with upper limb involvement. Neurology 1984;34(Suppl 1):173. 1107. Roberts M, Willison HJ, Vincent A: Multifocal motor neuropathy human sera block distal motor nerve conduction in mice. Ann Neurol 1995;38:111118. 1108. Robertson D, Davis TL: Recent advances in the treatment of orthostatic hypotension. Neurology 1995;45(Suppl 5):S2632. 1109. Robertson DRC, George CF: Treatment of post-herpetic neuralgia in the elderly. Br Med Bull 1990;46:113123. 1110. Robertson KR, Stern R, Hall CD, et al: Vitamin B12 deficiency and nervous system disease in HIV infection. Arch Neurol 1993;50:807811. 1111. Rodriguez G, Sanchez W, Chaleta JG, Soto J: Primary neuritic leprosy. J Am Acad Dermatol 1993;29:10501052. 1112. Roelofs RI, Hrushesky W, Rogin J, Rosenberg L: Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 1984;34:934938. 1113. Roman GC, Spencer PS, Schoenberg BS: Tropical myeloneuropathies: The hidden endemias. Neurology 1985;35:11581170. 1114. Roman GC: Tropical myeloneuropathies. In Dyck PJ, Thomas PK, Griffin JW (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, W.B. Saunders, 1993, pp 13221331. 1115. Ropert A, Metral S: Conduction block in neuropathies with necrotizing vasculitis. Muscle Nerve 1990;13:102105. 1116. Ropper AH: Unusual clinical variants and signs in Guillain-Barr syndrome. Arch Neurol 1986;43:11501152. 1117. Ropper AH: Severe acute Guillain-Barr syndrome. Neurology 1986;36: 429432. 1118. Ropper AH, Chiappa KH: Evoked potentials in Guillain-Barr syndrome. Neurology 1986;36:587590. 1119. Ropper AH, Albers JW, Addison R: Limited relapse in Guillain-Barr syndrome after plasma exchange. Arch Neurol 1988;45:314315. 1120. Ropper AH, Wijdicks EFM, Shahani BT: Electrodiagnostic abnormalities in 113 consecutive patients with Guillain-Barr syndrome. Arch Neurol 1990;47: 881887. 1121. Ropper AH, Wijdicks EFM, Truax BT: Guillain-Barr Syndrome. Philadelphia, FA Davis,1991 1122. Ropper AH: The Guillain-Barr syndrome. N Engl J Med 1992;326: 11301136. 1123. Ropper AH: Accelerated neuropathy of renal failure. Arch Neurol 1993; 50:536539. 1124. Ropper AH: Further regional variants of acute immune polyneuropathy. Arch Neurol 1994;51:671675. 1125. Rosenberg NL, Lacy JR, Kennaugh RC, et al: Treatment of refractory chronic demyelinating polyneuropathy with lymphoid irradiation. Muscle Nerve 1985;8:223232. 1125a. Rosenbaum R: Neuromuscular complications of connective tissue diseases. Muscle Nerve 2001;24:154169. 1126. Rosenberg RN, Lovelace RE: Mononeuritis multiplex in lepromatous leprosy. Arch Neurol 1968;19:310314. 1127. Rosenblum MK: Paraneoplastic and autoimmunologic injury of the nervous system: the anti-Hu syndrome. Brain Pathol 1993:3:199212. 1128. Rosenfeld T, Price MA: Paralysis in herpes zoster. Aust N Z J Med 1985;15: 712716. 1129. Ross MA: Neuropathies associated with diabetes. Med Clin North Am 1993; 77:111124. 1130. Rossini PM, Treviso M, Di Stefano E, Di Paolo B: Nervous impulse propagation along peripheral and central fibers in patients with chronic renal failure. Electroencephalogr Clin Neurophysiol 1983;56:293303. 1131. Roth G, Rohr J, Magistris MR, Ochsner F: Motor neuropathy with proximal multifocal persistent conduction block, fasciculations and myokymia. Eur Neurol 1986;25:416423. 1131a. Rotta FT, Sussman AT, Bradley WG, et al: The spectrum of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2000;173:129139 1132. Roullet E, Assuerus V, Gozlan J, et al: Cytomegalovirus multifocal neuropathy in AIDS: analysis of 15 consecutive cases. Neurology 1994:44:21742182. 1133. Roussy G, Corneil L: Progressive hypertrophic non-familial neuritis in adults. Ann Med 1919;6:206305. 1134. Roux S, Grossin M, DeBrandt M, et al: Angiotrophic large cell lymphoma with mononeuropathy multiplex mimicking systemic vasculitis. J Neurol Neurosurg Psychiatry 1995:58:365366 1135. Rowbotham MC: Managing post-herpetic neuralgia with opiods and local anesthetics. Ann Neurol 1994;35:S46S49.

