Chapter 23

Acquired Neuropathies
Anthony A.Amato, M.D. Daniel Dumitru, M.D., Ph.D.
CHAPTER OUTLINE Immune-Mediated Polyneuropathies Guillain-Barré 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 (Hansen’s 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.

In 1859, Landry defined the major clinical features of this neuropathy and coined the term acute ascending paralysis. Subsequently, Guillain, Barré, 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 GuillainBarré syndrome (GBS). Haymaker and Kernohan reported the histopathologic features of 50 fatal cases of GBS in 1949.565

938 — PART IV


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 2–4 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 > 125–150% of normal. • F-waves indicate proximal NCV slowing. • About 15–20% 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 1–4/100,000 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 60–70% of patients with AIDP note some form of acute illness (e.g., a viral syndrome) 1–3 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 Ropper’s 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

Chapter 23


illness. From 5–15% 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 2–4 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 4–8 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 1–2 years after disease onset and 5–10% 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 50–60 years, abrupt onset of profound weakness, need for mechanical ventilation, and distal CMAP amplitudes less than 10–20% 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 15–45% 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-cell–mediated 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-γ, 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

3.940 — PART IV CLINICAL APPLICATIONS Table 23-2. 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. A waves are unlikely to be observed. particularly during the disease’s manifestation within the first several weeks. the NCV must be < 80% of LLN. * Three of the four features must be present. If CMAP amplitude is > 80% of LLN. Fig. when the Fwave is used in this manner. If there is a gradual reduction in amplitude without . waveform duration and morphology. or baselineto-peak amplitude. In addition. and examination of insufficient number of nerves and muscles.g. An average F-wave latency or the difference between the minimum and maximum F-wave latencies may be more appropriate. Electrophysiologic criteria for demyelination have been developed to aid in the diagnosis of AIDP (Table 23-2). CMAP amplitudes. and computer simulation studies suggest a 50% drop in amplitude is more appropriate for the electrophysiologic evidence of conduction block. Abnormal temporal dispersion and possible conduction block • CMAP duration difference between the above proximal and distal sites of stimulation is > 15%. AIDP is a dynamic disease with variable rates of progression in different patients.. F-waves performed in 2 or more nerves (10–15 trials) 2. these techniques have not been studied in AIDP.156 One method of distinguishing between conduction block and temporal dispersion is to use small-segment (e. the F-wave latency must be > 120% of ULN. These parameters are used for the purposes of diagnosis. it is difficult to state with assurance whether conduction block is present (Fig. If CMAP amplitude is < 80% of LLN. Partial conduction block criteria • CMAP duration difference between the above noted proximal and distal sites of stimulation must be < 15%. pseudoconduction block).692.46 Motor Conduction Studies. the F-wave latency must be > 150% of ULN. A comprehensive review of the electrophysiologic literature regarding the various results in AIDP reveals both a number of consistent as well as contradictory findings. prognosis.9 Unfortunately.459.1118 Abnormal F-waves can be expected in as many as 80–90% of patients during the course of the disease. If the CMAP amplitude is > 80% of LLN. 23-1). An investigation documented that 93% of patients demonstrated multiple A waves in at least one limb within 7 days of symptom onset.243. A CMAP reduction of at least 30% for the arm nerves and 40% for the leg nerves seems appropriate. but the most likely explanations include the time during the course of the illness when the patient is examined.243. a hallmark is the asymmetric and multifocal character of the electrophysiologic abnormalities. If excessive temporal dispersion is found. In line with the multifocal character of the disease. proximal nerve segments. however.245. different recording and stimulating techniques. If the CMAP is < 80% of LLN. and • > 20% drop in CMAP negative spike duration or baseline-topeak amplitude. and F-waves.691. Prolonged distal motor latencies (DML) in 2 or more nerves 1. or diffusely throughout the peripheral nervous system.694. giving the appearance of conduction block (i. 30 or 40% reduction in CMAP amplitude or area). stimulate every centimeter) stimulations in the hope of localizing a focal reduction in amplitude. conduction block. conduction velocities. Regions to examine: • Peroneal nerve between fibular head and ankle • Median nerve between wrist and elbow • Ulnar nerve between wrist and below elbow 2. 2. Prolonged minimum F-wave latency or absent F-wave 1.751. 23-2). These autoantibodies most likely bind to the Schwann cells and activate the complement cascade.245.899 It is possible to observe multiple A waves in patients with AIDP. With respect to late responses.g. which increases the duration of the potential with a concomitant and compensatory reduction in amplitude. It is also possible to demonstrate conduction block at the nerve root level by using nerve root stimulation techniques. and prolonged F-wave latencies.249 However. If CMAP amplitude < 80% of LLN. If CMAP amplitude is > 80% of lower limit of normal (LLN). there must be less than a 15% increase in the negative peak duration in comparing the proximal to distal response.89.9. other studies have used stricter criteria (e. Slowing of nerve conduction may be preferentially localized to distal nerve segments. the NCV must be < 70% of LLN. the DML must be > 150% of ULN.. This guideline ensures that a reduction in amplitude is not a result of excessive temporal dispersion.245. slow conduction velocities. H-reflexes also should be attempted in the lower limb as a method of assessing possible proximal neural conduction failure. the DML must be > 125% of the upper limit of normal (ULN). In patients with AIDP.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. 3.901. 2. The most studied aspect of the peripheral nervous system in AIDP is neural conduction along the motor nerve fibers.46. The electrophysiologic hallmarks of demyelination include prolonged distal latencies. but usually peaks at about 4–5 weeks. different aspects of the peripheral nervous system are affected with respect to proximal versus distal from one patient to the next. it is possible for a single motor fiber to escape pathology and mediate a normal F-wave response. The electrophysiologic results are described in terms of the basic pathophysiology of demyelination with an occasional and variable secondary axonal loss component. this parameter is frequently abnormal (prolonged or absent).9 Of importance. and gaining insight into the fundamental pathophysiologic processes operational in the disease. temporal dispersion. The various parameters examined are the distal motor latencies. particularly early in the disease process.245 antigens on the Schwann cell because of this molecular mimicry. The shortest F-wave latency in a series of 10–15 applied stimuli is commonly used for diagnostic purposes..718a In patients with significant axonal loss and loss of the CMAP.e.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.46. CMAP conduction block or abnormal temporal dispersion in 1 or more nerves 1.998a. Inflammatory cells are subsequently recruited to complete the demyelinating process. Electrodiagnostic Medicine Criteria for Peripheral Nerve Demyelination* Conduction velocity reduced in 2 or more nerves 1.892a There are probably multiple reasons for these findings.9.996 Several different types of F-wave abnormalities may be noted. and • A > 20% drop in CMAP negative spike duration. failure to control temperature. Electrophysiologic Findings. leading to lysis of myelin sheaths.

in more chronic disease states or later in the acute disease process.789 The concept of conduction block is critical to understanding the pathophysiologic basis of symptoms in AIDP. it is somewhat easier to be certain of conduction block in the acute time frame compared with the more chronic manifestations of disease.119 The facial nerve may be affected as well as the supraorbital nerve. motor conduction studies can be normal or show only minor abnormalities. Brain 1984. whereby the negative and positive aspects of individual CMAP waveforms cancel each other.690 Within the first week. Subsequent reduction in function may be secondary to an associated axonal loss.The peak-to-peak hypothenar CMAP decreases over 90% when the Erb’s point stimulation site is compared with the wrist. Conduction block of nerve impulses leads to acute weakness and sensory loss. conduction block is probably present. if a marked reduction in amplitude can be localized to a short segment (2–4 cm).) an abrupt decline in CMAP area.156. 80–90% of patients with AIDP have abnormalities in at least one of the motor nerve parameters (distal CMAP latency. indicating essentially normal degrees of temporal dispersion. the improved clinical status probably results from conduction block resolution rather than remyelination or regeneration of the axons. temporal dispersion is the likely culprit. such as the carpal tunnel (median nerve). Albers and colleagues found that 70% of patients had demyelination in two or more nerves and 85% in one nerve. with permission. (From Brown WF. in acute disease presentations. not temporal dispersion. needle EMG of the diaphragm may be performed. particularly after plasmapheresis or intravenous immunoglobulin. Examination of the phrenic and facial nerves may be of interest in patients with AIDP.The corresponding waveforms are noted above the graphic depiction of amplitude reduction.243.484.1449 In addition to nerve conduction studies of the phrenic nerve.248 Excessive reductions in amplitude may be possible with moderate. conduction velocity. Second.1301 Some authorities suggest that conduction block is the earliest electrophysiologic abnormality in AIDP. Asbury.Chapter 23 ACQUIRED NEUROPATHIES — 941 Figure 23-1. alterations in conduction velocity may result in pseudoconduction block.245 to 135 patients with AIDP sequentially studied during the Dutch-GBS PE (plasma exchange) and IVIG trials. being noted in 74% of patients within the first 2 weeks.158 In patients with rapid recovery. Profound demyelination can most likely lead to significant axonal loss with diaphragmatic denervation. 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.892 The sensitivity of the criteria for diagnosing demyelination ranged from 3–36% during . however.243.1270 Conduction block in AIDP can be observed at common sites of entrapment. cubital tunnel (ulnar nerve).The net conclusion of these data is that the reduction in CMAP amplitude results from conduction block. Feasby TE: Conduction block and denervation in Guillain-Barré polyneuropathy. conduction block) within 5 weeks of onset.248 First.10. The maximum degree of motor conduction abnormality occurs within 3–8 weeks. However. The ulnar nerve is investigated 7 days following the onset of AIDP induced weakness. Using their own electrophysiologic criteria for demyelination.The accompanying graph describes the < 15% alteration in CMAP negative spike duration and peak-topeak potential duration. they can be evaluated with both direct facial nerve stimulation and the blink reflex.156. Therefore.954. F-wave latency. degrees of temporal dispersion secondary to phase cancellation effects. Loss of myelin leads to neural conduction failure. which reveals abnormalities in either or both pathways. and fibular head (peroneal nerve). However.73. within 5–7 days after acute axonal loss.245 Reports of lower percentages of patients with electrophysiologic abnormalities most likely result from examining the patients too early or incompletely.10.9. conduction block may occur without demyelination or before demyelination as a result of antibodies blocking ion channels at the nodes of Ranvier.156 The smaller myelinated nerve fibers may be affected first by conduction block with subsequent involvement of the larger fibers. but less than abnormal. relatively small reductions in CMAP amplitude may be a result of conduction block.9 Meulstee and colleagues applied the electrophysiologic criteria for demyelination designed by Albers.1081 Two important caveats about conduction block should be remembered.107:219–239. and Cornblath9.

1423 Sensory Conduction Studies. based on the CMAP findings.107:219–239. temporal dispersion of the CMAP waveforms.1312. other disorders (acute sensory neuronopathy or ganglionopathy) must be ruled out and detailed neurophysiologic studies performed in an attempt to detect subclinical motor abnormalities. can be affected more severely and earlier than the sural SNAPs.g. However. at which time significant and easily identifiable SNAP parameter alterations become obvious. thus predisposing it to a relatively more early disruption of function. accounting for slowing of the median SNAP across the carpal tunnel.1027. Sensory conduction velocities can be slow and distal latencies prolonged.561. because the specific nerves that were studied. it is difficult to state with certainty the most sensitive motor conduction parameter in confirming a diagnosis of AIDP.1333.156 However. Reduced SNAP amplitudes can result from secondary axonal degeneration. The North American Guillain-Barré Syndrome Study Group reported prolonged distal motor latencies and prolonged or absent Fwaves as the earliest abnormal features.930 The exact explanation is multifactorial. with permission.942 — PART IV CLINICAL APPLICATIONS Figure 23-2. the sural nerve usually is studied at a relatively more proximal location in the leg. or phase cancellation related to differential demyelination and slowing of the sensory nerve fibers. On the other hand.243. the timing of the studies in relationship to disease onset. however. Multiple sensory nerves should be examined in both upper and lower limbs. the sural SNAP).9. the various motor conduction parameters. Brain 1984. and the definition of “abnormal” vary in the published studies. range of 2–15 days after onset) to 13–46% during the third study (performed at a median of 34 days. The median nerve SNAP is recorded from the thinly myelinated terminal regions (or stimulated for orthodromic techniques).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. upper limb SNAPs. The sural and superficial peroneal SNAPs can be evaluated in the lower limbs as well as the median.996.. these findings may not be apparent during the first several weeks of the disease. The motor conduction abnormalities remain at their nadir for approximately 1 month and then gradually improve over the next several weeks to months. it cannot be differentiated from the excessive differential slowing effects on nerve conduction velocity. and radial SNAPs in the upper limbs. negative spike duration and peak-to-peak CMAP duration exceed the 15% limit. the mean distal CMAP amplitudes were reduced to approximately 50% of normal and declined further over the next several weeks. ulnar. careful investigation may reveal subtle motor nerve conduction abnormalities.9 Within 1 week of symptoms. and conduction block become apparent.894.243.9 There does not appear to be a correlation between the nerve conduction velocities or distal motor latencies and clinical severity of the neuropathy.) the first study (performed at a median of 6 days.9.806.1121 . Unfortunately.989a. Subsequently.1120 It can take 4–6 weeks for SNAP abnormalities to peak. but often they do not fall below 80% of the lower limit of normal. About 40–60% of patients eventually demonstrate either amplitude or conduction abnormalities of various SNAPs. One may easily conclude that conduction block is present. particularly the median nerve. where it is more heavily myelinated and does not traverse any potential entrapment sites.297. Rarely.989a.895. Considerable reductions in CMAP amplitude are noted when the most proximal response is compared with that evoked from the wrist.245. and the corresponding derived CMAPs are displayed. the slowing of conduction velocities. unlike most axonopathies.302. conduction block. It has been suggested that recognized entrapment sites are more prone to being affected. in which the earliest and most severe abnormalities involve the distal lower limb nerves (e. documenting excessive temporal dispersion and suggesting that if conduction block is present.871. range of 29–49 days after onset). Thus.872 although distal CMAP amplitudes less than 10–20% of normal are associated with a poorer prognosis. demyelinating diseases are just as likely to affect the median and ulnar SNAPs as they are to affect the sural SNAPs. Of note. Albers and colleagues noted that prolonged and diminished CMAP amplitude was the earliest abnormality. Feasby TE: Conduction block and denervation in GuillainBarré polyneuropathy. (From Brown WF.1059. 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). Three patients with AIDP are investigated within 2 weeks of symptom onset. some persons may present with what appears to be pure sensory symptoms and signs.1293 The parameter most adversely affected is SNAP amplitude.1331 With a pure sensory presentation. Some suggest that conduction block is the earliest recognizable electrophysiological abnormality in AIDP.866. but it may take a year or more for normalization. which is usually diminished or absent by the third or fourth week.

In addition. we give additional courses of PE or IVIG. The major presenting complaint in children is pain. The clinical. Plasma exchange (PE)431.1334 Thus.289. there is a gradual decline in the degree of abnormal spontaneous activity. however.946.523. immune complexes. A reduction in nerve conduction velocity was noted in . About 35% of patients demonstrate an abnormality.1119 or IVIG greater than 2 gm/kg is of any added benefit in patients with AIDP and a stable deficit. potentials maximize earlier in proximal muscles than in distal muscles. peaking at about the 6–15 weeks. and 22–60% had mean CMAP amplitudes less than 20% of the lower limit of normal. and autonomic dysfunction can occur. cranial nerve and respiratory muscle weakness.1180 Needle EMG Examination. Sural nerve biopsies in children with GBS demonstrate similar histopathologic abnormalities as those described in adults. 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. substantiating motor unit remodeling in patients with axonal loss. Clinicians need to be aware of the time frame for improvement in AIDP.447 The mean jitter for individual muscles remains normal.612.514 The French Plasmapheresis Group confirmed the effectiveness of PE. electrophysiologic studies demonstrated prolonged or absent F-waves in 81–88% within the first few weeks of symptoms. As in adults. Autonomic Testing. with some disease predisposition toward the proximal or nerve root regions.5 L) total exchange.1249 Although of interest. IVIG was shown to be at least as effective as PE. This may explain why patients demonstrate clinical sensory abnormalities and yet little in the way of electrophysiologic peripheral SNAP abnormalities.143.1059 Treatment with IVIG or PE should begin as soon as possible. time on a ventilator. occasional individual single muscle fibers may demonstrate mildly increased jitter.1053 Of importance.996 However. but of an insufficient degree to alter the value for all potential pairs.1203. PE. there is no indication for PE followed by IVIG or vice versa.612 develop a relapse after initial improvement. and the percentages of patients improving after 1 and 6 months compared with the control group. improvement with PE and IVIG is often not immediate.1387 These potentials are commonly observed within the first three weeks of clinical presentation.1334 have been demonstrated in prospective controlled trials to be effective in the treatment of AIDP (Table 23-3).1076 From 15 weeks onward.1334 Subsequent randomized studies confirmed the efficacy of IVIG in AIDP (see Table 23-3). Treatment. These abnormal potentials can appear in both proximal and distal muscles simultaneously. Over the course of the next 6–16 weeks. During the first few weeks of the disease process.514 and intravenous immunoglobulin (IVIG)1059. Central conduction times are found to be essentially normal.143.821. 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. which can be accomplished by 4–6 alternate day exchanges of 2–4 liters each.1021a. particularly in clinically weak muscles. Of interest. Not unexpectedly.9.0 gm/kg body weight infused over 2–5 days.515 AIDP in Children.514. randomized PE and IVIG studies ranged from 6 days to as long as 27 days.1118.148.844. in fact. some patients have done worse.311. The dose of IVIG is 2. one study noted no added benefit of IVIG after PE. the MUAP duration. complement.821 In large series of children with AIDP. 83–100% of the children also had reduced CMAP amplitudes. 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. The North American Trial revealed that PE reduced the time necessary to improve one clinical grade. preferably within the first 7–10 days of symptoms. corticosteroids do not appear beneficial in the treatment of AIDP.841 Singlefiber EMG reveals a mild to moderate increase in fiber density. Spontaneous potentials in the form of positive sharp waves and fibrillation potentials may first be seen between weeks 2 and 4. this parameter does not really contribute to the diagnosis or prognosis in AIDP and can be rather variable from trial to trial. The earliest motor finding in patients with AIDP is a reduced recruitment of MUAPs. laboratory.000–17.1048 An alternative method of assessing the sympathetic nervous system is to investigate the sympathetic skin response. and electrophysiologic findings in children with AIDP are similar to those noted in adults. Thus.431. there is an increase in all of these MUAP parameters. brainstem auditory evoked responses have generally revealed normal results but a few patients have demonstrated some slowing of conduction. time to walk unaided.1086 Almost 75% of children have an antecedent infection within two months of onset of symptoms.500 ml (14–17.1119 or IVIG182.Chapter 23 ACQUIRED NEUROPATHIES — 943 SEP Conduction Studies. No evidence indicates that PE beyond 250 ml/kg182.157 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. The needle EMG examination in patients with AIDP is primarily adjunctive to explore the possibility of other disease entities.370.11 A reduced number of normal-appearing MUAPs firing at rapid rates may be observed during low levels of force production. The mean time to improvement of one clinical grade in the various controlled. In a prospective controlled trial of IVIG vs.1382 Most studies have substantiated that the peripheral nervous system is variably affected. temporal dispersion or conduction block of CMAPs was found in 61–74% of cases. In patients who suffer such relapses. and number of phases are normal. However. Autonomic instability can be assessed by measuring the EKG’s R-R interval variation. The removed plasma is generally replaced with albumin. Myokymia can also be detected in patients with AIDP. especially in facial muscles. 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 mechanism of action of IVIG is not known. a 70 kg patient receives 14. one may not see dramatic improvement in strength in patients during PE or IVIG treatments.459. resulting in variable degrees of numbness. sensory loss (including sensory ataxia).605 A small study of 25 patients treated with IVIG and intravenous methylprednisolone345 did better than a historical control group treated with IVIG alone.431 PE is believed to remove autoantibodies.431. However. amplitude.967.1086 During these first two weeks. The total amount of plasma exchanged is 200–250 ml/kg of patient body weight over 10–14 days. as many as 10% of patients treated with either PE431.1334 However.64. patients are more likely to have prominent positive sharp waves and fibrillation potentials when the CMAP is profoundly reduced. generalized weakness. Unlike chronic inflammatory demyelinating polyneuropathy (see below).1118.9.446. or other humoral factors involved in the pathogenesis of AIDP. Furthermore. with a gradual taper over the ensuing weeks to months. Laboratory evaluation is remarkable for an elevated CSF protein as in adults.

821.397. Lancet 1997. AMSAN and AMAN) and poorer prognosis. sensory abnormalities are noted initially in the hands or feet and progress later.159. laboratory.1446.894. The prognosis of AMSAN is much poorer than in AIDP. recent infection with C.1311.896. with decreased or absent responses in 52–61% and prolonged distal latencies or slow conduction velocities in 9–54%. Feasby and colleagues initially reported this axonal variant of GBS in 1986.5%) 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. it can be difficult to distinguish primary axonopathy from secondary axonal degeneration. and complete areflexia is usually evident.1021a. although guarded.507 Clinically and at least by initial electrodiagnostic studies.This trial also had 128 patients randomized into a treatment group that received plasmapheresis (PE) followed by IVIG.894. Sensation to all modalities is reduced. intravenous immunoglobulin.1369 Histopathology. particularly GM1 antibodies. French Trial: French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome: Efficiency of plasma exchange in Guillain-Barré syndrome: Role of replacement fluids. jejuni and antibodies directed against antinerve gangliosides.944 — PART IV CLINICAL APPLICATIONS Table 23-3.507. As in AIDP. Plasma Exchange/Sandoglobulin GBS Trial Group: Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group: Randomized trial of plasma exchange. most children with AIDP have a satisfactory recovery. Fortunately. even those with significant reductions in CMAP amplitude.150. have been demonstrated in many patients with AMSAN.506. Ann Neurol 1987.1086 Acute Motor-Sensory Axonal Neuropathy Clinical Features.1447 Some patients with antecedent C.400. Prolonged distal motor latencies were evident in at least one nerve in 57–75% of children.. but this is controversial. patients with AMSAN are indistinguishable from those with AIDP.8 26 days 51days 21 (16.841.There was no statistically significant improvement in any outcome measures in this group compared with the groups that received PE or IVIG alone. is better than in adults. Schmidtz PIM.9 29 days 49 days 19 (16. and electrophysiologic similarities.22:753–761. 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.e. albuminocytologic dissociation of the CSF protein is usually evident during the course of the neuropathy.35:1096–1104.741.7%) North American Trial: Guillain-Barré Study Group: Plasmapheresis and acute Guillain-Barré syndrome.1312 recent histologic studies confirm that AMSAN is a real disease entity.506. Abnormal SNAPs were reported in about 70% of patients. N Engl J Med 1992. and combined treatments in Guillain-Barré syndrome.1097 Laboratory Features. In several reports . 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. Needle EMG examination revealed fibrillation potentials and positive sharp waves in at least one muscle in 27% of children. Guillain-Barré 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. Autonomic disturbances can be observed with respect to blood pressure instability and cardiac arrhythmias.896 Only a few children have been reported with AMSAN. there is some suggestion that the prognosis. The muscles of facial expression are also profoundly weak. Ophthalmoplegia may be noted as well as difficulty in swallowing.397 Although its existence was met with early skepticism. In patients biopsied late in the disease.424. and the Dutch Guillain-Barré Study Group:A randomized trial comparing intravenous immunoglobulin and plasma exchange in Guillain-Barré syndrome.349:225–230.1131. Dutch IVIG Trial: van der Meché FGA.1446 Some authorities suggest that C. Neurology 1985.507.143.326:1123–1129.1312. two or more nerves in 48% of patients and in at least one nerve in 70–84%.741. Most patients require ventilator support during the course of the disease. In addition. jejuni infection and GM1 antibodies have typical AIDP and a good recovery.1404 As with GBS. jejuni infection and GM1 antibodies are more commonly associated with axonal forms of GBS (i. most patients have a slow and incomplete recovery.

binding of the antibodies to neural epitopes may result in only physiologic conduction block.1311 Of the eight patients with unobtainable CMAPs. 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. some patients with inexcitable CMAPs and SNAPs clearly have had histologic abnormalities supportive of a primary axonal insult. Acute Motor Axonal Neuropathy Epidemiology. Griffin and colleagues reported the pathology of three patients with AMSAN who died early in the course of their illness.1359 A preceding gastrointestinal infection can be elicited in 10–60% of such cases. slow conduction velocities. who reported the clinical. laboratory. Rather. often to less than 30% of normal.896. jejuni infection.1026. not axonal degeneration). Pathogenesis. to distinguish AIDP from AMSAN by nerve conduction studies. In addition.868. especially those located in the distal regions of the limbs. prominent axonal degeneration affecting the ventral and dorsal roots and the peripheral nerves is evident. distal demyelination with conduction block could not be excluded. These findings were interpreted as most consistent with axonal degeneration.540. Patients generally make a good recovery within . it is impossible to distinguish AIDP from AMSAN.1447 Treatment.1404. Twenty seven of the 147 (18%) patients enrolled in the Dutch GBS trial comparing IVIG with PE were later classified as having AMAN.867. Ideally.397.437. Because similar cases subsequently were described throughout the world. leading to production of antiganglioside antibodies due to molecular mimicry. it may be impossible.424. demyelination and lymphocytic infiltrates are absent or only minimally present on nerve biopsy or at autopsy in patients with AMSAN. The first detailed descriptions of the AMAN variant of GBS were by McKhann and colleagues. Not unexpectedly.868 The median time of recovery is similar to that in typical AIDP. AMSAN is most likely due to an immunemediated attack directed against epitopes on the axon. Brown recorded CMAP amplitudes as the stimulator was moved from the common distal sites of stimulation (wrist and ankle) to within 50–100 mm of the motor point by “inching” technique. and in one instance to less than 1 m/s. Deep tendon reflexes may be normal or absent. treatment with either plasma exchange or IVIG is warranted. Serial nerve conduction studies may be helpful in determining the underlying pathology and prognosis.397.868 They initially named the disorder Chinese paralytic syndrome. In the presence of inexcitable motor nerves.1446. The needle EMG examination demonstrates markedly abnormal reductions in recruitment.507 The neural epitopes may be gangliosides. which are present on the nodal axolemma.or inexcitability of the motor nerve does not necessarily imply axonal degeneration.159.868.1447 AMSAN can follow C.868.1359 In northern China.585. Therefore. AMAN has been described in children and adults.821. the distal latencies of the CMAPs and the nerve conduction velocities. On the basis of its distinct histopathology. the histopathology of sensory and motor nerves suggested severe demyelination rather than primary axonal degeneration. some patients even develop hyperactive reflexes during the recovery period.540. the term acute motor neuropathy was believed to be more appropriate.1026. Nevertheless.1359 An antecedent illness has been described in 30–85% of patients with AMAN in large series. hypo. the CMAPs after wrists and ankle stimulation were markedly reduced or absent.1311. AMAN is the most common variant of GBS. Of 26 patients who initially had low-amplitude CMAPs.400. Similar histologic abnormalities are seen in AMAN (see below) but are not typical in AIDP. The distal muscles often are affected more severely than proximal limb muscles. They also noted that numerous macrophages were present in the periaxonal space of myelinated internode. 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). Several weeks after the presentation of major motor weakness. Triggs reported 34 patients with “GBS” who had low-amplitude or unobtainable CMAPs.1359 Clinical Features. and hyperhidrosis may occur. Of interest. low-amplitude CMAPs are one of the earliest electrophysiologic abnormalities noted in AIDP. at least initially. there is an abrupt onset of generalized weakness.109. Distal conduction block with or without demyelination can be responsible for the low-amplitude distal CMAPs.400. Electrophysiologic Findings.1334. should be normal or only mildly affected. although it is a rare condition. however. As the sites of stimulation were moved closer to the motor point. such as GM1 or GM1a.159 In each case.88. as were rare intraaxonal macrophages.88.894.1446. In three patients with AMSAN studied within the first week of symptoms. As discussed earlier. electrophysiologic.868. the CMAP potentials progressively increased in size. whereas demyelinating features are rare.1359 As in AMSAN. and histologic findings in cases of seasonal outbreaks of acute flaccid paralysis in northern China. Complement activation on nodal and later internodal axolemma and recruitment of macrophages may result in axonal degeneration.842 Nevertheless. The pathogenic basis of AMSAN is unknown and only speculative. Because it is difficult to distinguish AIDP from AMSAN clinically or electrophysiologically. sensory signs and symptoms are absent.616.841. the CMAP amplitudes never exceeded 10% of the lower limit of normal. it appears that AMSAN does exist. AMAN appears to be less frequent in other areas of the world but is still quite common. the patients believed to have electrophysiologic evidence of resolving distal conduction block had a better prognosis than patients whose distal CMAP amplitudes progressively declined.397.526.816 In contrast to AIDP. No prospective treatment studies have been performed specifically for AMSAN. serologic evidence of a recent C. These distal-most segments reportedly had slow conduction velocities. when obtainable. whereas three patients did poorly (presumably secondary to axonal degeneration). five made good recoveries (suggesting conduction block.1439 The SNAP amplitudes are also profoundly reduced or absent.1312 In fact.821.867.Chapter 23 ACQUIRED NEUROPATHIES — 945 of patients with inexcitable motor and sensory conduction studies. abundant fibrillation potentials and positive sharp waves can be detected in most muscles. at least initially.400 Axonal degeneration leads to profound loss of both myelinated and unmyelinated axons.1021a.507 They demonstrated that prominent axonal degeneration of the spinal roots and peripheral nerves without demyelination or significant inflammation was an early histopathologic feature. As many as 80% of teased fibers reveal axonal degeneration. jejuni infection can be demonstrated in 67–92% of patients. Cranial nerve deficits and respiratory failure requiring mechanical ventilation can be seen in up to one-third of patients.1359 Unlike AIDP and AMAN.616. blood pressure fluctuations. Early in the course or with mild disease.867.506. Autonomic dysfunction in the form of cardiac arrhythmias.243. The presence of prolonged distal latencies.616. Nerve conduction studies reveal markedly diminished amplitudes or absent CMAPs within 7–10 days of onset.507.

Facial weakness is evident in 32–57%. Of these possible GBS variants. As with AIDP and AMSAN.530 Macrophages are also evident over the nodes of Ranvier of large myelinated ventral motor root fibers. Serology evidence of recent C. Ophthalmoparesis can develop asymmetrically but often progresses to complete ophthalomoplegia.645. but the actual recurrence rate is not known. areflexia.586.559.868. Diminished CMAP amplitudes and early recovery also may be seen if degeneration is limited to the distal motor nerve terminal. No treatment trials have been devoted to AMAN.585 Electrophysiologic Findings.1283 In severe cases.105. Treatment. the macrophages can be seen encircling the nodes and dissecting beneath the myelin sheath into the periaxonal space. Other Variants of Guillain-Barré Syndrome Other variants of GBS include Miller-Fisher syndrome (ataxia. Whether the ataxia is secondary to sensory dysfunction or a cerebellar lesion is controversial. most patients have sensory ataxia. It is speculated that antibodies directed against the lipopolysaccaride membrane of Campylobacter cross-react with specific epitopes on the nodal axolemma (e.1359 Subgroup analysis of the AMAN group suggested that IVIGtreated patients may recover faster than PE-treated patients. when the rest of the nerve fiber appears otherwise normal. we generally treat AMAN patients with IVIG. 2 gm/kg over 5 days. In our experience.1124 These disorders may represent an oligosymptomatic form or forme-fruste of AIDP.96.867.585 Pathogenesis.868. albuminocytologic dissociation is the rule.616. idiopathic cranial polyneuropathy.616. jejuni and anti-GM1 and anti-GD1a antibodies can be identified in many patients with AMAN in addition to typical AIDP and AMSAN.1334.868 Laboratory Features. In severe cases. the distal latencies and conduction velocities are normal.1021a. in particular anti-GQ1b. Subsequently. Most patients with MFS have elevated CSF protein without significant pleocytosis. As discussed in the AIDP and AMSAN sections.1213 Clinical return of function usually begins within about 2 weeks after the onset of symptoms.96. C3d and C5b-9) on the nodal and internodal axolemma of motor fibers and precedes features of axonal degeneration. but pupillary involvement is uncommon. 27 of the 147 (18%) of the patients enrolled in the Dutch GBS trial comparing IVIG with PE were later classified as having AMAN. As noted above.585.1359 The absence of prominent CSF pleocytosis helps distinguish AMAN from poliomyelitis. pharyngeal-cervical-brachial weakness with or without ophthalmoparesis.867. Ho demonstrated active degeneration and severe loss of large myelinated intramuscular nerve fibers on muscle biopsies that included the distal motor nerve terminals.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.1359 Anti-GM1 and anti-GD1a antibodies are commonly detected in patients with AMAN and usually are associated with recent Campylobacter infection. PE is an alternative if IVIG is not available or is contraindicated. Miller-Fisher reported three patients with ataxia.213.530 These inflammatory cells insert through the Schwann-cell basal lamina into the nodal gap. Nearly one-half of patients describe paresthesias of the face and distal limbs.530 Deposition of IgG and complement is also evident on the nodes of Ranvier on teased fiber analysis and EM.868 Second attacks of the illness have been described in northern Chinese patients.1359 Histopathology. PE. As noted above. but the innermost myelin sheath (adaxonal lamella) appears intact. the axon retracts from the adaxonal Schwann cell. which it can mimic.585. but it is likely that patients were included in some of the AIDP trials comparing PE and IVIG.1359 Motor unit number estimate (MUNE) performed sequentially in 7 patients with AMAN demonstrated a marked decrease at the peak of illness. serologic evidence of a preceding infection with C.1448 .e. and dysarthria in 13–40% of patients.585 The mortality rate is less than 5%. GM1 or GD1a gangliosides). areflexia.530 The macrophages probably are recruited into the affected nodes and periaxonal space via complement-derived chemotropic factors..96.923a. Laboratory Features. C. There was no significant difference in outcome.g.946 — PART IV CLINICAL APPLICATIONS one year. dysphagia in 26–40%.1121 Serologic evidence of C. thereby resulting in conduction block.1121 There is a 2:1 male predominance with a mean age of onset in the early 40s. the axons then begin to degenerate. jejuni infection can be demonstrated in 67–92% of patients. Some patients progress to more severe generalized weakness similar to typical GBS. As they enter the perixonal space. Mild proximal limb weakness can be demonstrated in the course of the illness in approximately one-third of cases. with resolution of conduction block and nerve regeneration occurring later. The characteristic electrophysiologic feature on nerve conduction studies in AMAN is low-amplitude or unobtainable CMAPs with normal SNAPs. but residual distal limb weakness is common. and full recovery of function is typically seen within 3–5 months.526 Because of the ease of administration. when present.. Increased spontaneous activity in the form of fibrillation potentials and positive sharp waves and decreased recruitment of MUAPs usually can be appreciated.867.868.868. Diplopia is the most common initial complaint (39–78%).868. MillerFisher syndrome is best characterized. or PE followed by IVIG) between AIDP and AMAN in a subgroup analysis of 369 patients. 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. Ptosis usually accompanies the ophthalmoparesis. jejuni can be demonstrated in some patients as well as antiganglioside antibodies. An antecedent infection occurs in over two-thirds of the cases. F-waves are also usually unobtainable but.526. and paraparetic weakness. 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. CMAP amplitudes increased without a significant change in the MUNE. The earliest histologic abnormalities are noted at the nodes of Ranvier. and ophthalmoplegia).616. axonal degeneration occurs via complement-mediated damage to the axons.741a As clinical recovery began. show normal latencies. Clinical Features. regardless of treatment (IVIG.1359 When CMAPs are obtained.420 Since then. Histopathology and immunologic studies suggest that AMAN is caused by an immune-mediated attack against an unknown epitope on the nodal axolemma. ataxia is evident in 21–34% of patients at onset. as in AIDP. Other cranial nerves also can become involved. In 1956. Areflexia is evident on examination in over 82%.1118. The investigators suggested that the primary mechanism of early recovery in AMAN may be collateral reinnervation.530 These features contrast with the findings in AIDP: early deposition of immunoglobulin and complement on Schwann cells rather than the axons. and ophthalmoplegia—a syndrome distinct from GBS.923a.530 The nodal gaps can be appreciably lengthened. over 200 cases of Miller-Fisher syndrome (MFS) have been described either as case reports or small series of patients. Immunocytochemistry reveals deposition of IgG and complement activation products (i.

276.351.1055 These studies showed normal brainstem findings or only secondary chromatolysis of the oculomotor.78. CMAPs in the arms and legs are usually normal. Demyelination and mild inflammatory infiltrates were noted along the course of these cranial nerves. tying shoes. Treatment. recent antecedent infections.299. anti-GQ1b antibodies can be detected in most patients with MFS. the AAN criteria are looser clinically and do not require either proximal or symmetric weakness (see Table 23-4). are enriched with GQ1b. fibrillation potentials may be detected in facial muscles. usually in the twenties. The diagnostic criteria proposed by Barohn and colleagues require symmetric proximal and distal weakness.130.923a. Lymphocytic infiltrates were also apparent in the sensory ganglia of peripheral nerves.73.434.434.1118 EMG reveals minimal abnormalities. there is a slightly increased prevalence in men.1397 Minimally slowed motor conduction velocities (still within 80% of normal) and prolonged F-waves have been reported in only a few patients. Electrophysiologic Findings. 73. ataxia. an infection has been reported to precede 20–30% of CIDP relapses or exacerbations.11021142.1071. given the presumptive similarity in pathogenesis with AIDP. Clinical examination usually confirms weakness in proximal and distal arm and leg muscles. this resulted in massive quantal release of acetylcholine from nerve terminals and eventually blocked neuromuscular transmission. CIDP most commonly presents in adults with a peak incidence at about 40–60 years. trochlear. if weakness remains distal.1172.130. Distal upper limb weakness impairs fine motor dexterity (buttoning shirts.559 Evoked potential studies have given inconsistent results. although it is probably autoimmune.299. which distinguishes CIDP from GBS or AIDP.560a.1168a With increased recognition.73. Dyck retrospectively reported the clinical.Chapter 23 ACQUIRED NEUROPATHIES — 947 Histopathology. amplitude.1061 In a complement-dependent process. hereditary demyelinating neuropathy. and histologic features of 53 patients and termed the disorder chronic inflammatory polyradiculoneuropathy.1071.363 The pattern of disease progression in CIDP is analogous to multiple sclerosis.1297 and guidelines for the diagnosis of CIDP were developed.434 Blink reflex may be abnormal with facial nerve involvement. Of importance. AntiGQ1b antibodies stain sensory neurons in the dorsal root as well as cerebellar nuclei.1058.434. only distal weakness may be observed.862 The association of CIDP with infections has not been studied as extensively as in AIDP.e. and polyphasia can be seen. other diagnoses need to be considered (e. however. electrophysiologic.73. (2) chronic relapsing (fluctuations of weakness or improvement over weeks or months). leading to stubbing of toes and tripping.864. electrophysiologic. Dyck describe four typical clinical courses of progression in patients with CIDP: (1) chronic monophasic (15%).1168a However.1131a.249 Early in the course of the illness.1297 Weakness of proximal lower limb muscles results in difficulty with ambulating. and arising from a low soft chair or commode. 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. Pathogenesis. or abducens nuclei.73 In 1991. In mice infused with serum from patients with MFS. oculomotor fibers and the sensory ganglion.249 Modifications were recently proposed to distinguish CIDP from other forms of chronic acquired demyelinating polyneuropathy.1121 Most authorities believe that the clinical.1140 Other studies report normal evoked potentials or slowing localized to the peripheral nervous system. 249. including enteritis due to C. (34%). requiring treatment. paraprotein-related .477.96. CIDP has accounted for approximately 10–33% of initially undiagnosed peripheral neuropathies. (3) stepwise progressive (34%).304. and (4) steady progressive (15%). However.130. and histologic findings point to the PNS. a variant that Hughes’ termed subacute demyelinating.864. jejuni.622.. However. In contrast to limb CMAPs. Perhaps through molecular mimicry. The primary site of the immune attack (i.1168a.73.351 Relapses have been associated with pregnancy. the Ad Hoc Subcommittee of the American Academy of Neurology (AAN) proposed research criteria for the diagnosis of CIDP (Table 23-4). Distal lower limb weakness may cause foot drop. the GQ1b antibodies were observed to bind to neuromuscular junctions. picking up small objects). The pathogenic basis of MFS is not known. Decreased recruitment of MUAPs may be noted in weak muscles.864 Clinical Features. Some studies report central conduction abnormalities on somatosensory.1168a Some patients have a subacute onset over 4–8 weeks. and areflexia later evolved to severe quadriparesis characteristic of more typical AIDP. 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.73. which are prominently affected in MFS. 351 Torvik and Lundar proposed the name chronic inflammatory demyelinating polyradiculoneuropathy to underscore the demyelinating features.276. Subsequently. There are no controlled treatment trials of patients with MFS.1131a. Biopsy and autopsy data are limited and need to be viewed cautiously because some cases that began with ophthalmoplegia.351. However. whereas proximal weakness causes difficulties with performing activities requiring overhead hand use (grooming. laboratory. can be identified in most patients with MFS.249.351.603 The subsequent natural history of these subacute cases may be that of AIDP (spontaneous remission) or CIDP (chronic relapses or progression). Reduced facial CMAPs coincide with the loss or mild delay of R1 and R2 responses on blink reflex testing. it seems prudent to treat patients with either IVIG or PE.g.78.73. PNS or CNS) is controversial.147. As noted above. Similar to other variants of GBS. other large series of patients were reported73.1168a The relapsing form was recognized as early as 1914 by Hoerstermann and was described as recurrent polyneuritis. in particular the sensory ganglia and oculomotor fibers..353. climbing stairs. Symptoms and signs of the neuropathy must be progressive for at least two months.864.1216 Most patients present with relapsing or progressive symmetric proximal and distal weakness of the arms and legs.622. brainstem. putting books on a high shelf) and lifting or carrying heavy objects (groceries). increased MUAP duration.588 The progressive form of the neuropathy was reported as progressive hypertrophic neuritis1133 and chronic Guillain-Barré syndrome (GBS).560a. During recovery. autoantibodies directed against these infectious agents cross-react with neuronal epitopes.622 There is generally no abnormal spontaneous activity in limb or paraspinal muscles.303 Austin initially described the steroid-responsive nature of CIDP in 1958.353.477. mild to moderate reduction of facial CMAPs can be demonstrated in over 50% of patients with MFS.864.1297 The relapsing form has an earlier age of onset.477.363. affecting only the peripheral as opposed to central nervous system.887. and visual evoked responses.623.

Mandatory • Cell count < 10/mm3 if HIV-seronegative or < 50/mm3 if HIV-seropositive. .948 — PART IV CLINICAL APPLICATIONS Table 23-4. Laboratory studies. Diagnostic categories for research purposes. such as thyroid functions. Exclusionary:Vasculitis. pathology A and C. neurofilamentous swollen axons. 2. (b) > 150% of ULN if amplitude < 80% of LLN. and CSF A. • Mononuclear cell infiltration. in certain clinical circumstances other studies may be indicated. CSF studies 1. Albers JW: Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). amyloid deposits. including studies of proximal nerve segments in which the predominant process is demyelination. demonstrating demyelination/remyelination). Asbury AK. retinitis pigmentosa. and urine heavy metals. serum and urine immunoglobulin studies (including either immunofixation electropheresis or immunoelectropheresis). are required for confirmation. • 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. Research Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Clinical criteria 1. globoid cell leukodystrophy. Supportive criteria • Reduction in sensory CV < 80% of LLN • Absent H-reflexes. Supportive • Subperineurial or endoneurial edema. Mandatory: nerve biopsy showing unequivocal evidence of demyelination and remyelination. • Hypo. Mandatory • Nerve conduction studies. (3) Prolonged distal latencies in two or more nerves: (a) > 125% of upper limit of normal (ULN) if amplitude > 80% of LLN. or other evidence of specific pathology. (4) Absent F-waves or prolonged minimum F-wave latencies (10–15 trials) in two or more nerves: (a) > 120% of ULN if amplitude > 80% of LLN. or family history of a genetically based peripheral neuropathy • Sensory level • Unequivocal sphincter disturbance Physiologic studies 1. (b) > 150% of ULN if amplitude < 80% of LLN.ANA. (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 (p–p) amplitude between proximal and distal sites. Neurology 1991. patients meeting the above criteria are classified into the groups listed below. 2. routine chemistries. phytanic acid. Depending on the results of laboratory tests. • Negative Venereal Disease Research Laboratory Test 2. From Cornblath DR. Exclusionary • Mutilation of hands or feet.The following studies are suggested: CBC. • Prominent variation in the degree of demyelination between fascicles. minimum of 4 internodes each.These criteria are only suggestive of partial conduction block because they are derived from studies of normal subjects.Additional studies. (2) Partial conduction block or abnormal temporal dispersion in one or more motor nerves: peroneal nerve between ankle and below fibular head. 3. Supportive: elevated protein. such as stimulation across short segments or recordings of individual motor unit potentials. appropriate history of drug or toxic exposure known to cause a similar peripheral neuropathy. ichthyosis. Definite: clinical A and C. or intracytoplasmic inclusions in Schwann cells or macrophages indicating adrenoleukodystrophy. For instance. (b) < 70% of LLN if amplitude < 80% of LLN. porphyrins. Pathologic features 1. median nerve between wrist and elbow.or areflexia. 3. Probable: clinical A and C. Possible: clinical A and C and physiology A.41:617–618. metachromatic leukodystrophy. or ulnar nerve between wrist and below elbow. physiology A. 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. 2. Demyelination by either electron microscopy (> 5 fibers) or teased fiber studies (> 12% of 50 teased fibers. • “Onion-bulb” formation. Supportive: Large-fiber sensory loss predominates over small-fiber sensory loss. (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 p–p amplitude between proximal and distal sites. and HIV and hepatitis serology. and CSF A. long-chain fatty acids.The list of laboratory studies is not comprehensive. physiology A.This will usually involve all four limbs.