1066. Postma TJ, Vermorken JB, Liefting AJM, et al: Paclitaxel-induced peripheral neuropathy. Ann Onc 1995;6:489494. 1067. Powell RJ, Jenkins JS, Smith NJ: Peripheral neuropathy in thalidomide treated patients. Br J Rheum 1987;26:12. 1068. Powles RL, Malpas JS: Guillain-Barr syndrome associated with chronic lymphatic leukemia. Br Med J 1967; 3:286287. 1069. Prick JJG: Thallium poisoning. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, Vol. 36. Amsterdam, North-Holland Publishing, 1979, 239278. 1070. Prineas J: Polyneuropathies of undetermined cause. Acta Neurol Scand 1970;46(Suppl 44):172. 1071. Prineas JW, McLeod JR: Chronic relapsing polyneuritis. J Neurol Sci 1976;27:427458. 1072. Pringle CE, Belden J, Veitch JE, Brown WF: Multifocal motor neuropathy presenting as ophthalmoplegia. Muscle Nerve 1997;20:347351. 1073. Propp RP, Means E, Deibel R, et al: Waldenstroms marcroglobulinemia and neuropathy. Neurology 1975;25:980988. 1074. Przedbroski S, Liesnard C, Voordecker P, et al: Inflammatory demyelinating polyradiculoneuropathy associated with human immunodeficiency virus infection. J Neurol 1988;235:359361. 1075. Puechal X, Said G, Hilliquin P, et al: Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995;38:16181629. 1076. Purnell DC, Daly DD, Lipscomb PR: Carpal-tunnel syndrome associated with myxedema. Neurology 1968;108:151756. 1077. Quan D, Rich MM, Bird SJ: Acute idiopathic dysautonomia: electrophysiology and response to intravenous immunmoglobulin. Neurology 2000;54: 770771. 1078. Qureshi AI, Cook AA, Mishu HP, Krendel DA: Guillain-Barr syndrome in immunocompromised patients: a report of three patients and review of the literature. Muscle Nerve 1997;20:10021007. 1079. Rae-Grant AD, Feasby TE, Brown WF: A reversible demyelinating polyneuropathy associated with cancer. Neurology 1986;36(Suppl 1):81. 1080. Raff M, Asbury AK: Ischemic mononeuropathy and mononeuropathy multiplex in diabetes mellitus. N Engl J Med 1968;269:1722. 1081. Rail D, Stark R, Swash M: Improvement in nerve condition after plasma exchange for Guillain-Barr syndrome. J Neurol Neurosurg Psychiatry 1980;43: 1147. 1082. Raman PT, Taori GM: Prognostic significance of electrodiagnostic studies in the Guillain-Barr syndrome. J Neurol Neurosurg Psychiatry 1976;39:163170. 1083. Ramilio O, Kinane BT, McCracken GH: Chloramphenicol neurotoxicity. Ped Inf Dis J 1988;7:358359. 1084. Ramirez JA, Mendell JR, Warmolts JR, Griggs RC: Phenytoin neuropathy: Structural changes in the sural nerve. Ann Neurol 1986;19:162176. 1085. Rance NE, McArthur JC, Cornblath DR: Gracile tract degeneration in patients with sensory neuropathy and AIDS. Neurology 1998;38:265271. 1086. Rantala H, Uhari M, Niemela D: Occurrence, clinical manifestations, and prognosis of Guillain-Barr in children. Arch Dis Child 1991;66:706709. 1087. Rapoport AM, Guss SB: Dapsone induced peripheral neuropathy. Arch Neurol 1972;27:184185. 1088. Ravitts JM: AAEM minmonograph #48: Autonomic nervous system testing. Muscle Nerve 1997;20:919937. 1089. Read DJ, Vanhegan RI, Matthews WB: Peripheral neuropathy and benign IgG paraproteinemia. J Neurol Neurosurg Psychiatry 1978;41:215219. 1090. Rechtland E, Cornblath DR, Stern BJ, Meyerhoff JO: Chronic demyelinating polyneuropathy in systemic lupus erythematosis. Neurology 1984;34: 13751377. 