276. these onion bulbs are not as prominent as in Charcot-Marie-Tooth disease.986. and normal findings in 2–43. Sixty-eight to 80% of patients complain of numbness in the hands or feet.1194 As many as 25% of patients with CIDP or a CIDP-like neuropathy have an IgA.1131a When the nerve roots are involved. lymphoma.570. P0 and P2) are present in a small percentage of patients.351. and a wide-based gait may be found.477. forming so-called onion-bulbs. cholangiocarcinoma.864 An associated sensory ataxia.893. incontinence and impotence) are less common. and tacrolimus. or distal acquired demyelinating neuropathy).73. Schwann cell proliferation and edema can lead to a hypertrophic appearance of the nerve.479.24a.729.1131a. dysarthria and dysphagia in 9%. prognosis.726.1322 It is debatable whether such patients have an unusual form of diabetic neuropathy or superimposed CIDP.740.1168a Whenever a pure sensory neuropathy is present.902 Other medical conditions may be seen in association with CIDP or a CIDP-like neuropathy. and Castleman disease. Sensory examination is abnormal in 68–84% of patients.g. Analysis of teased nerve fibers is the best way to quantify histologic abnormalities.477. Antibodies directed against myelin proteins (e.1297 Leukocyte count in the CSF should be < 10/mm3 or < 50/mm3 in HIV-positive patients.130.351 Of interest. occurring in 15–50% of patients. some patients with diabetes mellitus develop symmetric proximal and distal weakness.130. Besides the association with the above lymphoproliferative disorders. IgG.380 It is not known whether the pathogenesis.1398 In addition.313. For example.313.886. Whether such patients have multiple sclerosis or if the CNS demyelination in CIDP represents a distinct immunologic disorder is not known. POEMS syndrome.73.398.351.73.247.351.1319 The CNS abnormalities can precede or follow the onset of CIDP.477.351.1217 Paraprotein-related CIDP is addressed in a separate section. consideration should be given to other diseases as well.351 Autonomic dysfunction (e.351. A total reduction in the number of myelinated fibers is also usually evident on biopsy.351.1364a Endoneurial and perineurial edema also may be appreciated on biopsy. and response to treatment of demyelinating neuropathies associated with these medical disorders are identical to those of idiopathic CIDP. see below) is debatable.241.274. Large series have demonstrated segmental demyelination and/or remyelination in 23–68%. As with AIDP.102. axonal degeneration in 5–42%.130. or endoneurium and is . occurring in less than 5% of patients. 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).363. the ventral rami.21.864 Vertigo related to vestibular involvement is a rarely reported complication.987.73.g.130. such as Sjögren’s syndrome or paraneoplastic neuronopathy. diplopia secondary to ophthalmoplegia in up to 8%. and papilledema in 1–7% of patients.73. 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. usually in the setting of graft-versus-host disease or transplant rejection.828. The demyelinating neuropathies associated with IgG and IgA monoclonal gammopathies of unknown significance (MGUS) are usually indistinguishable from CIDP.73. Patients also may develop a myelopathy due to compression of the spinal cord by hypertrophied nerve roots.589 Respiratory insufficiency secondary to intercostal muscle and diaphragm weakness has been reported in 8–15% of patients. 1005. diabetes mellitus.24.1300. carcinoma of the pancreas and colon. both of which are associated with sensory ganglionitis.22.1342 MRI with gadolinium may reveal hypertrophy and enhancement of the nerve roots and peripheral nerves. multifocal motor neuropathy. Chronic demyelination and remyelination result in proliferation of surrounding Schwann cell processes.130.864 Painful paresthesias are less common. a CIDP-like neuropathy may complicate bone marrow and solid organ transplantations. Barohn found small clusters of mononuclear inflammatory cells in only 10. electrophysiologically (evoked potential studies).610.1168a.351. or by MRI scans. systemic lupus erythematosus.340.73. particularly when it is asymmetric. monoclonal gammopathy of uncertain significance (MGUS). and lymphomatous or leukemic infiltration of nerve roots.1131a However.Chapter 23 ACQUIRED NEUROPATHIES — 949 neuropathy. cyclosporine.1012. perineurium..264.1289 Furthermore.340.236 although other groups have not verified this observation. The “inflammatory” component of CIDP is often not evident or is quite subtle on sural nerve biopsies (see Fig.73. Segmental demyelination and remyelination are the most prominent histologic abnormalities (Fig.276.1168a These large studies have reported CSF protein levels over 1200 mg/dl with a mean of about 135 mg/dl.g. although up to 10 % of patients have > 5 lymphocytes/mm3. As noted above. Lyme disease.24 Most patients with CIDP have areflexia or hyporeflexia. Laboratory Features.1131a. 23-3) but are not present in every biopsy because of the multifocality of the disease process. Cranial nerve involvement occasionally occurs but is usually mild and not the presenting feature.987 Some patients begin with only sensory symptoms and signs but later develop motor abnormalities. a few patients may have pure motor (10%) or pure sensory (5–10%) symptoms and signs. CIDP or a CIDP-like neuropathy has been described as a paraneoplastic complication of small cell carcinoma of the lung.30. posterior rami.893. with occasional involvement of the central nervous system.433 Some patients can develop dropped head syndrome secondary to neck extensor weakness.986.1168a Although most patients (at least 80%) have both motor and sensory involvement.740.1131a including HIV infection.1261. Enlarged nerves can be palpated in as many as 11% of patients.902 Histopathology. GM1 ganglioside.1071. 23-3).1139.73 The inflammatory cell infiltrate is evident in the epineurium..477. mixed demyelinating and axonal features in 12. Mild facial weakness is evident in 2–16%.477.477. inflammatory bowel disease.21.276. a positive Romberg sign. the cell count is usually normal. primarily affecting large-fiber modalities (vibration and touch). The peripheral nerve and nerve root regions are affected.351 The term chronic sensory demyelinating neuropathy has been applied to the few patients who have only sensory symptoms and signs. However.1033. a toxic-induced neuropathy resembling CIDP has been associated with certain medications such as procainamide.73. An elevated CSF protein (> 45 mg/dl) is found in 80–95% of patients. fall within the spectrum of CIDP or represent a distinctly different neuropathic disorder (e. and elevated CSF protein and have demyelinating nerve conduction studies and nerve biopsies that fulfill research criteria for CIDP (see section on diabetic neuropathies). or IgM monoclonal gammopathy. and melanoma.661.560a.887. Elevated CSF cell counts should lead to the consideration of HIV infection.31. Oligoclonal bands may be demonstrated in the CSF in approximately 65% of patients. most patients have sensory involvement. or both may be preferentially affected. hyporeflexia..7% of 56 sural nerve biopsies. an electrodiagnostic medicine evaluation in such patients usually reveals abnormalities affecting the motor nerves.1131a Whether patients with pure motor or sensory involvement. hepatitis. however.130.22.627.680 One study reported a high titer of antitubulin antibodies in patients with CIDP.5–20%.5% of teased nerve fibers.560a. approximately 3–5% of patients with CIDP also have evidence of CNS demyelination clinically.264.130.661.661.91 In our experience.

and demonstration of immunoglobulin and complement on peripheral nerve tissues. B. penetrate along intraperiod lines.). A. Dyck and colleagues reported perivascular inflammation. producing conduction block. these inflammatory changes were reported as slight and difficult to distinguish from normal controls.351 However. in 54% of patients and diffuse endoneurial inflammation in 23%. improvement in patients after plasma exchange.130 The percentage of nerve biopsies demonstrating inflammatory cells is increased when immunostaining for lymphocytes and macrophages is performed.363 Subsequently. including normal controls. In patients who fulfill the clinical and electrophysiologic criteria for CIDP and who have elevated CSF protein concentrations > 1 g/L. C.1364a The inflammatory component is composed of macrophages and CD8+ greater than CD4+ lymphocytes. The exact tissue antigen(s) and the interaction between the humoral and cellular arms of the immune response are not known.778 T-cells are the predominant source of MMP-2 and MMP-9.246. The pathogenic basis of CIDP is presumably autoimmune.). and CSF findings do not fulfill criteria for CIDP.363 However. However.276. Ultrastructural studies indicate activation of macrophages with penetration of the basement membrane and displacement of the Schwann cell cytoplasm.127. As evident from the above discussion. A macrophage can be seen engulfing an axon and digesting the myelin (epoxy-embedded. CIDP. The laying down of new . 911 However. Axons regain much of their original diameter after remyelination. the remyelinated internodes are shorter and thinner than normal.846. MMP-2 and MMP-9 (gelatinase A and B) have been shown to be upregulated in the peripheral nerves in patients with CIDP. raising concern about their pathogenic role.950 — PART IV CLINICAL APPLICATIONS Figure 23-3. Nevertheless. and finally engulf the disrupted myelin by endocytosis. large studies have found antimyelin antibodies by direct and indirect immunoflourescent techniques in only a few patients. conspicuous perivascular endoneurial inflammatory infiltrate was noted in only four specimens.g.846 Of note. Pathogenesis. a similar frequency of inflammatory cell infiltrate within nerves is seen in various neuropathies. the exact role played by the humoral and cellular arms of the immune system in the pathogenesis of CIDP is not fully understood. ion channels) probably are involved early in the pathogenesis of CIDP.246 Matrix metalloproteinases (MMP) are a family of endopepsidases with overlapping substrate affinities for various extracellular matrix proteins. which are capable of degrading components of the subendothelial basement membrane. mainly in the epineurium. Paraffins section reveals mononuclear inflammatory cells composed of lymphocytes and macrophages in the endoneurium (H&E stain. 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. however. nerve biopsy is a useful diagnostic tool. passive transfer experiments of plasma from patients with CIDP into laboratory animals has generally produced negative results. touidine blue stain. nerve biopsy findings in CIDP are not particularly sensitive or specific. 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. if the clinical. nerve biopsies have no additional diagnostic value. remyelination occurs by recruitment of normal Schwann cells. The denuded axons shrink in diameter as much as 50%.) often perivascular. In the largest series (95 nerve biopsies). antibodies directed against axonal elements (e. Several lines of evidence suggest involvement of humoral factors: the similarity between CIDP and AIDP and experimental allergic neuritis..363 Furthermore. electrophysiologic. touidine blue stain.363 The macrophages lyse the superficial myelin lamellae. thereby allowing inflammatory cells to disrupt the blood-nerve barrier and penetrate peripheral nerves.

and pseudoconduction block. demyelination can elevate the peripheral nerve excitation thresholds. The slowing is usually not as severe as that demonstrated in motor nerves.1168 Furthermore. These findings suggest that some component of the reduced SNAP conduction velocities may be related to the loss of large myelinated sensory nerve fibers. but the electrophysiologic abnormalities in such cases are axonal. Block of conduction. also may be important but have not been addressed in a scientific fashion. the distal latencies are often prolonged and conduction velocities slow. there is a significant reduction in motor nerve conduction velocity. and F-wave studies for each of the above-noted nerves.535. and F-waves in the arms. A prolonged distal latency or dispersed waveform favors demyelination with conduction block or pseudoconduction block. Sensory Nerve Conduction Studies.276. A similar discrepancy between the upper and lower limb SNAPs can be seen in a sensory ganglionopathy. Characteristically. Increased CMAP amplitudes. or slow conduction velocity) when the sural SNAPs are normal.1319 Subtle abnormalities.536.1227 It is mandatory to assess CMAP amplitude. thus requiring a greater current to stimulate the nerves. only possible conduction block can be assumed. 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 muscle’s end-plate region by motor studies alone. which in turn cause a leakage of current and increase the time required for the longitudinal current to reach the next node of Ranvier. reduced amplitude.152. conduction velocity was similar in proximal and distal segments.1168a F-waves are often unobtainable or have prolonged latencies (> 125–150% of the upper limit of normal) in patients suspected of CIDP.249.1005. particularly after several recurrences of demyelination and remyelination. absent F-waves. Electrophysiologic evidence of demyelination affecting multiple CMAP parameters is the most useful diagnostic test. This pattern suggests that the pathologic process is not length-dependent (as is typical of axonal neuropathies) and implies a primarily demyelinating disease. 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. Traditionally. usually to less than 70% of the lower limit of normal. which is necessary to continue propagating the action potential. In a study of 18 patients using the near-nerve technique. we routinely evaluate median and ulnar CMAPs.73.276. Therefore. The pathophysiologic basis for true conduction block was described above. conduction block. whereas others nerves are abnormal.172a Conduction block along the nerve may be present in lieu of demyelination by the postulated binding and blocking of ion channels by antibodies. prolonged latency.276. F-waves have been used to assess proximal conduction. but this process occurs at a comparatively much slower pace.986. Investigations have substantiated significant conduction block within a short distance of the endplate region.10. Recent studies demonstrate the utility of nerve root stimulation in diagnosing patients with CIDP.487. decreased conduction block.249.1098 For this reason.660. not demyelinating. However. sensory conduction slowing was only moderate in proportion to the degree of amplitude loss. because submaximal stimulation can produce falsely slower conduction velocities. Finally.152. paranodal and internodal demyelination impairs the propagation of the action potential down the nerve.888 One must ensure a supramaximal stimulus. and slightly increased conduction velocity may be seen in association with improvement in strength..864..1332 Clinical improvement is primarily the result of resolving conduction block.1332. The probability of finding abnormalities in motor conduction increases in individual patients if multiple nerves are examined.g.364. 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.130.1168a. and conduction block was evident in a minority of sensory nerves. leads to the typical onion-bulb appearance on biopsy. If the current leakage is excessive.73.153. conduction block should be localizable by inching techniques to sites not commonly predisposed to compression.723 In addition. We study multiple nerves because of the multifocal nature of the disease process. the wrist] and the motor nerve terminal). 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.887a.152. prolonged distal latencies. A characteristic finding is abnormal median or ulnar SNAPs (e. .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.1372 When sensory responses are obtainable. Demyelination of a nerve segment produces an increased transverse capacitance and reduced resistance in the area. A reduction in CMAP amplitude also can be seen at proximal and/or distal sites of stimulation. In performing nerve conduction studies in patients with suspected CIDP.49a. Albers and Kelly used a 30% drop in amplitude to define conduction block but did not take into account temporal dispersion. Some contribution to improvement may be related to some degree of collateral sprouting and regeneration of axons. None of the electrophysiologic criteria proposed for the diagnosis of CIDP mention sensory nerve conduction abnormalities. documenting the preferential distal involvement. there may not be enough current to depolarize the next node of Ranvier. temporal dispersion.49. the multifocal nature of the demyelination can differentially affect the conduction of individual motor nerve fibers. Peroneal and posterior tibial CMAPs and F-waves and sural SNAPs are studied in the lower limbs.10. Most patients (> 80%) with CIDP have low-amplitude or unobtainable SNAPs in both upper and lower limbs. 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. it is important to assess the proximal segments of the nerves. some nerves can have normal conduction studies. Motor Conduction Studies.Chapter 23 ACQUIRED NEUROPATHIES — 951 Schwann cell processes and basement membrane. is responsible for motor weakness.g. 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). percentage drop in amplitude or area used in defining conduction block by nerve conduction studies is controversial. Electrophysiologic Findings.152. The best-studied motor parameter is nerve conduction velocity.986. Physiologically.354.864.442. not slowing of velocity. Because there may be a preferential involvement of the nerve roots.1168a In addition. causing temporal dispersion of the CMAP.10.249 When temporal dispersion is greater than 15%.73. we use a 50% drop in amplitude or area to define conduction block.1071. Conduction block may resolve prior to remyelination by removal of these antibodies. SNAPs. Pseudoconduction block can result from interphase shifting and cancellation of the negative and positive waveform subcomponents of individual motor unit potentials with other potentials.1071.1168a.267. distal motor latencies are typically prolonged to 125–150% of the upper limit of normal.

aseptic necrosis of the hip. and type 2 muscle fiber atrophy.73. and diabetes mellitus.g. Intermittent high-dose intravenous corticosteroids may also be a useful therapy for CIDP and perhaps associated with fewer side effects. 100 mg every other day). if not contraindicated.73 Functional muscle recovery is first noted in the proximal limb muscles. such as the tibialis anterior.1071. Patients may respond to one mode of treatment when other forms of treatment have failed or become refractory. Using this mode of treatment. and occasionally gastrocnemius.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).73.364 The treatment of choice may depend on the patient’s other medical problems (e.447 Motor unit action potential amplitudes can be normal or increased in patients with CIDP. Austin was the first to demonstrate that steroids were beneficial in “recurrent polyneuropathy. and phases can be seen.354 We treat patients with prednisone.396. glucose intolerance. postmenopausal women. Widespread fibrillation potentials and positive sharp waves are commonly detected in the intrinsic foot muscles and more proximal muscles. with a reduction.351. Corticosteroids. Evoked Potential Studies.952 — PART IV CLINICAL APPLICATIONS Near-nerve needle recordings combined with the averaging of multiple responses may continue to reveal a small and temporally dispersed response. The upper limb has the same pattern of membrane instability (e.10. placebo-controlled trials using sham PE . (but not necessarily complete disappearance) during clinical remission.. hypertension. In patients with chronic denervation and reinnervation. During the recovery phase.150 Thus. cataract formation. depending on the duration and severity of the disease.986.477. uncontrolled case reports or small series. unavailability of PE. Multimodality evoked potential studies have been performed in numerous patients diagnosed with CIDP. expense of IVIG and PE.398.5 mg/kg (up to 100 mg) per day for 2–4 weeks.. in postmenopausal women.10.979. we recommend estrogen replacement.510. and (4) prolonged F-wave latency of at least 130% in one or more nerves. At this point. conduction block.g. we start alendronate (10 mg/day).9 months) and the time to maximal improvement averaged 6.g. Extensive documentation of needle EMG findings in patients with CIDP is lacking.10 Barohn. continued demyelination/remyelination and even mild axonal loss often result in the complete absence of the SNAP. Plasma Exchange.249 The electrophysiologic criteria for CIDP adapted by the AAN also take into account the distal latencies. (3) prolonged distal latency of greater than 130% in two or more nerves. increased MUAP duration. Electrophysiologic Criteria for Diagnosis. randomized.267.1168a The criteria developed by Barohn et al.423. but the degree of slowing is slightly different from the other proposed criteria and dependent also on the distal CMAP amplitudes. 1. peroneus longus. with few motor units firing at high rates. The degree of positive sharp waves and fibrillation potentials is relatively high during an exacerbation of the disease.562. controlled trial.g. In addition. patients with borderline low DEXA scores) We obtain baseline and periodic fasting blood glucose and serum electrolyte levels.6 months.238.1227 In patients with significant proximal weakness.979. Barohn noted that the time of initial improvement ranged from several days to five months (mean: 1. plasma exchange (PE). 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. occasional abnormalities can be observed in the quadriceps and hip girdle muscles. Treatment.1012.. low-carbohydrate diet to avoid excessive weight gain. (2) partial conduction block of 70% or temporal dispersion in one or more nerves.”54 and several later series showed similar improvement with steroids. symmetric proximal and distal numbness and weakness) and laboratory features (e. we taper the prednisone no faster than 2.276.1201. PE was found to be effective in patients with CIDP in several retrospective.73.910 The significant side effects related to long-term corticosteroid treatment include osteoporosis.249 Bromberg compared the electrophysiologic criteria proposed by Albers and Kelly.g. weight gain. Randomized control trials have demonstrated efficacy of corticosteroids. amplitude. Subsequently. more commonly found in the hand intrinsic than the more proximal muscles). they make no mention of distal latencies. Single-fiber EMG demonstrates an increase in fiber density and jitter.788. then switch to alternate-day treatment (e.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. Dyck found no significant difference in efficacy between IVIG and PE.886.. and somatosensory evoked potentials have revealed that central conduction along the pathways examined by the respective tests is unquestionably slowed in some patients.1372 Needle EMG Examination. and intravenous immunoglobulin (IVIG) in the treatment of CIDP. increased CSF protein) are compatible with the diagnosis. If a patient has or develops osteoporosis. a moderate degree of improvement in SNAP parameters to the low normal ranges may be observed.. A reduced recruitment pattern is observed.73 and the AAN and found no statistically significant difference in the sensitivity (range: 48–64%) in 70 patients who fulfilled clinical criteria for CIDP. and F-wave latencies in addition to conduction velocity slowing.1310 Two prospective. Significant improvement in strength was noted in 95% of patients after one year of treatment. this should not dissuade the clinician from treatment if the clinical features (progressive. We recommend physical therapy and an exercise program to reduce these side effects. many patients with CIDP do not fulfill electrophysiologic criteria for the diagnosis. avoid IVIG in patients with renal insufficiency) and accessibility (e. hypertension. double-blinded. temporal dispersion. require slowing of motor conduction velocity in at least two nerves to less than 70% of the lower limit of normal. Various electrophysiologic criteria have been proposed for the diagnosis of CIDP.1005.g. the dose of prednisone is slowly decreased by 5 mg every 2–3 weeks to 20 mg every other day. However. Patients need to be instructed about a low-sodium.5 mg every 2–3 weeks. conduction block.1319 Anatomic lesions noted in corresponding white matter tracts on MRI scans substantiate these neurophysiologic abnormalities in central conduction pathways. We obtain baseline bone density studies and repeat the study every 6 months while patients are taking prednisone. In a prospective.. and also start alendronate (5 mg/day). brainstem auditory evoked. hypokalemia.1227 Dyck and colleagues confirmed the efficacy of prednisone in a randomized control trial. Visual evoked. temporal dispersion or F-wave latencies abnormalities. especially in the distal limb muscles. Alendronate also can be started to help prevent osteoporosis in patients who may be particularly susceptible (e.73 However.73.249. shortage of available IVIG). We prescribe calcium (1000–1500 mg/day) and vitamin D (400–800 IU/day) for osteoporosis prophylaxis. Paraspinal muscles reveal membrane instability in some patients.

we try to avoid exacerbations of weakness. Subsequent dosing depends on clinical response. Cyclosporine.864. and vomiting have limited its use. exchanges can be scheduled every 1–2 weeks and the duration between exchanges gradually increased. and future malignancy. associated with adverse side effects. one a young child. teratogenicity. cross-over studies convincingly demonstrated that IVIG is efficacious in CIDP.55. we administer IVIG (2 gm/kg) every 4 weeks and gradually try to increase the interval between courses as tolerated. Approximately 12% of patients receiving azathioprine develop fever. another small trial study found no improvement with IVIG therapy.1354 Subsequently. in which case PE may restore responsiveness to IVIG. IVIG proved beneficial as a first-line therapy in previously untreated CIDP patients. we have found that after several relapses some patients do not improve to baseline and are left with a deficit even after treatment. 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.1043. in patients with severe generalized weakness because the response may be quicker to PE than to prednisone alone.535 Unfortunately response to treatment is transient.. stroke. We usually do not treat CIDP with azathioprine alone. patients with poorly controlled diabetes mellitus or HIV infection) or in whom IVIG is contraindicated (e. PE alone can be used but requires indefinite repeated treatments.355 However. PE.510. placebo-controlled trial. We have used azathioprine in combination with prednisone in patients resistant to prednisone taper.. after the initial course of IVIG. Both oral (50–150 mg/day) and monthly pulses of intravenous cyclophosphamide (1 gm/m2) have been reported to be beneficial in some patients.341 In addition.Chapter 23 ACQUIRED NEUROPATHIES — 953 demonstrated the efficacy of PE. Patients who are IgA-deficient due to IgE anti-IgA antibodies or a congenital deficiency may develop anaphylactic reactions to IVIG. aiming for a trough level of 150–200 mg/dl. or IVIG. Several retrospective reports suggest that cyclosporine can be effective in some patients with CIDP. increased risk of infection and future malignancy..1354 In 1990. hepatotoxicity. usually lasting only a few weeks.g. larger double-blind. The time frame and dose of IVIG treatments need to be individualized. and cyclophosphamide. Thus. and technically difficult in some patients. and vomiting. In addition.1338.354. Interferons. No specific guidelines have been established for treating CIDP with PE.721. gingival hyperplasia. the dose of azathioprine was small (we go up to 3 mg/kg/day) and the duration of this study was too short.1353.144 Rare thrombotic complications (e. One method of dosing is to repeat IVIG courses after subsequent relapses. one often can determine earlier whether such patients may have an immune-responsive neuropathy.72.1284 Some patients develop headaches. It can sometimes take longer than 9 months before any benefit is noted from azathioprine in other immunologic disorders. alopecia.887a A beneficial response to interferon β-1a was reported in a child with relapsing CIDP. Van Door report benefit of IVIG in a small double-blind.547 Significant improvement with α-interferon was reported in two patients.476 Recently. A few patients have aseptic meningitis. A few reports involving single cases or a small series of patients suggest that azathioprine at doses of 100–300 mg/day with or without concurrent prednisone is effective in CIDP.547. bone marrow suppression. allows a lower dose of prednisone) has not been adequately addressed. requiring discontinuation of the drug.g. and flu-like symptoms.247. We exchange approximately 200–250 ml/kg body weight in 5 or 6 exchanges over a 2-week period. Therefore. Azathioprine. placebo-controlled. 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. who was unresponsive to prednisone. risk of infection. and increased risk of infection and future malignancies (mainly skin cancer and lymphoma). Thereafter. Initially. Intravenous Immunoglobulin.218 Subsequently. which may contain some IgA. Whether azathioprine has a prednisone-sparing effect (i. abdominal pain.1338 Dyck and colleagues compared PE with IVIG in an observer-blinded. hirsuitism. 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.1398 The major side effects of hemorrhagic cystitis. nausea. Some patients require more exchanges for maximal improvement. Of importance.1071. azathioprine. In this way. 9month study of 27 patients with CIDP noted no significant benefit when azathioprine (2 mg/kg/day) was added to prednisone. diffuse myalgias. a serum IgA level should be assayed in patients before administering IVIG. randomized. We use PE alone in patients in whom we wish to avoid long-term prednisone (e. We have used PE. Cyclophosphamide. the same authors conducted a double-blind. IVIG has become the treatment of choice in CIDP.587. which are costly. tremor. patients require repeated courses of IVIG because improvement is only transient.709. myocardial infarction) perhaps are related to hyperviscosity.g.476. we begin IVIG treatment with a dose of 2 gm/kg body weight over 2–5 days.332.. diabetes and superimposed CIDP-like neuropathy). randomized trial and found no clear difference in efficacy.g.1377 A prospective. including prednisone. CBCs and urinalysis must be monitored frequently in patients treated with cyclophosphamide.1147 Harada and colleagues reported a beneficial response to α-interferon as a first-line treatment in one patient. either in combination with prednisone or in steroid-refractory cases. The major side effects of cyclosporine include nephrotoxicity. but it is an option in patients who cannot be given prednisone.92 IVIG is well tolerated by most patients. Several uncontrolled studies have been reported showing improvement in CIDP patients with IVIG. Monthly pulsed intravenous cyclophosphamide is associated with less risk of hemorrhagic cystitis. neutropenia is common but rarely clinically significant. PE. IVIG.186. We monitor CBC and LFTs every 2 weeks while adjusting the dose of azathioprine and once a month when the dose is stable.1147 Gorson et al. treatment needs to be individualized. placebocontrolled.1337 However.1016.386.364 For many authorities. unblinded study of α-interferon in 16 patients with CIDP refractory to conventional therapies and found that 56% improved with α-interferon. hypertension.477. Electrolytes and renal function need to be monitored closely.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. There are a few reports of CIDP patients benefiting from α-interferon. but nonblinded. performed a prospective. nausea. chronic intermittent PE or the addition of immunosuppressive agents is required.e. even in those refractory to other modes of therapy.536. We initially administer cyclosporine at a dose of 4–6 mg/kg/day orally. and cyclosporine. usually in combination with prednisone. Only a few retrospective studies evaluated the use of cyclophosphamide in the treatment of CIDP. However. As with PE. cross-over study of interferon .698 Other side effects include bone marrow suppression.24a Because the response to PE is generally faster than the response to prednisone. Some patients become refractory to IVIG.

480. the multifocal nature of CIDP results in nonuniform slowing of conduction velocities. With childhood onset.442.954 — PART IV CLINICAL APPLICATIONS β-1a in 10 patients with CIDP and found no benefit.1168. Recently.1437 Most patients presented with a late-onset distal and symmetric sensorimotor neuropathy. electrophysiologic.and IgA-MGUS. more than 90% of patients improve with therapy. Clinical symptoms reflected mainly a sensory disturbance. CMT is associated with symmetric and diffuse involvement of the peripheral nerves.389. although prospective control trials have not been performed. except that patients with IgM neuropathy had more significant tremor.g. or asymmetric motor involvement may fulfill AAN criteria249 and could have been included in other series of CIDP patients. and 3 IgA). temporal dispersion. demyelinating features were uncommon.232.218.73. and Suarez and Kelly1265 reported the features of 39 patients with MGUS neuropathy (23 IgM. Yeung reported 62 patients with MGUS neuropathy (IgM 46. These patients are much less responsive to specific forms of therapy and skew the prognosis in these series. and distal arm and leg weakness to diagnose CIDP.1036.363 Criteria for CIDP developed by Barohn73 and the AAN249 allow for CIDP with concurrent illnesses. 10 patients in the IgM group had mixed axonal-demyelinating studies. It is not clear whether MGUS-related demyelinating neuropathies are distinct from CIDP. In contrast.476 patients with MGUS.1218. Demyelinating and axonal neuropathies seem to occur at relatively similar frequencies in IgG. Sensory ataxia and tremor were common. 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.1146a.1265 There were no significant clinical or electrophysiologic differences between IgM MAG-positive and IgM MAG-negative patients.748 Although IgG is the most common paraprotein in the general population. 816. Thus.. the family history is an important starting point.768.476. or prognostic (including response to treatment) differences between IgM-MGUS neuropathy with or without antiMAG antibodies. and electrophysiologic features are similar to those in adulthood. mild distal weakness.423. IgG 11. interferon β-1a was not effective in a small study of four patients who failed to achieve a satifisfactory response to other forms of immunotherapy. nerve conduction studies revealed demyelination in only 2 patients in the IgG group and 8 patients in the IgM group. PE..1220.360.1064. monoclonal gammopathy) who have clinical.736 Total Lymphoid Irradiation. or IVIG). Children respond to the standard forms of treatment.1168a We have found that patients treated early are more likely to respond. are involved in the pathogenesis of at least some types of idiopathic polyneuropathy.1318. IgA 5). IgM vs. Children commonly present with difficulty in ambulating.661. IgG/IgA and axonal vs.1265 In both series. demyelinating neuropathy) and directly comparing the demyelinating subgroups of MGUS neuropathy with idiopathic CIDP. there is an increased incidence of peripheral neuropathy in patients with MGUS.1216. Slightly more than half of the IgM patients were anti-MAG positive.527 In addition. more attention has been devoted to subcategorizing the clinical and electrophysiologic features of the different types of MGUS-neuropathy (e. nerve biopsies were significantly different in the IgM group compared with the IgG and IgA groups.1125 Prognosis. 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.535. Most IgM patients had features of demyelination on nerve biopsy along with widely spaced myelin sheaths and deposition of immunoglobulin on the nerves. and electrophysiologic criteria of demyelinating sensorimotor neuropathy should be classified as having CIDP is a matter of debate. In contrast.1168a Dyck and colleagues suggest that paraprotein-related neuropathies should be separated from idiopathic CIDP.668 Furthermore. laboratory.969 IgM-MGUS neuropathies are typically demyelinating but can be axonal. and widely spaced myelin sheaths and immunoglobulin deposition were not seen in patients with IgG and IgA neuropathy. including monoclonal gammopathies of uncertain significance (MGUS).1168a Other studies have reported that only 66% of patients respond to one of the three main therapies for CIDP (prednisone. However.and IgA-MGUS neuropathies.. temporal dispersion and conduction block are not seen on electrophysiological studies. Whether patients with paraproteins (i. but data and statistical analysis were not provided.1147.” We require symmetric. and chronic progressive forms of CIDP can begin in childhood. histologic.1168. underscoring the need for early diagnosis and treatment.789 Furthermore. whether they had distal weakness only or both proximal and distal weakness). The incidence of paraproteins in patients with peripheral neuropathy is higher than in the general population.560a. IgG 24.969.536 or include73.699. In our experience.661 Some series of patients with CIDP have chosen to exclude351. Obviously. There was no significant difference between the various subgroups.g.1287.1227. An electrodiagnostic medicine evaluation can be of considerable help in determining the correct diagnosis. CNS involvement. IgA 10). and conduction block. 13 IgG. Weakness was only a minor feature.1346 The clinical. The IgM-MGUS neuropathy seems to be less responsive to various immunotherapies than IgG.360. at least 50% demonstrate a subsequent relapse within the next 4 years and less than 30% achieve remission off medication. Gosselin480 described the clinical. IgM is by far the most common monoclonal protein in patients with peripheral neuropathy.661. Nerve conduction studies apparently were not significantly different from patients with idiopathic CIDP. patients in the IgM-MGUS group experienced more disability related to the sensory loss.1437 The clinical and electrophysiologic features of polyneuropathy associated with monoclonal gammopathies are heterogeneous and imply a multifactorial pathogenesis. Monophasic. and electrophysiologic features of 65 patients with MGUS neuropathy (IgM 31.1217.972 At least 50% of the IgM-MGUS group have antibodies directed against myelin-associated glycoprotein (MAG).480. There does not appear to be any significant clinical.130.1168a Progressive course. Most studies indicate that IgM-MGUS neuropathies are distinct from IgG and IgA-MGUS neuropathies. Charcot-Marie-Tooth disease [CMT]).130 CIDP in Children.e. however. Total lymphoid irradiation was reported to be effective in 3 of 4 patients unresponsive to prednisone or cyclophosphamide.. Lines of evidence suggest that paraproteins.167. laboratory. the Mayo group performed a double-blinded trial of . particularly IgM monoclonal proteins. Subsequently.360. 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. In the series of Suarez and Kelly. Paraprotein-related Neuropathies and CIDP. CIDP may be confused with a hereditary neuropathy (i. relapsing. proximal.480 Most series have not taken into account the distribution of muscle weakness in patients with MGUS-neuropathies (e.477 The differences in response rates among studies may relate to how the authors defined “CIDP.480. and particularly axonal loss have been associated with a poorer long-term prognosis. laboratory.1168a Patients with mainly sensory symptoms.e.

” many were associated with slow conduction velocities and prolonged distal latencies and F-waves.831 Axonal Variant of 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.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. doubleblind placebo-controlled trial of interferon-α in IgM-MGUS neuropathy and found no beneficial response.219. Several retrospective studies and unblinded or uncontrolled prospective series have reported benefit with corticosteroids. nerve histopathology is neither sensitive nor specific and can be normal or show features more suggestive of an axonopathy rather than a demyelinating polyneuropathy.644 Conduction block greater than 50% in multiple nerves was evident from nerve conduction data in another report.237.672.924. whether the patients have no weakness/only mild distal weakness or if they demonstrate both proximal and distal weakness). which results in a short TLI (< 0.661 Three patients reported symptomatic improvement in sensory symptoms. There are only a few prospective. Perhaps. acute motor and sensory axonal neuropathy). and less severe weakness than patients with idiopathic CIDP.657 One series of five patients commented on normal sural nerve conduction studies. who was initially responsive but then became resistant to therapy.73 In fact.334. placebo-control study (PE vs. as many as 25% of patients later develop an underlying malignancy. is that the disability of many patients is related predominately to sensory impairment. four patients with idiopathic CIDP were reclassified. the MGUS-CIDP group had more severe sensory conduction abnormalities. Katz and colleagues treated 10 patients with IgM-MGUS and distal acquired demyelinating symmetric neuropathy with a variety of immunomodulating therapies.282 Only modest benefit from IVIG was noted: two patients had improvement in strength. there was no improvement in clinical motor function or motor nerve conduction studies.830 The same investigators subsequently performed a prospective. if one carefully reads the reports suggesting an “axonal CIDP. immunoabsorption. Some series have focused only on IgM-MGUS neuropathy. Of note.830 There was improvement in sensory deficits as measured by the Clinical Neuropathy Disability Score with interferon-α. developed multiple myeloma. controlled treatment trials of IgM-MGUS neuropathy. and tibial motor nerves. Other authors have commented on the shortened TLI in IgM-MGUS. The study illustrates that MGUS is not necessarily benign. Although analyzing the response to treatment is limited by the retrospective nature of the study and varying therapeutic regimens. patients with CMT type 1. crossover study of IVIG in 11 patients with demyelinating IgMMGUS neuropathy. In addition. 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). similar to typical CIDP. one POEMS syndrome. sham pheresis in 21 patients with IgM and 19 IgG/IgAMGUS neuropathy. Surprisingly. and one had less sensory impairment. however. A few reports in the literature suggest that there is an axonal variant of CIDP. but it did not reach statistical significance. but none had objective improvement in the motor examinations.203. One patient. as previously mentioned. even in IgM-MGUS neuropathy. ulnar. and patients with idiopathic CIDP without MGUS.150 Furthermore. However.969 Treatment is another controversial issue in regard to MGUS neuropathy. by pattern of weakness (i.25). was later found to have a plasmacytoma.360 There was a trend toward improvement in the IgG/IgA group but not in the IgM group. This time frame is too short for improvement based on regeneration of axons and is more consistent with remyelination or reversal of conduction block. most patients with “axonal CIDP” improved within weeks to a few months of starting some form of immunotherapy. we agree with Feasby that the concept of an axonal form of CIDP is premature.1216–1218 Patients with MGUS-CIDP had a more indolent course. particularly in IgM-MGUS with or without antiMAG antibodies. Dalakas performed a double-blind.g. Recently. PE.. and another Castleman’s disease. the idiopathic CIDP group had a significant greater improvement rate (88%) than the MGUS-CIDP group (50%). A doubleblind.672. which is difficult to measure objectively.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. patients with CIDP who are or become refractory to therapy should be reevaluated for monoclonal gammopathy and underlying malignancy.657. however. Subgroup analysis of patients with IgMCIDP revealed a smaller terminal latencies index (TLI).Chapter 23 ACQUIRED NEUROPATHIES — 955 PE vs.644. futures studies will prove the existence of an axonal CIDP. particularly patients with MGUS.. more frequent sensory disturbance with ataxia.1400 A major obstacle in designing and interpreting these studies. placebo-controlled.971.649 The TLI in the antiMAG positive patients was significantly shorter than in normal volunteers. however. A small TLI is indicative of distal accentuated demyelination.746.748.1064. 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. as discussed above. acute motor axonal neuropathy. Another unresponsive patient developed acute myelogenous leukemia.401 Distal Acquired Demyelinating Symmetric Neuropathy It may be more helpful to classify patients with acquired demyelinating polyneuropathies.964.1216 In a long-term follow-up study. 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. as in GBS (e.1007. prospective trial comparing IVIG (10 patients) with interferon-α (10 patients) in IgM-MGUS neuropathy also found modest benefit from IVIG. Katz and colleagues described the clinical and electrophysiologic features of 53 consecutive patients with an acquired symmetric demyelinating . Three MGUS-CIDP patients were also reclassified. sham pheresis) was performed in patients with MGUS neuropathy.360 Improvement was noted in only IgG and IgA MGUS neuropathy. most patients reported with “axonal CIDP” had elevated CSF protein.649. An open-label. and IVIG.1218 Two developed MGUS. one-third of patients with CIDP do not fulfill the strict research criteria for the diagnosis. laboratory.107.768 Furthermore.e. For now.1321 although its existence is controversial. who was unresponsive to treatment.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. Simmons and colleagues compared the clinical. The third patient. although not in the “demyelinating” range. particularly in regard to IgM-MGUS. The TLI can be calculated as follows: TLI = terminal distance (mm)/conduction velocity (m/s) × distal latency (ms). randomized. cytotoxic agents.

.660. patients with idiopathic DADS or CIDP usually demonstrated objective improvement with immunotherapy. 12 distal sensory loss plus ankle dorsiflexor and foot intrinsic weakness).1029. many articles about MMN credit Lewis790 and colleagues with the initial description. Muscle Nerve 2001. with permission. 647. Multifocal Motor Neuropathy Multifocal demyelinating neuropathy with conduction block was first described by Lewis and colleagues in 1982. IVIG = intravenous immunoglobulin.e. distal > proximal. Anti-MAG antibodies were found in 67% of patients with IgMDADS neuropathy.790 They described five patients with asymmetric motor and sensory loss who had persistent conduction block on conduction studies of motor nerves.956 — PART IV CLINICAL APPLICATIONS Comparison of the Chronic Acquired Immune-Mediated Demyelinating Polyneuropathies CIDP DADS None or only mild symmetric distal weakness Yes. In contrast. CMAPs = compound motor action potentials. MADSAM = multifocal acquired demyelinating sensory and motor. The authors found no significant electrophysiologic differences between IgM-DADS. 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.661 Of the 53 patients.661. Most of the following reports described patients with pure or predominantly motor multifocal neuropathies with conduction block or other electrophysiologic features of demyelination. Most importantly.189.406. whereas patients with idiopathic DADS and CIDP (with or without an associated monoclonal protein) usually improved with therapy.722. MAG = myelin-associated glycoprotein.1049. . 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.) neuropathy. The patients also had objective sensory abnormalities on nerve conduction studies and sensory nerve biopsies. defined by the authors as necessary for the diagnosis of CIDP. Some patients with objective sensory abnormalities and probable MADSAM neuropathy have been included in some series of MMN.407. 30 patients had only distal symptoms (8 pure sensory loss. distal and symmetric Symmetrically reduced or absent Demyelinating features. SNAPs = sensory nerve action potentials. or CIDP.1025. 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). 2 IgG kappa). patients with IgM-DADS neuropathy demonstrated a poor response to immunotherapy. including analysis of the terminal latency index. termed multifocal acquired demyelinating motor and sensory (MADSAM) neuropathy.1050. In contrast. CB = Conduction block.1168a Monoclonal proteins were detected in 20 of 30 cases of DADS neuropathy (18 IgM kappa. 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). arms > legs Yes. including CB Normal Usually normal Rarely present Table 23-5. Clinical features Weakness Symmetric proximal and distal weakness Yes. arms > legs No Asymmetrically reduced or absent Demyelinating features. CSF = cerebrospinal fluid. Distinguishing the acquired forms of chronic demyelinating polyneuropathies by clinical phenotype (i. 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. Barohn RJ: Clinical spectrum of chronic inflammatory demyelinating polyneuropathies.1131 Nevertheless. Only 5 patients with CIDP (22%) had a monoclonal gammopathy (4 IgG kappa and 1 IgM lambda). (From Amato AA. response to treatment. MMN = multifocal motor neuropathy. This entity became known as multifocal motor neuropathy (MMN).50. including CB Abnormal Usually elevated Rarely present MMN Asymmetric. We consider patients with objective sensory loss in addition to motor dysfunction to have a different neuropathy. pattern and distribution of involvement) is useful in predicting the presence of IgM monoclonal proteins and. 23 had proximal and distal arm and leg weakness.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).24:311–324. symmetric Symmetrically reduced or absent Demyelinating features including CB Abnormal Usually elevated Occasionally present. more importantly. idiopathic DADS.1027. DADS = distal acquired demyelinating symmetrical. The term distal acquired demyelinating symmetric (DADS) neuropathy was applied to these patients (Table 23-5). asymmetric Asymmetrically reduced or absent Demyelinating features.