1091. Rees JH, Gregson NA, Hughes RAC: Anti-ganglioside GM1 antibodies in Guillain-Barr syndrome and their relationship to Campylobacter jejuni infection. Ann Neurol 1995;38:809816. 1092. Rees JH, Soudain SE, Gregson NA, Hughs RA: Campylobacter jejuni infection and Guillain-Barr syndrome. N Engl J Med 1995;333:14151417. 1093. Reeves ML, Seigler DE, Ayyar DR, Skyler JS: Medial plantar sensory response: Sensitive indicator of peripheral nerve dysfunction in patients with diabetes mellitus. Am J Med 1984;842846. 1094. Reik L, Burgdorfer W, Donaldson JO: Neurologic abnormalities in Lyme disease without erythema chronicum mirgrans. Am J Med 1986;81:7378. 1095. Reik L: Peripheral neuropathy in Lyme disease. In Dyck PJ, Thomas PK, Griffin JW (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, W.B. Saunders, 1993, pp 14011411. 1096. Reinstein L, Ostrow SS, Wiernik PH: Peripheral neuropathy after cis-platin (II) (DDP) therapy. Arch Phys Med Rehabil 1980;61:280282. 1097. Reisin RC, Cersosimo R, Garcia Alvarez M, et al: Acute axonal GuillainBarr syndrome in childhood. Muscle Nerve 1993;16:13101316. 1098. Rhee EK, England JD, Sumner AJ: A computer simulation of conduction block: Effects produced by actual block versus interphase cancellation. Ann Neurol 1990;28:146156. 1099. Rich MM, Teener JW, Raps EC, et al: Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 1996;46:731736. 1100. Rich MM, Bird SJ, Raps EC, et al: Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 1997;20:665673.

Chapter 23
1136. Rowinsky EK, Chaudhry V, Forastiere AA, et al: Phase 1 pharmacologic study of paclitaxol and cisplatin with granulocyte colony-stimulation factor: Neuromuscular toxicity is dose-limiting. J Clin Oncol 1993;11:20102020. 1137. Roytta M, Raine CS: Taxol-induced neuropathy: Chronic effects of local injection. J Neurocytol 1986;15:483496. 1138. Rubin D, Daube JR: Subacute sensory neuropathy associated with EpsteinBarr virus. Muscle Nerve 1999;22:16071610. 1139. Rubin M, Karpati G, Carpenter S: Combined central and peripheral myelinopathy. Neurology 1987;37:12871290. 1140. Rudolph SH, Montesinos C, Shanzer S: Abnormal brainstem auditory evoked potentials in Fisher syndrome [abstract]. Neurology 1985;35(Suppl):70. 1141. Rukavina JG, Block WD, Jackson CE: Primary systemic amyloidosis: A review and an experimental, genetic, and clinical study of 29 cases with particular emphasis on the familial form. Medicine 1956;35:239334. 1142. Rushworth G, Gallai V: A clinico-pathological study of three cases of post-infectious polyneuritis with severe involvement of cranial nerves. Acta Neurol 1979;34:351364. 1143. Russell JW, Powles RL: Neuropathy due to cytosine arabinoside. Br Med J 1974;4:652653. 1144. Russell JW, Windebank AJ, McNiven MA, et al: Effect of cisplatin and ACTH 4-9 on neural transport in cisplatin induced neurotoxicity. Brain Res 1975; 676258267. 1145. Russell JW, Windebank AJ, Podratz JL: Role of nerve growth factor in suramin neurotoxicity studied in vitro. Ann Neurol 1994;36:221228. 1146. Rustam H, Hamdi T: Methyl mercury poisoning in Iraq: A neurological study. Brain 1974;97:499510. 1146a. Ryan MM, Grattan-Smith PJ, Procopis PG, et al: Childhood chronic inflammatory demyelinating polyneuropathy: Clinical course and long-term outcome. Neuromusc Dis 2000;10:398406. 