whereas weak and atrophic muscles are usually associated with depressed or absent reflexes.718. 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.1025. at best.557 Anti-GM1 sera raised from immunized rabbits produced abnormalities in sodium and potassium channels in isolated rat myelinated motor nerve fibers. clonus.774a. Early descriptions of MMN led to debate as to whether MMN is a distinct entity or simply a variant of CIDP.998a.189.660. across the brachial plexus. reduction of antibody titer correlates with clinical improvement after immunotherapy1049.140. other studies have demonstrated no such correlation. In a selective series of 16 patients with MMN (no patients with even mild sensory abnormalities were included).. these antibodies can be considered only a marker of the disease. a patient may have reduced strength in the ulnar-innervated hand intrinsic muscles.406.1027.209. but if there is objective sensory loss.. weakness. spasticity. 1027. wrist drop. obviating a C8/T1 spinal level disorder. typically in the distribution of individual peripheral nerves. the muscle involvement is in the distribution of individual peripheral nerves. 1031. decreased muscle bulk can result in time from secondary axonal degeneration.133. there is often evidence of conduction block in multiple upper and lower limb nerves (Fig. as previously discussed. The disparity between motor and sensory nerve involvement suggests that the autoimmune attack may be directed against an antigen specific for the motor nerve. it is reasonable to conclude that conduction block is present.1289a MMN is commonly misdiagnosed as amyotrophic lateral sclerosis (ALS). but corticospinal tract signs (i. Pathogenesis. histopathology. however.660 Weakness typically progresses over several years to involve other limbs. and a secondary inflammatory attack may result in demyelination. CSF protein is usually normal in patients with MMN. According to some reports.1028. although not without some doubt.765. Rare patients may develop respiratory weakness due to involvement of the phrenic nerves.1098. the average age of onset was 40. When there is a greater than 50% amplitude reduction from proximal to distal stimulation sites. combined with sparing of muscle bulk points to the diagnosis of MMN.209 The male-to-female ratio is approximately 3:1. extensor plantar responses) are not seen. or foot drop. A reduction in the distal CMAP amplitude can be seen in chronic lesions due to secondary axonal loss. This finding . Across the focal segment displaying conduction block. the multifocal peripheral nerve involvement.660.648. The pathogenic role for antiganglioside antibodies is not known.1289a Conduction block is not located at the expected common nerve entrapment sites.g.1025. temporal dispersion is not present. insidious progression and misdiagnosis of the disorder.1027. as opposed to spinal root level of dysfunction.248. 30–50 mm) can be identified with the drop in amplitude.133.832.207. and response to treatment. hence producing pseudoconduction block. The age at onset of symptoms is usually early in the fifth decade of life. We have not found these antibodies useful for diagnosis of MMN.122a Physical examination reveals weakness in a multifocal pattern in the upper and lower limbs. A helpful feature is the lack of atrophy in weak muscle groups early in the course of the illness. There are no universally accepted criteria for defining definitive conduction block. there has been no correlation between the presence or absence of antiganglioside antibodies and response to immunotherapy in some series. however. Typically.1303 Although opinions still vary. The above symptoms and signs can appear quite similar to a lower motor neuron variant of ALS. paralleling a peripheral nerve(s) as opposed to the spinal segmental/root distribution seen in motor neuron disease.1028.1050. As noted above.6 years (range: 2–20 years) at the time of diagnosis. Fasciculations may be observed in affected limb muscles.1027.722.1168a.1049. yet the median-innervated thenar muscles are completely normal. and essentially preserved sensation is certainly suspicious for an anterior horn cell disorder. Twenty to 84% of patients with MMN have detectable IgM antibodies directed against gangliosides.1169. MMN is believed to be immune-mediated.1271.1050. mainly GM1 but also GM2.204.1131. In high titers the antibodies appear to be rather specific for MMN. this hypothesis is only speculative.133. provided this finding persists for more than 5–8 days.189. In contrast to CIDP and MADSAM.1168a.Chapter 23 ACQUIRED NEUROPATHIES — 957 Clinical Features. ranging from the second to eighth decade of life.1285. not spinal roots. Deep tendon reflexes are highly variable in that unaffected regions can be normal.647.406. The incidence of MMN is much less than that of ALS. and a focal region of nerve (e.1050. but the sensitivity of the test is too low.205. conduction velocity is markedly reduced. The result is a reduction of the CMAP amplitude with proximal stimulation secondary to the normal dispersion of motor nerve conduction velocities. or nerve root region. Conduction block may be present not only in multiple different nerves but also at several locations along the course of the same nerve. initial involvement was in the arms in 12 (75%) and in the legs in four patients (25%). but in the mid-forearm or leg. however.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 studies37.50. The most sensitive and specific test is the nerve conduction study (see below).1168a.1072 but are uncommon.965 Furthermore. Sensory examination should be normal.1131.647.1320 but not in others.5 years (range: 20–64 years) with an average duration of illness of 7. upper arm.1150 The importance of these antibodies in terms of pathogenesis is unknown and continues to be vigorously debated. Cranial nerve abnormalities in MMN have been described646. suggesting demyelination. Multifocal motor neuropathy (MMN) is an immune-mediated demyelinating neuropathy characterized clinically by asymmetric weakness and atrophy.209 Electrophysiologic Findings.660 Patients develop focal muscle weakness accompanied by cramps and fasciculations.50.1028. However. However.648.1283 An immune attack directed against an ion channel may account for conduction block of neural impulses. For example. diagnosis is delayed by several years because of the slow. Patients generally present with intrinsic hand weakness. In a series of patients with MMN. 23-4). one should consider MADSAM neuropathy. not all patients with MMN have detectable antiganglioside antibodies.722. Occasionally.1289a A completely absent response to proximal stimulation with a persevered response to distal stimulation is considered sound evidence of conduction block. The presence or absence of antiganglioside antibodies in a patient who has electrophysiologic abnormalities consistent with MMN adds little to the diagnosis.e. Mild sensory symptoms have been described.660. The region of blockade can be localized to relatively small regions of nerve between 30–100 mm when short-segment (1-cm intervals) stimulation is used. Laboratory Features. 763.1029 The observation of fasciculations. remodeling of motor units can create MUAPs with long durations that may phase-cancel with other motor units.1107. Onset in the lower limbs also can occur. usually beginning in the distal upper limbs. some large neuromuscular centers diagnose one case of MMN for every 50 patients with ALS. In MMN. as noted above.101. normal or even mildly hyperactive reflexes can be elicited. particularly in chronic lesions.1049. In chronic disorders with severe axonal loss.

) may be observed in motor neuron disease.1013.660. A marked reduction in SNAP amplitude normally found in sensory nerves (phase cancellation) can confound this attempt.1131. Needle EMG findings depend on several factors.648. Motor and sensory nerve conduction studies of the left median nerve in a patient with multifocal motor neuropathy with conduction block.958 — PART IV CLINICAL APPLICATIONS Figure 23-4. Instead.133.1013 The electrophysiologic features of demyelination have been noted to improve with treatment in some but not all cases. a gradual reduction in MUAP size is seen with increasing separation of stimulation sites.189. with permission. For example. slow conduction velocities. positive sharp waves and fibrillation potentials are commonly detected in degrees commensurate with the amount of nerve . 1030. Stimulation of the median nerve in a control subject demonstrating normal temporal dispersion and reduction in both CMAP and SNAP amplitude.1289a other features of demyelination (i. When secondary loss of axons has occurred. 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. the numbers of motor units with rapid firing rates are reduced..1025. Stewart JD.205. but careful analysis reveals an absence of focal reduction in amplitude. Sumner AJ: A syndrome of asymmetric limb weakness with motor conduction block.235.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.1029.1049.e. A. Note that sensory conduction across the same nerve is essentially unaffected and quite similar to the control nerve. Further investigations are required to resolve the issue. The previously defined criteria of conduction block with respect to AIDP and CIDP may be valid. B. When a clinically weak muscle is investigated. Although motor conduction block has been considered the electrodiagnostic hallmark of MMN.40:118–127.The marked reduction in SNAP amplitude is a normal phenomenon secondary to significant temporal dispersion and phase cancellation.646. particularly with sequential stimulation sites every centimeter.189.660. (From Krarup C.1027.660. This finding is documented with or without axonal loss because conduction block and denervation appear essentially the same with respect to MUAP recruitment.406.722. if a blockade of neural conduction is found in the median nerve CMAP at the mid-arm level.660. median nerve SNAPs should be documented with stimulation at the wrist and mid-forearm segments. there are no sensory conduction abnormalities in the mixed peripheral nerve in the region where conduction block can be demonstrated in motor fibers. Neurology 1990. giving the false impression of conduction block.763.1094 Diagnosis does not require conduction block if other features of demyelination are present. but debate continues.646. and prolonged or absent F-waves) are typically present on motor nerve conduction studies.763.1050.50.1131 Unaffected muscles should demonstrate no abnormalities. 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.189. temporal dispersion. prolonged distal latencies.1131 Of importance.774a The sensory nerves characteristically demonstrate normal SNAP parameters using surface or near-nerve recording techniques.

we favor using theterm MADSAM neuropathy to underscore the distinction between these patients and patients with MMN. Intravenous cyclophosphamide was the first immunosuppressive agent demonstrated to be effective in MMN.1285. reported that sensory nerve biopsies of 11 patients with MMN showed a slightly increased number of thinly myelinated large caliber axons. this high dose of intravenous cyclophosphamide (3 gm/m2) is associated with alopecia. Patients should be treated with mesna and well hydrated to avoid hemorrhagic cystitis.1168. Several series. asymmetric distribution. we recommend lowering the initial intravenous pulse of cyclophosphamide to 0.324.50. Subsequently.1168.1303. in which CSF protein concentration is usually normal. these demyelinating features were “never extensive.57.1025. A few reports of motor nerve and mixed motor and sensory nerve biopsies have demonstrated features of demyelination and remyelination.790 Clinical features.1049 Azathioprine has been administered in a few patients without noticeable improvement.Chapter 23 ACQUIRED NEUROPATHIES — 959 injury and clinical wasting.456. however. We have rarely used cyclophosphamide. Fasciculation potentials and. Most reports of sensory nerve biopsies in MMN describe normal findings. Unfortunately.1168a Although we believe that MADSAM neuropathy probably represents an asymmetric form of CIDP. and histologically.456.989. a similar degree of improvement has not been seen with prednisone.1131a. and significant bone marrow suppression.5 or 1. electrophysiologically.774a IVIG is given initially in a dose of 2 gm/kg over 2–5 days with subsequent maintenance courses as necessary.1168 As noted previously. The average age of onset is in the early 50s (range: 14–77 years).965 Whether such patients constitute a separate nosological entity.1330 Histopathology. However. PE. Oral cyclophosphamide in combination with IVIG may prolong the interval between IVIG infusions. Efficacy has been demonstrated in numerous studies.989. There is a 2:1 male predominance.989.1330 In patients with demyelination localized to the cervical roots or brachial plexus. Some series have noted that later age of onset832 and patients who have significant muscle atrophy133 do not respond as well to treatment.23.23. Therefore. The term multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy was coined to describe this suspected variant of CIDP (see Table 23-5).1303. In MMN in which patients with sensory signs were excluded.757 These abnormalities improve after treatment.790. Most patients have decreased or absent muscle stretch reflexes in a multifocal.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. with small onion bulb formations. including optic neuritis. myokymic discharges may be noted.1329. Motor and sensory losses conform to a discrete peripheral nerve distribution rather than a generalized stocking or glove pattern.1303. Some patients describe pain and paresthesias. In contrast to CIDP and MADSAM neuropathy. or minimal axonal degeneration.722. there have been several series of patients who resemble MMN but have objective sensory abnormalities clinically.660. or azathioprine. some have complete areflexia.478. similar to the management of CIDP. In patients who cannot tolerate IVIG. have included patients with mild objective sensory deficits or abnormal sensory NCS. suggesting that the improvement is not just a placebo response. as an alternative to MADSAM neuropathy.205.763.478.1168a. There is usually a 2–3 year lag from the onset of symptoms to diagnosis.1025 Anecdotally.478. given its short-term and long-term side effects. The subsequent doses can be titrated upward or downward as tolerated. only 1 of 45 tested patients with MADSAM neuropathy have had detectable GM1 antibodies.5–1.647. however. The initial dose of intravenous cyclophosphamide in large series of patients has been 3 gm/m2 given over an 8-day period. A muscle with clinical weakness but preserved bulk is likely to reveal few if any fibrillation potentials and positive sharp waves. There are differences in CSF protein and GM1 antibodies between patients with rigorously defined MADSAM neuropathy and MMN (see Table 23-5).1303.251.1289a including one double-blinded placebo-controlled trial. rarely.1025. Histopathology. large-diameter fibers and scattered demyelinated fibers in most reported cases (Fig.722.23. Laboratory Test Results. trigeminal.660.1030.1027. which enhance in some. MRI scans have demonstrated enlarged nerves.891 Improvement usually is noted within a few days or first few weeks of treatment.973.989. only 1 of 11 patients with MMN had an elevated CSF protein.251 Corse et al.1168.406.478. the legs also can be be initially involved and often become affected over time.1329.456. We give three courses of monthly IVIG before concluding that a patient has failed treatment.50.133.646.”251 They described no evidence of subperineurial or endoneurial edema or mononuclear inflammatory cell infiltrate in the epineurium or endoneurium.989. and mild perivascular inflammation. represent a focal variant of CIDP. Nausea can be managed with ondansetron or gransetron.722.1168.268. mild loss of myelinated fibers.1025.832.205. however.1289a No double-blinded. over 70% of reported patients improved clinically after treatment. not all patients with MMN respond to IVIG. and facial nerve palsies.0 gm/m2) or oral cyclophosphamide (2 mg/kg) can be instituted after 1 month. Onset is usually insidious and slowly progressive with initial involvement usually in the arms.1168.647 Treatment. In contrast. or simply have MMN with mild sensory involvement is the subject of some debate. nausea and vomiting. Recently.722. the concept is useful because it emphasizes that the disorder is not merely a variant of MMN with associated sensory findings. However.1168.790.1049. There are now over 50 well-described patients with MADSAM neuropathy. we have found a similar lack of efficacy with azathioprine. cases. most patients with MMN (range: 56–90%) have antibodies to GM1.0 gm/m2 to avoid severe side effects. IVIG is now the treatment of choice in MMN.200. small onion bulb formation.1303.1330 The signs and symptoms of MADSAM neuropathy are essentially those of mononeuropathy multiplex. hemorrhagic cystitis.1168a CSF protein is elevated in 60–82% of patients with MADSAM neuropathy (mean level of around 70 mg/dl).965.406.251 The histologic features on sensory nerve biopsy in MMN are in sharp contrast to those seen in CIDP. few patients (<3%) with MMN improve with high doses of corticosteroids or PE.790. the demyelination appeared asymmetric between and within nerve fascicles in at least one reported case.832.1329.973.1329.1329 . 23-5).973. however.965. monthly courses of intravenous cyclophosphamide (0.1049 Some groups have noted scant findings of demyelination and remyelination on sural nerve biopsies.133. the eponym LewisSumner syndrome also has been used in recognition of the clinicians who first described this neuropathy. Cranial neuropathies have been reported.56. oculomotor. but not all. placebo-controlled trials have been performed with cyclophosphamide. patients with MMN should have no objective sensory abnormalities clinically or on NCS. Sensory nerve biopsies demonstrate many thinly myelinated. Single-fiber EMG reveals increased fiber density and jitter in clinically weak and unaffected muscles. since the reported efficacy of IVIG in MMN. Multifocal Acquired Demyelinating Sensory and Motor Neuropathy As discussed above.647 Of note.456.

retrospective series have demonstrated that most patients with MADSAM neuropathy improve with IVIG treatment.478. mild perivascular inflammation. Patients often complain of “weakness” when referring to difficulty with gait or clumsiness.1303.790. Idiopathic sensory neuronopathy has been reported in over 100 patients. In contrast to MMN but similar to CIDP. We believe that MADSAM falls into the spectrum of CIDP and probably has a similar pathogenesis. The deficit can be more impaired in the arms than legs. These causes of sensory neuronopathy are discussed in their relevant sections. Numbness can begin in the face.478. long-duration MUAPs that recruit early. in which cyclophosphamide is the only other medication reported to be beneficial besides IVIG.989.973. which is typically associated with anti-Hu antibodies. nerve conduction studies in MADSAM neuropathy demonstrate conduction blocks.989. Clinical Features. prolonged distal latencies. Usually. the sensory studies are also abnormal.23.1445 There is a slight female predominance. and other systemic disorders also are associated with a sensory neuronopathy. the sensory symptoms are generalized. Pain and temperature sensations are less affected. unlike length-dependent axonal neuropathies. As with CIDP and MMN.1168a Electrophysiologic Findings. similar to those in patients with generalized CIDP. axonal loss secondary to severe multifocal demyelination may cause a similar clinical picture. Although this feature can suggest an ischemic process. touidine blue stain). Marked reduction in vibration and position sense is evident on examination.44. or limbs.989.1329 Pathogenesis. Prominent. There has been no evidence of necrotizing vasculitis on any reported biopsies. The differential diagnosis of sensory neuronopathy includes paraneoplastic syndrome. B-cells.1168. patients describe clumsiness of the hands and gait instability.277. these symptoms are related to the severe sensory . The course can be monophasic with a stable or remitting deficit.456.973.1168 Similar asymmetric abnormalities had been reported in three other patients with MADSAM neuropathy.1168a In contrast This disorder is believed to be caused by an autoimmune attack directed against the dorsal root ganglia. infectious agents. However. temporal dispersion.973. some surrounded by early onionbulb formations (epoxy-embedded. or chronic relapsing.1168. chronic progressive. prolonged F-waves. A few patients experience a flu-like illness with or without diarrhea shortly before the onset of symptoms. A smaller percentage of teased fibers show features of axonal degeneration (range: 0–6%).973 Asymmetric involvement was apparent on motor nerve biopsy in one patient with MMN at the site of conduction block. so-called idiopathic sensory neuronopathy is discussed below. but they can remain asymmetric.1257. Although prospective. We believe that MADSAM and CIDP are distinct from MMN.1329.790.960 — PART IV CLINICAL APPLICATIONS to MMN. many cases of sensory neuronopathy have no clear etiology. trunk.647 Asymmetric fiber loss with demyelination may represent the pathologic correlate of the clinical neurologic findings of asymmetric demyelinating mononeuropathy multiplex. The electrophysiologic abnormalities improve with treatment. Symptoms begin asymmetrically and in the upper limbs in nearly one-half of patients. The pathogenic basis for MADSAM neuropathy is not known.1419 Hyperesthesia with prickly.23. and slow conduction velocities in one or more motor nerves. and the mean age of onset is 49 years (range: 18–81 years).1330 A similar response to IVIG is noted with CIDP and MMN.1303 This difference illustrates the importance of distinguishing MADSAM from MMN. SNAPs are usually absent or small in amplitude.73 the AAN criteria do not require symmetric deficits. as demonstrated by objective sensory abnormalities and differences in laboratory results.456. Teased fiber preparations reveal demyelinated or remyelinated internodes in 3–88% of the fibers.249 In contrast to the CIDP classifications established by Dyck351 and Barohn. Treatment. and response to steroids.1419. The pathogenic basis for the asymmetric involvement is unclear. lancinating pain can also develop during the course but is usually not the presenting or most prominent symptom. Certain medications or toxins. The most common presenting complaint is numbness. Because of the prominent large-fiber sensory loss. often described as a “dead” or “novocaine-like” feeling.705. although some have noted nonspecific. controlled trials have not been performed.456.1168.537.1232 The neuronopathy can present acutely with an abrupt onset over a few hours or develop more insidiously over several months or years.1303 A biopsy specimen from the brachial plexus in one patient demonstrated prominent infiltrates consisting of mainly T-cells and. to a lesser extent. Manual muscle testing is usually normal.1168a MADSAM neuropathy and CIDP are similar with respect to CSF and sensory nerve biopsy findings as well as response to corticosteroids.790. Sural nerve biopsy demonstrates a mild loss of myelinated nerve fibers and many thinly myelinated fibers. MADSAM neuropathy meets the CIDP criteria formulated by the Ad Hoc Subcommittee of the American Academy of Neurology (AAN) AIDS Task Force. 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.411. most patients with MADSAM neuropathy also demonstrate improvement with steroid treatment. EMG may reveal fibrillation potentials and positive sharp waves as well as polyphasic. histopathology. Some muscle groups may appear weak because of impaired modulation of motor activity due to the proprioceptive defect. Mutlifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome.23. Figure 23-5.790.1232.23.456. hence the terms sensory neuronopathy and ganglionopathy are more appropriate than sensory neuropathy. and sensory ganglionitis related to Sjögren’s syndrome. asymmetric loss of large myelinated nerve fibers between and within fascicles may be seen on nerve biopsies. Despite extensive evaluation.1168.989.