1147. Sabatelli M, Mignogna T, Lippi G, et al: Interferon alpha may benefit steroid unresponsive chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 1995;58:638639. 1148. Sabin TD, Swift TR, Jacobson RR: Leprosy. In Dyck PJ, Thomas PK, Griffin JW (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, W.B. Saunders, 1993, pp 13541379. 1149. Sachs GM: Segmental zoster paresis: an electrophysiological study. Muscle Nerve 1996;19:784786. 1150. Sadiq SA, Thomas FP, Kilidireas K, et al: The spectrum of neurologic disease associated with anti-GM1 antibodies. Neurology 1990;40:10671072. 1151. Sagar HJ, Read DJ: Subacute sensory neuropathy with remission: An association with lymphoma. J Neurol Neurosurg Psychiatry 1982; 45:8385. 1152. Sagman DL, Melamed JC: L-Tryptophan induced eosinophilia-myalgia syndrome and myopathy. Neurology 1990;40:16291630. 1153. Sahenk Z, Mendell JR, Couri D, Nachtman J: Polyneuropathy from inhalation of N2O cartridges through a whipped-cream dispenser. Neurology 1978;28: 485487. 1154. Sahenk Z, Brady ST, Mendell JR: Studies on the pathogenesis of vincristineinduced neuropathy. Muscle Nerve 1987;10:8084. 1155. Sahenk Z: Toxic neuropathies. Semin Neurol 1987; 7:917. 1156. Sahenk Z, Barohn RJ, New P, Mendell JR: Taxol neuropathy: an electrodiagnostic and sural nerve biopsy finding. Arch Neurol. 1994; 51:726729. 1157. Said G: Perhexiline neuropathy: A clinicopathological study. Ann Neurol 1978;3:259266. 1158. Said G, Lacroix C, Andriev JN: Necrotizing arteritis in patients with inflammatory neuropathy with human immunodeficiency virus (HIV-III) infection. Neurology 1987;37(suppl 1):176. 1159. Said G, Lacroix-Ciaudo C, Fujimura H, et al: The peripheral neuropathy of necrotizing arteritis: A clinicopathological study. Ann Neurol 1988;23:461465. 1160. Said G, Lacroix C, Chemouilli P, et al: Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: Clinical and pathological study. Ann Neurol 1991;29:139146. 1161. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A: Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 1994;35: 559569. 1162. Said G, Elgrably F, Lacroix C, et al: Painful proximal diabetic neuropathy: Inflammatory nerve lesions and spontaneous favorable outcome. Ann Neurol 1997;41:762770. 1163. Said G: Necrotizing peripheral nerve vasculitis. Neurol Clin 1997;15: 835848. 1164. Salisbury RE, Dingeldein P: Peripheral nerve complications following burn injury. Clin Orthop 1982;163:9297. 1165. Sanche-Guerrero J, Guterre-Urena S, Vidaller A, et al: Vasculitis as a paraneoplastic syndrome. Report of 11 cases and review of the literature. J Rheumatol 1990;17:14581462. 1166. Sander EACM, Peters ACB, Gratana JW, Hughes RA: Guillain-Barr syndrome after varicella zoster infection. J Neurol 1987;234:437439. 1167. Sandler SG, Tobin W, Henderson ES: Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 1969; 19:367374. 1168. Saperstein DS, Amato AA, Wolfe GI, et al: Multifocal acquired demyelinating sensory and motor neuropathy. The Lewis-Sumner syndrome. Muscle Nerve 1999;22:560566.

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Chapter 23
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Chapter 23
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