1445 Some degree of MUAP alterations. patients consistently miss their nose and the examiner’s stationed finger. We refer patients to ophthalmology for Rose-Bengal stain and Schirmer’s test.Chapter 23 ACQUIRED NEUROPATHIES — 961 ataxia resulting from the loss of proprioception. whereas plantar reflexes are flexor. Only rare patients exhibit CSF pleocytosis.1419 They noted significant loss of both large and small myelinated nerve fibers as well as axonal atrophy. including anti-GD1b. In regard to facial sensation and the blink reflex. Once the cell body of the sensory neuron is destroyed. When the eyes are closed. Idiopathic Autonomic Neuropathy Clinical Features. Treatment.6.537 These ganglia were severely depleted of neurons.1419 MRI scan can reveal gadolinium enhancement of the posterior spinal roots.1419 Myokymic discharges were recorded in one patient with chronic progressive sensory neuronopathy. Windebank et al.1419 An abnormal blink reflex favors a nonparaneoplastic etiology for sensory neuronopathy but does not exclude an underlying malignancy. the sensory neuronopathy can precede the onset of malignancy or sicca symptoms (i.52 However. were detected in this patient’s serum. Patients exhibit a positive Romberg sign and. is described in a few patients.1371.277. a trial of immunotherapy may be warranted.e.1371 Increased signal abnormalities on T2-weighted images may be seen in the posterior columns of the spinal cord. Furthermore.1419. Idiopathic sensory neuronopathy is a diagnosis of exclusion. when the eyes are closed. antinuclear. and IVIG. and SS-B antibodies should be ordered to look for evidence of Sjögren’s syndrome.537. SS-A. Decreased recruitment is not a prominent feature.24. Young et al. Electrophysiologic Findings. particularly anti-GD1b antibodies.g. but the ganglioside GD1b has been hypothesized to be the target antigen. Subacute sensory neuronopathy also has been associated with recent Epstein-Barr virus infection. Some studies have shown a preferential loss of large myelinated fibers compared with small myelinated fibers. which is abnormal in patients with sensory neuropathy. which also can present with a sensory neuronopathy. Pertinent laboratory and malignancy work-up should be ordered. and histologic description of acute .1445 However.1335 The neuronal epitope to which the autoantibodies are directed is still unknown.347 However. Motor nerve conduction studies either are normal or reveal only mild abnormalities. and antibodies directed against this ganglioside have been detected in some patients with idiopathic sensory neuronopathy. it will not regenerate. In the acute setting or in patients with a chronic progressive deficit. were the first to report a detailed clinical. 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.1138 Laboratory Features. or IgA). and Wallerian degeneration of the posterior nerve roots and dorsal columns was evident. Needle EMG is usually normal. Thus. dry eyes and mouth). the masseter reflex or jaw jerk.504 Of importance.1419.770 Some patients have a monoclonal gammopathy (IgM. distal motor latencies and F-waves are usually normal. An autopsy performed 5 weeks after onset of idiopathic sensory neuronopathy in one man revealed widespread inflammation involving sensory and autonomic ganglia. PE.1445 When SNAPs are obtainable. is usually normal in patients with sensory neuronopathy. it is difficult to assess efficacy of any specific treatment regimen because none has been studied in a prospective. suggesting chronic motor unit remodeling. The disorder is believed to be caused by an autoimmune attack directed against the dorsal root ganglia. reside in the dorsal root ganglia of the PNS.705. have been demonstrated in some cases of idiopathic sensory neuronopathy associated with IgM monoclonal gammopathy. nonspecific perivascular infiltrate occasionally is seen. However. a few patients may improve spontaneously. Serum from patients with idiopathic sensory neuronopathy immunostains dorsal root ganglia cells in culture and inhibits neurites. controlled fashion. In addition. IgG. Pathogenesis. A lip or parotid gland biopsy is obtained in all suspected patients. the distal sensory latencies and nerve conduction velocities are normal or only mildly abnormal. The CMAP amplitudes are reduced in less than 20% of patients.1371. Immunohistochemical analysis suggested a CD8+ T-cell–mediated cytotoxic attack against the ganglion neurons. antiganglioside antibodies.1257..537 Of note. Various modes of immunotherapy have been tried. The most prominent electrophysiologic abnormality is absent or low-amplitude SNAPs. found no difference in the median myelinated fiber diameter from control biopsies..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. Patients may have only mild dysmetria with eyes open. One also should inquire about sicca symptoms. Sjögren’s syndrome).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. these disorder should always be kept in mind.1419 Antiganglioside antibodies. The CSF protein is normal or only slightly elevated in most patients. the upper limbs also may begin to move in space. paraneoplastic syndrome. Deep tendon reflexes are decreased or absent. Sensory nerve biopsies demonstrate a reduction in the total number of myelinated nerve fibers. However.277. A detailed history and examination are essential to exclude toxin-induced neuronopathy. or disorder related to connective tissue disease (e. therefore.1232. in a study of 22 sural nerve biopsies. This problem can be readily demonstrated by having the patient perform the finger-nose-finger test with eyes open and then closed.663. Most patients have difficulty in knowing the position of their feet and hands in space. Histopathology. 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-cell–mediated ganglionitis. double-blinded. the motor neurons and roots were spared.1413 However.271. Likewise. Usually there is a lack of inflammation in peripheral nerve specimens. Rabbits immunized with purified GD1b develop ataxic sensory neuropathy. 411. Likewise. there is no indication to treat a patient with a stable deficit.1419 Motor nerve conduction velocities are normal or only slightly decreased. the afferent cell bodies lie in the gasserian ganglia outside the CNS. and many stabilize even without treatment. The sensory cell bodies innervating the limbs. laboratory.281 GD1b is localized to neurons in the dorsal root ganglia. although a mild. H-reflexes and blink reflexes typically are unobtainable. although a few patients may have positive sharp waves and fibrillation potentials in the distal upper and lower limb limb muscles.51. 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.1419 Segmental demyelination is also absent on nerve biopsies. including corticosteroids. in contrast. so-called pseudoathetoid movements. not surprisingly describe more gait instability in the dark.

231.875. dry eyes and mouth. type of autonomic deficits. prednisone.1266 There are no serologic or immunologic abnormalities in the blood. there have been several small reports.407. The authors speculated that the mechanism was autoantibodies directed against calcium channels on presynaptic autonomic nerve terminals and. as indicated by complaints of nausea.e. laxatives.5 mg/day and can be gradually increased to 40 mg/day in divided doses (every 2–4 hours) as necessary. intermittent selfcatheterization. Primary vasculitis Large vessel vasculitis. and enemas may be needed in patients with constipation. The CSF often reveals slightly elevated protein without pleocytosis.818 Sympathetic skin response may be absent.35.1088 Cardiovascular studies reveal orthostatic hypotension and reduced variability of the heart rate to deep breathing in over 60% of patients. We begin treatment at 0. or postprandial bloating is the second most common symptom (over 70% of patients). and degree of recovery.1266 Laboratory Features. Recently. polyarteritis nodosa. exaggerated fall in blood pressure during early phase II of the response. and 80% of patients had various degrees of widespread sympathetic and parasympathetic dysfunction. tingling.1077.865. medium. However.86. although a few have diminished amplitudes and slightly prolonged distal latencies. As many as 30% of patients also described numbness.875 Fluodrocortisone is effective for increasing plasma volume.407. diarrhea.566.1348.g. the neuromuscular junction. Vasculitides Associated with Peripheral Neuropathy in 12–97% of the body. is also effective and can be used in combination with fluodrocortisone.1434 There appears to be heterogeneity in onset.. malignancy). or large vessel).1442 Reduced density of mainly small diameter myelinated nerve fibers has been described.874. Histopathology..950. bethanechol). to a lesser extent.1262.1266 Most patients have abnormal thermoregulatory sweat tests with areas of anhidrosis Table 23-6. Vasculitis is a histologic diagnosis requiring transmural inflammation and necrosis of the blood vessel walls. whether autoantibodies to calcium channels were present in this patient was not reported.950.1288. Supine plasma norepinephrine levels are not different. drug reactions. Muscle strength was normal. giant cell (temporal) arteritis Medium and small vessel vasculitis Polyarteritis nodosa Churg-Strauss syndrome Wegener’s 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.1442 recovery tends to be incomplete in most. and other immunosuppressive agents have been tried with variable success. Wegener’s granulomatosis) or secondary to other systemic disorders (connective tissue diseases. Most patients had a monopathic course with progression followed by plateau and slow recovery or stable deficit. Necrotizing vasculitis results in ischemia in tissue supplied by the injured vessels. most limited to one or two patients with idiopathic autonomic neuropathy.1441.1266.553. urinary retention or incontinence. which are present on presynaptic autonomic nerve terminals.406.1077. 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. Quantitative sensory testing may reveal abnormalities in thermal thresholds..1 mg every 3–4 days until blood pressure is controlled. Mere perivascular inflammation is a nonspecific finding and does not necessarily indicate vasculitis (necrotizing vasculitis).e. Scant epineurial perivascular inflammation may be seen. or erythromycin.1266 An abnormal response to Valsalva maneuver (i. Midodrine is started at 2. but in one report stimulated single-fiber studies demonstrated increased jitter.962 — PART IV CLINICAL APPLICATIONS pandysautonomia. or reduced or absent overshoot of systolic and diastolic pressures during phase IV) can be demonstrated in over 40% of patients. Vasculitic disorders can be classified based on the caliber of involved vessel (i. small. Routine nerve conduction studies and EMG are usually unremarkable. Fluodrocortisone is administered only in the morning or in the morning and at lunch to avoid nocturnal hypertension. Electrophysiologic Findings.388. cisapride. Churg-Strauss disease.1266 The most important aspect of management is supportive therapy for orthostatic hypotension and bowel and bladder symptoms. Gastrointestinal hypomotility can be treated with metaclopramide. Most patients have normal sensory conduction studies. or other modes of therapy. and impotence are often present. vomiting. The disorder is thought to result from an autoimmune attack directed against peripheral autonomic fibers or the ganglia. absent recovery of systolic and diastolic blood pressure during late phase II. A subset of patients may have antibodies directed against calcium channels.g.1266 Although some patients exhibit complete recovery. and dysesthesia of the hands and feet. infection. Gastrointestinal studies can demonstrate hypomotility anywhere from the esophagus to the rectum. 1230. Pathogenesis.1125a . but standing levels are significantly reduced compared with normal controls.1442 Subsequently. Nerve biopsies have been performed on only a few patients.889. IVIG. Bulking agents.1266 Motor conduction studies are normal.1266. Midodrine. constipation.388.35.1 mg/day and increase by 0.818.. The most common symptom was orthostatic dizziness or lightheadedness (about 80% of patients).1262.865.1440 Needle EMG is generally normal. or whether the vasculitis is systemic or isolated to the peripheral nervous system (PNS) (Table 23-6).1230. Summated quantitative sudomotor axon reflex test (QSART) scores are abnormal in 85% of patients. ileus. Treatment.1077 With increased rate of stimulation the amount of jitter decreased. Thermoregulatory impairment with heat intolerance and poor sweating was also present in most patients. a peripheral α1-adrenergic agonist.1266 Approximately 20% of patients had selective cholinergic dysfunction. presence or absence of somatic involvement. Conclusions about the efficacy of immunotherapy are limited by the retrospective and uncontrolled nature of most reports.566. whether the vasculitis is primary (e. Patient may require cholinergic agonists (e. Stacks of empty Schwann cell profiles and collagen pockets can be seen. Blurred vision.1266 Specialized tests to look for abnormalities of the autonomic nervous system are required for diagnosis.1348.519.1077.701. Urology should be consulted in patients with neurogenic bladders.1041. PE. Gastrointestinal involvement.1440.

In patients with the distal symmetric pattern. but there is significant overlap of clinical manifestations. (From Kissel JT. .) Clinical Features. complement. Active Wallerian degeneration is evident on plastic/epoxy resin sections and teased fiber preparations. creating a distinctly asymmetric pattern of involvement. with permission. Diagrammatic representation of the three patterns of peripheral nerve involvement commonly encountered in vasculitic neuropathies.700. 23-7).1125a. Another important observation is the asymmetric nerve fiber loss between and within individual nerve fascicles. Usually.1020.701. In overlapping mononeuritis multiplex.701 The first is a mononeuropathy multiplex or multiple mononeuropathies.697.701. In this example.700. and superficial radial sensory nerves are the most appropriate to consider for biopsy. The diagnostic yield is increased when both nerve and muscle are biopsied. yet asymmetric pattern of involvement.997. multiple neighboring nerves are involved on both sides of the body.697. sensory loss and weakness are located in the typical glove-and-stocking distribution. producing the classic glove-and-stocking deficit similar to most distal symmetric polyneuropathies. both motor and sensory fibers are affected. and membrane attack complement on blood vessels. so-called overlapping mononeuropathy multiplex. the patients demonstrate a combination of right peroneal.1159 The definitive histologic diagnosis of vasculitis requires transmural inflammatory cell infiltration and necrosis of the vessel wall (Fig.1159 Each specific disease has unique characteristics of its primary systemic manifestations. The result is a generalized.697. is formed when the same nerves on both sides of the body are affected but to differing degrees and in differing distributions. found in 60–70% of cases at the time of diagnosis. over time fairly uniform and generalized involvement of peripheral nerves can develop. thus distinguishing this form of dysfunction from distal symmetric polyneuropathy.Chapter 23 ACQUIRED NEUROPATHIES — 963 Figure 23-6.519. individual nerves create an asymmetric pattern of clinical involvement.700. The mononeuropathy multiplex patterns (simple and overlap forms) are the most common. particularly in terms of peripheral nerve involvement. and left ulnar nerves affected.234. Several individual nerves may be affected.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). superficial sensory peroneal. because the peroneus brevis muscle can be biopsied at the same time. the sural. A second pattern. Histopathology. Neurol Clin 1992.There is a certain degree of asymmetry when the same nerve on the left vs.701 We prefer the superficial peroneal nerve. whereas a distal symmetric polyneuropathy is evident in approximately 30–40% of patients. In patients with suspected vasculitic neuropathies. with variations on a central theme of vascular compromise.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.10:761–781. if it is clinically involved. 23-6). right superficial radial.1393 Immunocytochemistry often reveals deposition of immunoglobulin (IgM and/or IgG). Mendell JR:Vasculitic neuropathy.697 The differential diagnosis of patients with a mononeuropathy multiplex pattern is quite broad (Table 237).997. Three patterns of peripheral nerve involvement can be appreciated (Fig.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.701. Finally. resulting in numbness and weakness conforming to specific nerve distributions. In true mononeuritis or mononeuropathy multiplex. the right is considered.563. All of the vasculitic disorders have certain clinical features in common.

716 Stroke is another important complication.81. an asymmetric pattern of motor conduction abnormalities between limbs can be demonstrated. Unfortunately. MCTD) Nonsystemic vasculitis neuropathy Remote effect of cancer Diabetic microangiopathy Amyloidosis Atherosclerotic vascular disease Drug-induced (e. 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. The interested reader is encouraged to pursue the specific citations noted for each disease about particular electrodiagnostic medicine findings.132. which produces conduction failure.716 GCA affects medium-sized and large vessels. When obtainable. Polyarteritis nodosa is used as a template disease to illustrate what can be anticipated in vasculitic axonal sensorimotor neuropathies. There are two forms of giant cell arteritis (GCA): temporal arteritis and Takayasu arteritis. For example.Only temporal arteritis has been associated with peripheral neuropathy. whereas conduction velocities are normal or only mildly reduced compared with the lower limit of normal.1115 The cause probably is related to ischemia. mononeuropathy multiplex pattern reveals asymmetric SNAP abnormalities. Reduced recruitment of MUAPs is also evident in the distribution of the affected nerves.g. The distal muscles are more likely than the proximal muscles to demonstrate such abnormalities.997. To be sure.g.g. whereas the right sural and left superficial peroneal SNAPs are relatively unaffected.176 Corticosteroids are usually highly effective in patients with GCA.982. as many as one-third of temporal artery biopsies lack definitive features of arteritis..468. and can be observed in patients either with mononeuropathy multiplex or generalized sensorimotor forms of involvement. plexopathies.1393 Sensory nerve conduction studies typically reveal SNAP amplitude reductions in the distribution of the affected nerves. Motor conduction studies reveal similar findings to those noted for sensory nerves.193. 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. there are minor variations for each disorder and individual patients.176.176.517–519. Polyarteritis nodosa (PAN) is the most common of the necrotizing vasculitides with an incidence ranging from 2–9 per million. SLE. Patients usually complain of headaches and diffuse myalgias. Distal latencies are normal or slightly prolonged.176 The classic histologic feature is an inflammatory infiltrate with giant cell formation in the blood vessels.. . Jaw and tongue claudication is not uncommon.964 — PART IV Table 23-7. Vision loss secondary to ischemic optic neuropathy occurs in 8–23% of patients.907. but the descriptions noted are generally applicable. Laboratory evaluation is remarkable for elevated ESR in 97% of patients.1345. motor unit remodeling results in MUAPS of long duration and relatively increased amplitude. 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. With mononeuropathy multiplex. or generalized sensorimotor peripheral neuropathy. The CMAP is commonly absent or significantly reduced in the affected nerves.624. Fwaves may be difficult to obtain in nerves with severe axonal loss. The electrodiagnostic medicine findings noted in this section pertain to all of the specific disorders listed below. PAN is a systemic disorder Electrophysiologic Findings. which fire in reduced numbers. The needle EMG examination characteristically demonstrates fibrillation potentials and positive sharp waves in muscles innervated by the affected nerve.579. traumatically induced) Secondary compression neuropathies (e.176 The temporal artery is often tender. e.701. Documenting fibrillation potentials in a specific nerve distribution can be quite helpful in delineating the pattern of a mononeuropathy. and a cord can be palpated. the left sural and right superficial peroneal SNAPs may be absent or reduced in amplitude.563. A .. amphetamine. particularly the aortic arch and all its branches..1125a The onset is usually between 40 and 60 years of age.g.g. Approximately 14% of patients with temporal arteritis have peripheral nerve involvement.. CLINICAL APPLICATIONS Mononeuropathy Multiplex: Differential Diagnosis Ischemic neuropathies Polyarteritis nodosa Wegener’s granulomatosis Churg-Strauss syndrome Connective tissue disorders associated with vasculitic neuropathies (e. Of interest.697. Primary Systemic Vasculitic Disorders Affecting Medium-sized and Small Vessels Polyarteritis Nodosa. The same comments apply to the upper limbs.162. F-waves latencies are normal or only slightly prolonged.800. In long-standing disease. including the internal and external carotid arteries and vertebral arteries.700.g. radiculopathies. RA. Primary Systemic Vasculitic Disorders Affecting Large and Medium-sized Vessels Giant Cell Vasculitis. superimposed on generalized peripheral nerve disease. it is possible to observe conduction block in some patients with vasculitic neuropathies.193.162.860. resulting in multiple mononeuropathies. sulphonamides) Demyelinating neuropathies Multifocal motor neuropathy (MMN) Multifocal acquired sensory and motor neuropathy (MADSAM) Paraproteinemic polyneuropathies (e.

the lungs are generally spared. complement. The association of eosinophilia with asthma is highly suggestive of the diagnosis. Sural nerve biopsy demonstrates necrotizing vasculitis with obliteration of the vessel lumen. Ischemia of the kidneys can lead to renal failure.1259 The early symptoms of respiratory disease (nasal discharge. Eosinophils are also present in the infiltrate but not as extensively as the T-lymphocytes. consisting of varying degrees of hepatic. Granuloma formation and eosinophilic infiltration are not present on nerve biopsies. Immunoperoxidase stain demonstrates deposition of complement (C3) in the walls of affected blood vessels. renal. may be evident in 25–60% of patients. livido reticularis.794 Wegener’s Granulomatosis.519. and alpha-2 globulins also are elevated. as in PAN. fever. hemoptysis.983. As many as one-third of cases are associated with hepatitis B antigenemia. and distal gangrene. because of its perinuclear staining pattern. whereas common asthma usually develops before the age of 35 years.963. nasal polyposis.519 Besides the peripheral neuropathy. hepatitis C and HIV infection have been reported with PAN.517. Creactive protein. In CSS. asthma begins later in life. The pathogenic mechanism of PAN is unknown. Churg-Strauss syndrome (CSS) is a rare disorder that manifests much like PAN. 16–49% of patients with CSS develop necrotizing glomerulonephritis. and serum IgG and IgE levels.193. Immunocytochemistry can demonstrate deposition of IgM. Wegener’s granulomatosis is a rare disorder consisting of necrotizing granulomatous involvement of the upper and lower respiratory tract and glomerulonephritis. B. Either a mononeuropathy multiplex or generalized symmetric pattern of involvement can be found. papules. multisystem dysfunction is also present.162. PAN primarily affects medium-sized arteries. In contrast to PAN. the other systemic manifestations of CSS are similar to those in PAN.Chapter 23 ACQUIRED NEUROPATHIES — 965 Figure 23-7. complement-mediated vascular damage plays a secondary role. smaller vessels may be involved.519.222.701.393. Pulmonary infiltrates are present in nearly one-half of patients. C-reactive protein. but the frequency of PNS and CNS involvement is similar. Rather than an ischemic nephropathy.621 Cranial neuropathies.590. Fifty to 70% of patients with PAN have evidence of peripheral neuropathy. and elevated ESR. Vasculitis. particularly the second. and sinusitis followed by asthma.701 The infiltrate is composed mainly of CD8+ T-cells and macrophages. often > 109/L.519 Histopathology reveals necrotizing vasculitis involving medium-sized and small arteries and veins.240. Mononeuropathy multiplex is the most common pattern of involvement. endothelial cell-mediated process. including petechiae.701 Churg-Strauss Syndrome (Allergic Angiitis/Granulomatosis).519. Leukocytosis with normochromic anemia usually is seen. CSS also is associated strongly with antineutrophil antibodies (ANCA). intravascular and extravascular granulomas are evident in and around these blood vessels.519 Abdominal angiograms may reveal a vasculitic aneurysm. which may be helpful in patients with nondiagnostic biopsies. muscular. A. Skin lesions. About 30–50% of patients may have some form of neurologic dysfunction.519 Vasculitis of the gastrointestinal tract can manifest as abdominal pain or bleeding. however. and seventh nerves.and medium-caliber arteries in multiple organs. These p-ANCA antibodies are present in as many as two-thirds of patients. Laboratory evaluation is remarkable for elevated ESR greater than 60 mm/hr in 78–89% of patients.1125a The incidence is roughly one-third that of PAN. subcutaneous nodules. their absence can be useful in distinguishing PAN from Churg-Strauss syndrome. and membrane-attack complement on blood vessels. In particular.560. and dyspnea) and facial pain help to distinguish this from other vasculitic disorders. IgG. Less commonly.162.519 Laboratory evaluation is remarkable for eosinophilia. and the sciatic nerve or its peroneal or tibial branch is the most frequently affected nerve. are involved in approximately . Symptoms and signs of systemic vasculitis occur an average of 3 years after onset of asthma. primarily myeloperoxidase or p-ANCA. skin. They typically develop allergic rhinitis. Kissel and Mendell suggest a T-cell–dependent.560. The inflammatory infiltrates consist mainly of CD8+ cytotoxic T-lymphocytes and CD4+ helper T-lymphocytes. and loss of appetite are usually noted.519 Rheumatoid factor. rheumatoid factor. cough. patients with CSS usually present with respiratory involvement. sixth.634. The presence of peripheral neuropathy correlates with the severity of renal involvement. Constitutional symptoms of weight loss. Orchitis is also a classic symptom of PAN. However. involving small.335. Besides the differences in respiratory and renal system involvement. usually in association with asthma and hypereosinophilia. Polymorphonuclear cells may be evident in the area of fibrinoid necrosis. leukocytosis. Cranial neuropathies and CNS involvement are uncommon (< 2% of patients).1125a. although only 15–20% have peripheral neuropathy.519 In addition. Myalgias and arthralgias are frequent (30–70% of patients).621. and gastrointestinal involvement. multiple mononeuropathies are found in 64–75% of patients.

The incidence of peripheral neuropathy in patients with various type of cryoglobulinemias ranges from 25–90%.452 The most common agents associated with vasculitis of the PNS are viruses. Infection-related Vasculitis. transmural and perivascular inflammation of small blood vessels without necrosis is the most common histopathologic feature. Hepatitis serology is negative.1125.701 Unlike PAN. true vasculitis as the basis of the neuropathy is much less common.412. is evident in most patients. venules.1280. Behçet’s Syndrome. As the name implies. The specificity of c-ANCA for Wegener’s granulomatosis is 98% and the sensitivity is 95%.1443 However. Essential mixed cryoglobulinemia (ECM) refers to situations in which mixed cryoglobulinemia is found without a systemic disorder other than viral hepatitis.985. also is associated with a variety of peripheral neuropathies. connective tissue diseases. however.963 Laboratory evaluation is remarkable for the presence of antineutrophil antibodies directed against proteinase-3. The neuropathy can result from ischemia due to hyperviscosity or vasculitis related to immune-complex deposition in small .945.519. Sjögren’s syndrome. Type I cryoglobulins most frequently occur in patients with plasma cell dyscrasias. MPA is about one-third as common as PAN.519. symmetric polyneuropathy.997 Secondary vasculitis associated with connective tissue disease is most common in rheumatoid arthritis. The central nervous system is affected (brainstem strokes. usually immunoglobulins directed against polyclonal immunoglobulins. short-term treatment with corticosteroids is often necessary and useful.1254 The pathogenesis most likely relates to a complement-mediated leukocytoclastic reaction. The most common are small cell carcinoma of the lung (SCCL) and lymphoma. These disorders are discussed more fully in the section.606.1295. Recent studies have revealed that most cases of EMC are associated with hepatitis C antigenemia.845.701 Vasculitis Secondary to Essential Mixed Cryoglobulinemia. a medium-sized systemic vasculitis. opioids). Secondary Systemic Vasculitides Vasculitis Associated with Connective Tissue Disease. prostate. and.639. usually IgM. dysesthesias as well as motor weakness and clinically and electrophysiologically may resemble patients with true peripheral nervous system vasculitis.1307.428.682.1173 Inflammation of pulmonary capillaries leads to diffuse alveolar damage and interstitial fibrosis. Polyneuropathy complicates 14–36% of cases. Extracapillary proliferation forms crescents in the majority of glomeruli.990. followed by systemic lupus erythematosus. thus the name c-ANCA.990 As noted previously. Borrelia burgdorferi. although c-ANCA antibodies occasionally can be detected. human immunodeficiency virus (HIV).450. and capillaries. but a mononeuropathy multiplex pattern also may occur. Nevertheless. There are three types of cryoglobulins.1357. Rather. except that the lungs are often involved.701. several cases of SCCL were associated with anti-Hu antibodies. Kidney biopsy reveals the presence of focal segmental thrombosis and necrotizing glomerulonephritis. directed against polyclonal IgG. cocaine. The clinical symptoms of microscopic polyangiitis (MPA) are similar to those of PAN. Various malignancies have been associated with “vasculitis” of the peripheral nervous system. Cryoglobulins are circulating immune complexes. and IgA directed against polyclonal IgG. Lyme disease caused by the spirochete.145. Behçet’s syndrome is characterized by recurrent oral and genital ulcerations associated with inflammation of the eye. less frequently. this is a nonspecific abnormality. Type II and III are the most common and are also called mixed cryoglobulinemia. microscopic polyangiitis affects small arterioles.1173 Impaired renal function. Microscopic Polyangiitis.” Malignancy-related Vasculitis.1375 Additional manifestations include arthritis. Type III cyoglobulins are a mixture of polyclonal IgM. Cutaneous manifestations predominate the clinical picture.701 Nevertheless. most of the reported cases are not associated with necrotizing vasculitis. distal. The clinical.1327 Most patients also demonstrate a painful.935. bile duct. and electrophysiologic features are similar to those of PAN.701. such as a lymphoproliferative disorders. The different forms of peripheral neuropathy associated with connective tissue disorders are discussed in more detail in a subsequent section. amphetamine. hypersensitivity vasculitis secondary to drug reactions is a self-limited process. The cause is unknown. as illustrated by increased BUN and creatinine as well as hematuria. the average age at onset is 50 years. Of note. Cryoglobulins are immunoglobulins that precipitate out of solution when exposed to a cool temperature but dissolve into solution when warmed. psychosis) more frequently than the peripheral nervous system. In contrast to systemic necrotizing vasculitis.1165. but also are associated with small-vessel vasculitis related to cryoglobulinemia (discussed below). but carcinoma of the kidneys. Mononeuropathy multiplex related to HIV or CMV infection occurs in up to 3% of patients with AIDS. Men are believed to be affected more commonly than women.966 — PART IV CLINICAL APPLICATIONS 10% of cases as a result of extension of the nasal or paranasal granulomas rather than vasculitis.1158 Hepatitis B and C can cause PAN. Laboratory evaluation usually demonstrates the presence of p-ANCA antibodies. Vasculitis of the CNS is much more common with drugs of abuse (e. Either a mononeuropathy multiplex or generalized sensorimotor peripheral neuropathy may be present.24 Furthermore. which can caused by vasculitis. IgG. Drug-induced Hypersensitivity Vasculitis. but the PNS occasionally is involved. skin lesions. there are few or no immune deposits on the blood vessels.184.800.519. The vasculitis is similar to PAN. cytomegalovirus (CMV). Patients with the paraneoplastic anti-Hu syndrome can present with symmetric or asymmetric sensory loss.809. “Neuropathies Related to Infection. including herpes varicella zoster. Peripheral neuropathy is a frequent complication in patients with underlying connective tissue diseases. Type I cyroglobulins are composed of monoclonal immunoglobulins. Granulomatous infiltration of the respiratory tract and necrotizing glomerulonephritis also are seen. rare cases of vasculitic neuropathy have been reported in patients with cancer.g. systemic sclerosis. and hepatitis B and C.161. The lack of peripheral eosinophilia and eosinophilic infiltrates on biopsy and the absence of asthma help to distinguish Wegener’s granulomatosis from CSS.291. meningoencephalitis..24 Lymphomas can be complicated by nonvasculitic paraneoplastic neuropathies. Type II cryoglobulins are composed of a combination of monoclonal IgM and polyclonal immunoglobulins directed against polyclonal IgG. Vasculitis with peripheral nervous systemic complications can result from a number of infectious agents. thrombophlebitis. Mixed cryoglobulinemia can be associated with other diseases. affecting medium-sized and small blood vessels. and stomach also have been described. and vasculitic lesions involving the small to medium-sized arteries. histologic.621 The immunofluorescent staining pattern is diffuse within the cytoplasm. lymphomatous infiltration of the nerves can cause multiple mononeuropathies or generalized neuropathy. and hepatitis B and C.

1159. Pulsed cyclophosphamide is generally continued for at least 1 year.0–2. Electrophysiologic studies are similar to those in PAN. Survival rates are similar to age-matched controls.805 However. Matrix metalloproteinases (MMP) are a family of endopepsidases with overlapping substrate affinities for various extracellular matrix proteins. Treatment of Vasculitic Neuropathy Systemic vasculitis is treated intially with a combination of corticosteroids and cyclophosphamide.0 mg/kg is a more potent suppressor of the immune system but is associated with more adverse side effects (e. There can be subclinical involvement of muscle.778 T-cells are the predominant source of MMP-2 and MMP-9. Laboratory testing may demonstrate elevated ESR or low ANA titers. One patient has been reported with evidence of conduction block.519 Hypersensitivity vasculitis and isolated PNS vasculitis can be treated with prednisone alone.697.412. Oral cyclophosphamide at a dose of 1. the prognosis is considerably better than that for systemic vasculitic disorders.560. tacrolimus. some have suggested that vasculitis may be more likely to be evident on peroneus brevis muscle biopsies than on a superficial peroneal nerve biopsy. the neuropathy may be more likely to respond to corticosteroids alone or to require a shorter duration of cyclophosphamide.Chapter 23 ACQUIRED NEUROPATHIES — 967 epineurial blood vessels. We prefer monthly intravenous pulses of cyclophosphamide at a dose of 500–1000 mg/m2 of body surface area.1239 Azathioprine. but the clinical manifestations of the disease suggest preferential involvement of the peripheral nerves.519. during which time the risk of infection is greatest. We generally initiate corticosteroid treatment with pulsed methylprednisolone (1 gm intravenously every day for 3 days). hemorrhagic cystitis) than intravenous pulses. Patients should be vigorously hydrated to minimize bladder toxicity.358.955.169 Several prospective but uncontrolled series have suggested that IVIG can be beneficial in the treatment of systemic vasculitis. up to 100 mg/day) as a single dose in the morning. Using this protocol. Immune complex deposition on these blood vessels can be appreciated. and total viral clearance was seen in 24% of cases—a substantial .184.5 mg/kg/day. and chlorambucil may be tried in refractory cases. Nerve conduction studies show borderline normal or somewhat reduced conduction velocities. the 7-year survival rate of hepatitis B-related PAN was 83%. After intravenous pulses of cyclophosphamide.621 Such patients may require lifelong immunosuppressive therapy. 450. the median and ulnar nerves display similar findings.1163 The clinical. Patients with CSS often require continued low-doses of prednisone secondary to associated asthma. a few patients demonstrate significant reductions in velocity.1295. the leukocyte count drops with a nadir after 7–18 days. We continue with high-dose corticosteroids and cyclophosphamide treatment until the patient begins to improve or the deficit at least stabilizes. Of importance. The vasculitis typically involves small and mediumsized arteries of the epineurium and perineurium. There is less experience with other immunosuppressive agents in the treatment of vasculitis.800.292. as discussed in the section about chronic inflammatory demyelinating polyneuropathy.701 Corticosteroids were used to treat systemic vasculitis in the 1950s.or C-related PAN require special treatment. Collateral treatment includes calcium and vitamin D supplementation as well as bisphosphonates to prevent and treat steroid-induced osteoporosis. The trigger for this rather selective vasculitis is not known.1125a. Cyclophosphamide is started at the same time as corticosteroids and can be given orally or in intravenous pulses.g. Urinalysis is obtained every 3–6 months after treatment because of the risk of future bladder cancer. we switch to alternate-day prednisone (100 mg qod). Plasma exchange and antiviral agents such as vidarabine or α-interferon are used to control the course of the illness.. as apparent on muscle biopsies.800 In long-standing disease. conduction velocities are mildly reduced. marked improvement was noted in 76% of patients with Wegener’s granulomatosis and remission occurred in 69%. 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. MMP-2 and MMP-9 (gelatinase A and B) are upregulated in the peripheral nerves in patients with nonsystemic vasculitis.682. other studies failed to demonstrated much improvement with IVIG.169. Sensory studies demonstrate an absence or reduction in the SNAP amplitudes. MPA. After 2–4 weeks.563. F-wave studies are abnormal in most patients at some time during the course of the disease. electrophysiologic. oral dosing should be tried before concluding that the patient failed cyclophosphamide treatment. Sodium 2-mercaptoethane sulfonate (mesna) is given to reduce the incidence of bladder toxicity.517. Some suggest using corticosteroids only during the first few weeks of treatment to manage life-threatening manifestations of systemic vasculitis. HBeAG/HBeAB conversion rate was 51%. Subsequently. In fact. and histopathologic features of isolated peripheral nerve vasculitis are quite similar to those of PAN. Conventional treatment with high-dose corticosteroids and cyclophosphamide may allow the virus to persist and replicate.234 Patients can manifest with multiple mononeuropathies or a generalized symmetric sensorimotor polyneuropathy.1020.291. with an occasional nerve having a conduction velocity reduced to less than 70% of the lower limit of normal.3 mg/kg/week) in combination with corticosteroids.704. then switch to oral prednisone (1. We check complete blood counts and urinalysis before each treatment. except that other organ systems are not significantly involved.519 Afterward the corticosteroids are abruptly discontinued.1101 Patients with hepatitis B. and ondansetron is used to diminish nausea. Furthermore. prednisone is gradually tapered by 5 mg every 2–3 weeks. however. and isolated PNS vasculitis but occur in as many as 50% of cases of Wegener’s granulomatosis. Vasculitis isolated to peripheral nerves accounts for 30–58% of vasculitic neuropathy. In an open-label study of low-dose methotrexate (0. and the 5-year survival rate increased from 10% to 55% by the midto-late 1970s.1327 When present. Relapses are uncommon in PAN.15–0.519 The addition of cyclophosphamide to corticosteroids further increased the 5-year survival rate to over 80%.519. Motor studies reveal an absence or significant reduction in the CMAP amplitude of the lower limb nerves. although stroma cells of the perineurium and endoneurium are an additional source. usually within 4–6 months. thereby allowing inflammatory cells to disrupt the bloodnerve barrier and penetrate into peripheral nerves. Nonsystemic Vasculitis Nonsystemic or Isolated PNS Vasculitis.945. These MMPs are capable of degrading components of the subendothelial basement membrane. cyclosporine. thus increasing the risk of liver failure. affecting the lower limb nerves to a greater degree than the upper limb nerves.1159 although this has not been our experience. If patients do not respond to pulsed cyclophosphamide.

A sensory ataxia with pseudoathetosis is often evident.883 Some degree of abnormality in motor conduction can also be detected with mild reductions in amplitude and slowing of conduction velocity. anhidrosis. recovery is unlikely.62.39. Muscle strength testing is usually normal. Several studies have reported that αinterferon (3 million units 3 times/week) is efficacious in treating hepatitis C-related mixed cryoglobulinemia..678.546. However. which is responsible for conveying sensory nerves responsible for facial sensation and the blink reflex. Some cases may be caused by necrotizing vasculitis.490. fixed tachycardia.490. and involvement can be quite asymmetric or even unilateral. biopsy of sensory nerves reveals a reduction in the total number of myelinated fibers.122.455.51 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. Muscle weakness may be present but is milder than the sensory symptoms. especially position sense and vibration. In contrast. the sensory neuronopathy is poorly responsive to immunotherapy. there is marked abnormality in the SNAPs as evidenced by a significant reduction in amplitude and mild to moderate reductions in velocity.1336 Peripheral neuropathy or neuronopathy can be the presenting feature of Sjögren’s syndrome and may occur before any sicca symptoms. NEUROPATHIES ASSOCIATED WITH AUTOIMMUNE CONNECTIVE TISSUE DISEASES Sjögren’s Syndrome Clinical Features. necrotizing vasculitis can be seen.504 Perivascular lymphocytic (CD8 T-cells) inflammation of the endoneurial or perineurial vessels also may be found.883 Rarely. lies outside the CNS as well. and peripheral neuropathy is evident in at least one-half of cases.g.490.492.490. and occasional dryness of other mucous membranes.294. hepatitis C has been implicated in most cases of mixed cryoglobulinemia. an abnormal blink reflex is more suggestive of a sensory neuropathy due to Sjögrens syndrome as opposed to a paraneoplastic etiology. The specific antigen(s) and trigger of the autoimmune attack are not known.317. if at all.490. Electrophysiologic Findings.1125a. Plasma exchange may be beneficial in patients who continue to deteriorate on α-interferon.451.650 Histopathology. Necrotizing vasculitis is uncommon in Sjögren’s syndrome but may be responsible for as many as onethird of the cases of neuropathy associated with the disorder. Most patients with Sjögren’s syndrome have antinuclear.504. EMG is normal. Vasculitis is present in 8–25% of patients with RA.883 A burning sensation and paresthesias can also occur.1125a. the upper limbs can be more severely affected than the lower limbs in sensory neuronopathies.504 Rheumatoid Arthritis Rheumatoid arthritis (RA) affects approximately 1% of the population. The central feature of Sjögren’s syndrome is the sicca complex.504.451.451.481a A particularly interesting complication of Sjögren’s syndrome is sensory neuronopathy or ganglionitis. characterized clinically by xerophthalmia (dry eyes). Decreased or absent deep tendon reflexes are seen.504 Pathogenesis.39. Once the cell body has degenerated. There can be asymmetric involvement electrophysiologically. some investigators have suggested mild improvement or at least some stabilization of function with various forms of immunotherapy. and orthostatic hypotension. Schirmer’s test and Rose-Bengal stain are useful for diagnosing keratocunjuctivitis.504.490.968 — PART IV CLINICAL APPLICATIONS improvement from that seen with corticosteroids with or without cyclophosphamide or plasma exchange. The diagnosis is confirmed by demonstrating a lymphocytic invasion of salivary glands on a biopsy of the parotid gland or lips. the distal sensorimotor neuropathy associated with Sjögren’s syndrome). sensory cell bodies innervating the limbs reside in the dorsal root ganglia of the PNS.758.490.343. In patients with a sensory neuronopathy. The sensory neuronopathy appears to be caused by an autoimmune attack directed against the sensory ganglia. The CNS manifestations can mimic transverse myelitis or multiple sclerosis. There is a significant female predominance. a short course of corticosteroids may be required to control the initial manifestations of systemic vasculitis.546. A decreased density of small unmyelinated fibers may also be seen. Treatment. Unfortunately. xerostomia (dry mouth).52 In fact.451. immunosuppressive agents may be beneficial. In patients with the distal sensorimotor form of peripheral neuropathy. Rarely.451. A positive Romberg sign is noted in patients with lower limb involvement. . Laboratory Features. 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.518 As noted above. Symptoms can involve the arms more than the legs.e.451. When vasculitis is suspected.682 As with PAN due to hepatitis B or C. although the examination may reveal some “weakness” secondary to impaired sensory modulation of motor activities. There is no specific treatment for neuropathies related to Sjögren’s syndrome.826 In contrast to length-dependent axonopathies (e.504 Biopsy of the dorsal root ganglion has demonstrated lymphocytic (mainly CD8 Tcells) infiltration and degeneration of cell bodies.492.826. Motor conduction studies are minimally affected.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.883. The pathogenetic basis of the distal sensory or sensorimotor polyneuropathy is unknown but is presumably autoimmune. Furthermore. The CSF is usually normal. Needle EMG examination reveals some degree of fibrillation potentials and positive sharp waves with MUAP alterations suggestive of motor unit remodeling (i. Nonspecific perivascular inflammation involving perineurial or endoneurial blood vessels is more commonly seen. blink reflexes are also abnormal. Peripheral nerve biopsies in patients with the more typical symptoms of sensorimotor polyneuropathy demonstrate axonal degeneration and some degree of secondary segmental demyelination. In patients with sensory neuronopathy.451. If the trigeminal nerve is affected.758.1336 Patients develop progressive numbness and tingling of the limbs. Many patients have signs of autonomic insufficiency with Adie’s pupils. the gasserian ganglion. The onset can be acute or insidious. SS-A/Ro. and onset is typically in middle adult life. autonomic neuropathy is the primary manifestation. particularly those of larger caliber.. Most patients have an axonal sensorimotor neuropathy characterized by numbness and tingling in the distal portions of the limbs. increased amplitude and duration with reduced recruitment). Physical examination demonstrates reduced sensation to all modalities. Sensation also may be diminished in the trigeminal nerve distribution. and SS-B/La antibodies in the serum. Distal latencies are not usually altered to a significant degree. Peripheral neuropathy occurs in 10–50% of patients with Sjögren’s syndrome.39. which may also involve the face.175.

1052.495.607a. sclerodactyly.392. gastrointestinal tract. and telangiectasis) is considered a limited form of scleroderma.850.307. and polymyositis.773.1226 Nerve conduction studies generally demonstrate a generalized.579.366 Mixed Connective Tissue Disease Mixed connective tissue disease (MCTD) represents an overlap syndrome of SLE.997.863 A few patients present with multiple mononeuropathies presumably secondary to necrotizing vasculitis.60.193.1090 Such patients can have demyelinative features on nerve conduction studies and nerve biopsies.319.1187 Rheumatoid vasculitis can present with mononeuropathy multiplex.307.707. Rare patients display a generalized sensorimotor polyneuropathy quite similar to AIDP or CIDP.1430a Most patients manifest with slowly progressive distal sensory loss. systemic lupus erythematosus (2%).1454 The most commonly affected regions of the central nervous system are the meninges. but true vasculitis is quite rare. Raynaud’s phenomenon. Some of these cases may be related to a low-grade vasculitis that was missed on biopsy because of sampling error.1402. mixed connective tissue disease (26%).1407. Electrophysiologic features are similar to those in other forms of necrotizing vasculitis. Mild reduction in CMAP amplitudes and a slight slowing of motor conduction velocities also can be seen.1187.1290 Peripheral neuropathy occurs in 5–14% of patients and usually manifests as a distal symmetric. Cranial mononeuropathies also can develop.532 The CREST syndrome (calcinosis.1247. Sarcoidosis is a multisystem granulomatous disorder affecting the liver.863. if it occurs at all. and pituitary gland.196.1178. mucous membranes. which can progress to significant visual impairment or even blindness.1075.772. the more likely the multiple mononeuropathies are to fuse and overlap. muscle tissue. The second and eighth cranial nerves are also frequently affected.606.Chapter 23 ACQUIRED NEUROPATHIES — 969 making it the third most common cause of vasculitic neuropathy after PAN and isolated PNS vasculitis. creating an increasingly symmetric neuropathy. The peripheral aspects of the nervous system frequently affected are the cranial and peripheral nerves. The clinical.1226. and rheumatoid factor in the serum. the mechanism may be related to other undefined factors or toxic medications. Sjögren’s syndrome (2%). dysesthesias. but peripheral neuropathies also occur. which can be affected bilaterally.467.1286 Central nervous system complications are more common. and lung. The most commonly affected cranial nerve is the trigeminal.878. The diagnosis is based on the presence of multiple organ system involvement and laboratory criteria. although in rare patients the neuropathy is the presenting feature. parotid gland. Immunosuppressive therapy is beneficial in SLE patients with neuropathy related to vasculitis. and electric shock-like or pricking/tingling sensations involving the face. although one small study reported a mild distal axonal sensorimotor polyneuropathy in 10% of patients. Some patients may present with a clinical pattern quite similar to a radiculopathy of single or multiple nerve roots. One investigation found a number of different disorders associated with involvement of the trigeminal nerve: undifferentiated connective tissue disease (47%). as demonstrated by numbness. 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. 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. Electrophysiologic features are similar to those with any form of necrotizing vasculitis. weight loss. Women are affected more commonly than men. Many patients have a mild autonomic neuropathy. esophageal dysmotility. Patients with an AIDP or CIDP-like neuropathy should be treated accordingly (see sections on AIDP and CIDP). primarily sensory axonopathy with absent or diminished SNAP amplitudes. Mucosal lesions of the nose and sinuses are common. rheumatoid arthritis (2%).1454 The cause is unknown.1125a.878. 1125a. Occasional involvement of the seventh and ninth cranial nerves also can occur. especially about the nerve root region. Laboratory elevation is remarkable for the presence of antinuclear antibodies (ANA).508. Immunosuppressive agents are less likely to be effective in patients with a generalized sensory or sensorimotor polyneuropathy without evidence of vasculitis.377. hypothalamus. Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a common connective tissue disease with a prevalence in adults of 1 in 2000. Hilar adenopathy is noted on chest radiographs with transient erythematous subcutaneous nodules about the pretibial region accompanied by arthralgias. and dermatomyositis (1%). overlapping mononeuropathy multiplex. A common finding on presentation is acute granulomatous uveitis.707. A common presentation is a mononeuropathy multiplex pattern of remitting cranial nerve palsies. suggesting an autoimmune pathogenesis. and central and peripheral nervous system. scleroderma (19%). mainly sensory polyneuropathy. spleen. elevated ESR.1401 The vasculitic neuropathy usually manifests 10–15 years after manifestations of other symptoms of RA. Systemic Sclerosis (Scleroderma) Scleroderma manifests as progressive fibrosis of the skin. With generalized root involvement.697 The longer the disease progresses. However. or generalized symmetric pattern of involvement.606.1401 Vasculitic neuropathy develops in 40–50% of patients with RA. patients may present with signs . and histologic features suggest a necrotizing vasculitis as the cause of the neuropathy. and fatigue are the presenting complaints of most patients. 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. The most commonly involved cranial nerve is the seventh nerve. Anywhere from 2–27% of patients with SLE clinically develop a peripheral neuropathy.1187. Palpable peripheral lymph nodes may be noted.87 SARCOIDOSIS Clinical Features. Nonspecific constitutional symptoms of fever. There has been no detailed study of neuropathy in patients with MCTD. kidney.850.607a.1407. Nerve histopathology in such cases reveals thickening of the epineurial and endoneurial blood vessels as well as perivascular inflammation.1402. The peripheral or central nervous system is involved in about 5% of patients with sarcoidosis.1430a Large prospective series have reported electrophysiologic abnormalities in 24–56% of patients with SLE. The pathogenic basis of the neuropathy is not known. scleroderma.162. Essentially any cranial nerve can be involved in the remitting and relapsing course of the disease. Multiple mononeuropathies have been described in a small percentage (1–2%) of patients with CREST syndrome. electrophysiologic.

vasculitis (including cryoglobulinemia).849 In addition. The cranial nerves and mononeuropathies of the peripheral nervous system are likely to result from direct neural invasion and compression. however.42. may respond well to corticosteroid treatment. no histology was described in these cases. and polyphasia are increased. Mild perivascular inflammation may be evident.190. but cases with generalized weakness. Sarcoidosis is an autoimmune disorder although the cause and pathogenic mechanism are unclear. first coined the term perineuritis in their detailed description of two patients who developed pain and dysesthesias in the distribution of cutaneous nerves. The major histopathologic finding is noncaseating granulomas in various tissues. ESR.190. and . Other idiopathic cases have been described with similar features. IDIOPATHIC PERINEURITIS Perineuritis is a nonspecific histologic abnormality with inflammation and thickening of the perineurium. some patients present with symptoms and signs suggestive of a slowly progressive primarily sensory. and epineurium) associated with lymphocytic angiitis. The most prominent histologic abnormality is thickening and fibrosis of the perineurium.848 Asbury et al.42 The predominant histologic abnormality was inflammation confined to the perineurium. Electrophysiologic Findings. The nerve conduction velocities are usually within 75–80% of the lower limit of normal. In patients with the symmetric sensorimotor peripheral neuropathy.714. Treatment. The electrophysiologic abnormalities may resolve to various degrees with treatment. affecting mainly the distal upper and lower limbs. which can be demonstrated by electrodiagnostic medicine evaluation. especially the facial nerve.1251 Likewise. perineuritis evident on biopsy does not imply a distinct neuropathic disorder. motor.446.42. Patients who fulfill the clinical and electrophysiologic criteria for CIDP typically have elevated CSF protein.1251 In these various conditions. MUAP duration.190. affecting all regions of the supporting neural structures (endoneurium. Muscle strength is usually preserved. a combination of these two insults. nerve biopsy can reveal profuse infiltration of the nerve by multiple sarcoid tubercles. However. patients appear to return to a propensity for developing compromise of the nervous system. amplitude. connective tissue diseases. ulcerative colitis. 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.849.42. the SNAPs may be absent or reduced in amplitude.980 If patients are resistant to corticosteroids. or sensorimotor peripheral neuropathy. Some investigators have reported deposition of immunoglobulins in the epi-. such as vasculitis. Finally. including ANA.1386 Patients described pain when the nerves where stretched. Hypesthesia and hyperpathia are noted on examination. There is a combination of axonal loss and demyelination. Histopathology. serum protein electropheresis. A few patients may have more profound slowing. ischemia.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. symmetric motor and sensory loss indistinguishable from AIDP or CIDP.190.1251 The course can be remitting and relapsing. other immunosuppressive agents can be tried (e. who complain of migrating areas of sensory loss.1251. Of note. Patients with neurosarcoidosis. Matthews reported a patient with “migratory sensory neuritis of Wartenberg”. Other patients develop chronic. The most common involvement of the peripheral nervous system is a subclinical mononeuropathy multiplex. there is a lack of information about electrodiagnostic medicine evaluation of cranial nerves.849. Clinical Features.941. or other ill-defined factors.394. Unfortunately. dysesthesias.. Laboratory Features. peri. and vasculitic profile.1251 Deep tendon reflexes are typically normal in patients with pure sensory symptoms. Blink reflexes also may demonstrate either absence or amplitude reductions in R1 and possibly R2. There are significant degrees of positive sharp waves and fibrillation potentials. there have been several reports of patients without an underlying systemic disorder in whom perineuritis was the most prominent feature on biopsy.955a. as expected.195 Such patients have normal motor conductions and CMAP amplitudes. and weakness in the distribution of multiple individual nerves. The clinical presentation is variable. When the peripheral nerves are affected. Patients with perineuritis related to diabetes or vasculitis develop a mononeuropathy multiplex picture with sensory loss. The presence of an abnormal laboratory work-up should lead to the consideration of an underlying systemic disorder. whereas recruitment is decreased. Pathogenesis. suggestive of AIDP or CIDP. liver function tests. the nerve biopsy did not mention features of perineuritis. 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. Less commonly. perineurium. which we term the idiopathic perineuritis group.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.707. Unfortunately. and lymphoma and other malignancies. Histopathology. Wartenberg was the first to allude to this group of patients. the most common finding is an absence or reduction in SNAP amplitudes in a mononeuropathy multiplex pattern. hyperpathia. Large-fiber sensory functions are typically less affected than small-fiber modalities.970 — PART IV CLINICAL APPLICATIONS and symptoms quite similar to AIDP or CIDP. cyclosporine).1436 Perineuritis also has been described in patients who fulfill clinical and electrophysiologic criteria for AIDP or CIDP. progressive. which indicates a demyelinating as opposed to axonal component of nerve damage. The needle EMG examination is also normal. Laboratory evaluation is usually normal in patients with idiopathic perineuritis.g. the authors did not believe that their patients had the sensory neuritis described by Wartenburg because of their less prominent pain. particularly of the cranial nerves. Despite the frequent occurrence of cranial neuropathies. A positive Tinel’s sign is often present over involved nerves. elevated CSF protein may be seen in diabetic patients with multiple mononeuropathies or lumbosacral polyradiculoplexopathies. CSF protein is usually normal in patients with pure sensory symptoms. One expects to see reduced facial nerve CMAPs amplitudes and some degree of abnormal spontaneous activity on needle EMG. after cessation of treatment. have been reported.1215. Perineuritis can be seen on nerve biopsies of patients with neuropathies associated with diabetes mellitus. Peripheral neuropathy may result from direct compression. a subgroup of patients may have a distinct neuropathy.849 Such cases with idiopathic perineuritis may represent a distinct neuropathic disorder. Patients with a polyradiculopathy may have normal SNAPs but abnormal CMAPs.1251 Chronic inflammatory cell infiltrates composed of lymphocytes and macrophages should be confined to the perineurium. In patients with subclinical neuropathy.

Perineuritis may cause damage via ischemia. the greater auricular nerve. and cancer (e. Whether perineuritis is a distinct disorder is debatable. is believed to result from the eosinophilia or some byproducts of the eosinophils. hematologic. Perineuritis..955a.906. the sural nerve. peri-. In addition. and borderline leprosy (Table 23-8). Patients with true vasculitis or CIDP should be treated with immunosuppression. NEUROPATHIES ASSOCIATED WITH INFECTIONS LEPROSY (HANSEN’S DISEASE) Clinical Features. a slowly progressive symmetric sensorimotor polyneuropathy develops over time.” Typically. Patients have variable responses to immunotherapy.e.1148 The host’s immunologic status determines which form of the disease develops.938. As with the tuberculoid subtype. Furthermore. Texas). thickened perineurium.. but as in the tuberculoid form. including the ulnar nerve at the medial epicondyle. myasthenia gravis. including the peripheral nervous system.g. Pathogenenesis. In tuberculoid leprosy. The disorder manifests clinically by muscle twitching (myokymia) at rest.635. Some patients have an associated inflammatory myopathy. nerve trunks can be affected with time. or PE. The most common neurologic manifestation of tuberculoid leprosy is mononeuropathy or mononeuropathy multiplex. face. In early disease. cardiac. South America. The syndrome can occur with or without other signs or symptoms of a peripheral neuropathy.42. The organism has a predilection for the cooler regions of the body (e.. cell-mediated immunity is significantly impaired. Three primary clinical manifestations of the disease are commonly recognized: tuberculoid. in which patients also experience generalized myokymia.20.914. muscle stiffness and cramps that are worse after activity. cyclophosphamide) in patients with mainly sensory disturbances. suggesting a possible ischemic basis.1251 Treatment. as are the muscle stretch reflexes.1405 A vasculitic component usually is not involved with this disease except for the skin.g. Continued multiplication and infiltration of the organism into the epi-. and the loss of nerve fibers can be asymmetric between and within fascicles. and its prevalence may be increasing with the rise in HIV infection.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. but it is endemic in certain areas of the United States (i. Patients with borderline leprosy have the highest incidence of neurologic complications. the peroneal nerve at the fibular head. and neurologic abnormalities. Hawaii. The microorganism Mycobacterium leprae (an acid-fast bacteria) causes leprosy. lymphoma. impairment of nutrient and toxin flow to and from nerve fibers in the endoneurium.20. the natural history of the disorder may be one of remissions and relapses. and the superficial radial nerve at the wrist. and anhidrosis. but the sporadic form is more common.849.331. in potassium channels have been demonstrated in hereditary episodic ataxia. limbs) rather than warmer regions such as the groin or axilla. The pathogenic basis for the neuropathy is not known but may be autoimmune. and excessive sweating. Mutations . The more superficial nerves in the vicinity of the skin lesions also may be affected. Distal weakness ensues as the motor nerves become involved in the infiltrative process.938. erythematous borders. The multiple organ dysfunction.1111. or direct humoral or cellular autoimmune attack against the nerve fibers. producing confluent and symmetrical areas of rash. leading them to be thickened and easily palpable.906. In advanced disease.223. Clinical and electrophysiologic evidence clearly suggests that the disorder is characterized by an axonal sensorimotor peripheral neuropathy.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. The pathogenic basis is unknown but probably autoimmune. resulting in an extensive infiltration of the bacilli process. Large sensory fiber modalities are relatively spared. The clinical and electrodiagnostic features as well as the treatment of Isaacs’ syndrome are discussed in greater detail in Chapter 16. this subsequently was demonstrated to be a nonspecific finding and can be seen in normal controls. the cell-mediated immune response is intact. A peripheral neuropathy may occur in 6–14% of patients. The acquired disorder may be associated with other autoimmune conditions (e.1103 The skin lesions appear as well-defined.. anesthesia. and Europe. the median nerve at the distal forearm. scattered hypopigmented patches and plaques with central anesthesia and raised.906. Electrophysiologic Findings. The organisms multiply virtually unchecked and disseminate hematogenously. cooler regions of the body are more susceptible. thymoma. In lepromatous leprosy. The major electrophysiologic abnormality in idiopathic perineuritis is reduced or absent SNAPs. small cell carcinoma of the lung)—the latter perhaps on a paraneoplastic basis.1390 These nerves can become encased within granulomas. Africa. and endoneurium result in the appearance of a progressive stocking-glove neuropathy. The small number of patients studied and the retrospective nature of such reports limits conclusions about treatment. CIDP). leading to focal. IVIG. facial neuropathies can occur.20. however. manifesting as either generalized peripheral neuropathy or mononeuropathy multiplex. It is most commonly found in Southeast Asia. Some patients with the acquired form of neuromyotonia have autoantibodies directed against the voltage-gated potassium channels of peripheral nerves.1215.g. lepromatous. Prednisone appears to diminish pain in patients with idiopathic pure sensory neuritis. leading to superimposed mononeuropathies. A loss of myelinated nerve fibers due to axonal degeneration may be seen. ISAACS’ SYNDROME Isaacs’ syndrome (also know as neuromyotonia or syndrome of continuous muscle fiber activity) may be inherited.938. there is a predilection for involvement of specific nerve trunks. the superficial cutaneous nerves of the pinnae and distal limbs are affected. circumscribed inflammatory lesions involving the skin or nerves.938.. although this positive effect does not necessarily persist.1103 Clinical manifestations tend to be more severe in the lepromatous subtype. We have tried prednisone and IVIG in such idiopathic cases with variable success but have not used more aggressive immunosuppression (e.g.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).20.Chapter 23 ACQUIRED NEUROPATHIES — 971 endoneurium190.190.

The Th1 cells produce interleukin-2 and gamma interferon. which is between one and ten at treatment onset. often falls to zero within 3–4 months of successful therapy. γ-IF Few localized and well-demarcated large skin lesions. mononeuropathies. 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. Rarely. and organism-laden. The features of the borderline tuberculoid (BT) form range between the TT and BB forms. a ratio of viable to nonviable organisms. bacilli cannot be demonstrated.1103. foamy macrophages with minimal granulomatous infiltration. The impaired cellular immunity of borderline patients results in mycobacterial spread but is still active enough to generate an inflammatory response.635. 10 Multiple. and 10. More recently. 23-8).1148 Tuberculoid leprosy and lepromatous leprosy represent the two extremes of disease manifestation. including multiple mononeuropathies in atypical locations. From Altman D.1111 Lepromatous neuropathy should be suspected in patients without skin lesions who live in endemic areas. Histopathology depends on the host’s immune response (see Table 23-8). patients with borderline leprosy can have histologic features of both tuberculoid and lepromatous leprosy. Th2 lymphocytes. Of note. Laboratory.938 The morphologic index (MI). As the name suggests. In the lepromatous form. with permission. and Histopathological Features of Leprosy Mid-Borderline Leprosy (BB) Positive or negative (2–5-mm induration 2–4 Moderate Cell-mediated immunity: unstable (can range and switch from intact to absent) Size. The MI. which in turn lead to activation of macrophages. symmetric small macules and papules. J Clin Neuromusc Dis 1999. The .972 — PART IV CLINICAL APPLICATIONS Clinical.20. which are surrounded by Th2 cells. peroneal nerves). patients with leprosy present with an isolated peripheral neuropathy without skin lesions. ulnar. has been used as a measure of treatment efficacy. Immunological. and borderline lepromatous forms of the disease.. Virtually all cases of pure neuritic leprosy have the tuberculoid or borderline tuberculoid subtypes of the disease.e. On the other extreme. the lepromatous form is dominated by Th2 cells. Histopathology. three subtypes bridge these polar extremes: the borderline tuberculoid. 5. The tuberculoid form defines one end of the spectrum. thereby downregulating cell-mediated immunity and inhibiting macrophages. the lesions demonstrate large numbers of infiltrating bacilli. number.938.1148 Histologically. the tuberculoid form is characterized by granulomatous centers formed by macrophages and Th1 cells. The immunologic state is considered unstable in borderline patients in that the immune response and clinical manifestations can shift up and down the spectrum. borderline. in which the Th1 cells predominate. Pathogenesis. Lepromin test Bacterial index Immunology Tuberculous Leprosy (TT) Positive (> 5-mm induration) 0 Cell-mediated immunity: intact Th1 > Th2 lymphocytes Cytokines expressed: IL2. are diffusely infiltrating Fite stain: slight positive Neuropathies can range in the spectrum seen in TT to LL Scant lymphocytes. The clinical and pathologic spectrum of the disease depends on the host’s immune response to M. polymerase chain reaction and serum antibody testing have been used for diagnosis. 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. forms of leprosy (Fig.Amato AA: Lepromatous neuropathy. leprae and reflects the relative balance between Th 1 (helper) and Th2 (suppressor) T cells (see Table 23-8).20 In addition. 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 Hansen’s Disease Center.906.1:68–73. and typical lesions extend throughout the dermis. older lesions form plaques and nodules Table 23-8. if present. median. Diagnosis of leprosy has traditionally been made through skin lesion biopsy with the Fite method of acid-fast bacilli staining. and mononeuropathy multiplex. Thus. and appearance of skin lesions are intermediate between those seen in TT and LL poles Lepromatous Leprosy (LL) Negative (0–2-mm induration) 5–6 High (up to 10) Cell-mediated immunity: absent Th2 > Th1 lymphocytes Cytokines expressed: IL4.938. which produce interleukins 4. patients can develop generalized symmetric sensorimotor polyneuropathies.906 Caseation may or may not be present. Carville LA. 5.The features of the borderline lepromatous (BL) form range between BB and LL forms of leprosy. such as the brachial plexus.

is the reversal reaction.20. Treatment.1349 Some patients may reveal a pattern of abnormality more consistent with a mononeuropathy multiplex as opposed to diffuse peripheral nerve involvement. which occurs in patients at the lepromatous pole of the disease.700.1274.20. although a number of other agents have recently demonstrated efficacy. an expanding erythematous circular region surrounding the original tick bite is noted. the latencies are usually not significantly prolonged. when affected. killed leprae. Borderline leprosy.938 The reversal reaction results from a shift to the tuberculoid end of the spectrum with an increase in cellular immunity. also called bull’s eye) and resolves spontaneously by about one month. However. Prevention of leprosy is the ultimate goal and involves multiple strategies.681. and clofazimine is presently the mainstay of treatment.635. Some reports include a suggestion of conduction block. gamma-interferon. Three stages of the disease are recognized: (1) early infection (erythema migrans: localized). Multidrug therapy with dapsone.1190. with the lower limbs slightly more affected than the upper limbs.20. sparfloxacin. Chemoprophylaxis of childhood contacts with daily rifampin for 6 months is currently recommended.652. ENL is due to the slow degradation of antigens (bacterial debris). These findings are consistent with the pathologic observation of mild to moderate degrees of axonal loss. A potential complication of therapy. particularly in borderline leprosy. perfloxacin. and chemically modified organism. Approximately 12–24 hours of tick attachment is required to accomplish secondary host infection. are abnormal. spanning the spectrum between the tuberculoid and lepromatous forms.20.906. Sensory evaluations demonstrate a whole spectrum of findings with a general impression that SNAPs are usually absent in the lower limb. The organism Borrelia burgdorferi. if available. Upregulation of the cellular response is characterized by excessive release of tumor necrosis factor-alpha. High-dose corticosteroids appear to blunt this adverse reaction and may be used prophylactically in high-risk patients at treatment onset. and (3) late-stage infection. Motor nerve conduction velocities are usually reduced. a spirochete transmitted by ticks. A second type of reaction to treatment is erythema nodosum leprosum (ENL). approximating the mononeuropathy multiplex pattern.642.870. primarily in the small muscles of the hand and feet as well as the ankle dorsiflexors and evertors. Within one month after a bite from an infected tick. LYME DISEASE Clinical Features. The reduction in velocity is usually 60–70% of the lower limit of normal. One or two weeks after the initial tick bite. including BCG. whereas in other patients a generalized lower worse than upper limb pattern is obvious.287. including thalidomide.938 Various vaccinations are available. This can result in an exacerbation of the rash and neuropathy as well as the appearance of new lesions. The SNAP conduction velocities are moderately reduced but usually not less than 60% of normal.1126. but a few patients may demonstrate values less than 20 m/s in both upper and lower limbs.1010. which can occur at any time during treatment of the disease.1126.1390 Treatment typically requires two years of therapy to achieve full eradication of the organism.1206 The MUAPs tend to be reduced in number. The phrenic and facial nerves can be involved and electrophysiologic studies in these nerves. often with brief hospitalizations to ensure understanding and compliance with multidrug regimens. minocycline. the proximal segment may reveal slightly lower velocities than the forearm segment. Distal motor latencies are normal or only mildly prolonged.1246.1274 When the SNAPs are present. thalidomide. 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. The CMAP may be reduced in various nerves.287. but these notations are made only in passing. the neuropathy also may be exacerbated. starting with prompt diagnosis and treatment of suspected cases. subcutaneous nodules.Chapter 23 ACQUIRED NEUROPATHIES — 973 borderline subtypes exhibit immune responses. systemic . the erythema migrans is not noticed by all patients. Electrophysiologic Findings. It is not unusual for some patients to have a mononeuropathy multiplex pattern of abnormal SNAP findings.938. and reduced in amplitude in the upper limb. A tick acquires the spirochete by feeding on an infected host animal and then transmits the spirochete to its next host during feeding. Figure 23-8. resulting in antigen-antibody complex and complement deposition in affected tissue. ENL can be treated with corticosteroids or.870 Needle EMG examination reveals mild to moderate degrees of positive sharp waves and fibrillation potentials.525.938 ENL is associated with the appearance of multiple erythematous. This disorder is not localized to the continental United States but occurs world-wide. and interleukin-2 with new granuloma formation.58. sometimes painful. rifampin.29. Within the upper limb.1126. It then develops a somewhat variable appearance with a clear central region (erythema migrans.20. (2) disseminated infection.1095 A hard-bodied tick known as Ixodes dammini (deer tick) is responsible for the disease in most cases. and clarithromycin (see Table 23-8).642. no criteria are defined and no waveform traces provided. is responsible Lyme disease (named for the Connecticut town where it was first detected). firing at high rates with increased amplitude and durations as well as numbers of polyphasic potentials. ofloxacin.

but the sural nerve is typically affected. reduced facial nerve CMAP.1098. or shoulder attacks of inflammatory arthritis become manifest. These symptoms may persist for years.i.1175. Laboratory Features.543. and musculoskeletal systems. provided a careful search is made. Treatment. Pathogenesis. perineurial.1011. a patient may present with symptoms and signs suggesting a myopathy as opposed to neuropathy.000 U/kg/day in divided doses for 10–14 days.1325. and abnormal blink reflexes). The third stage is characterized by destructive joint changes due to the inflammatory changes in the synovium of affected joints. 500 mg PO QID.d.665. Western blot analysis is useful to confirm a positive ELISA. small-amplitude potentials. The tibial or peroneal nerve may reveal reduced CMAP amplitudes with normal or borderline distal motor latencies.600. Nerve biopsies can reveal perivascular infiltration of plasma cells and lymphocytes around small endoneurial. A reduction in both upper and in particular lower limb SNAP amplitudes is found. Electrophysiologic Findings. depending on the stage of the disease. the findings vary. A neuropathy can arise in association with the toxin produced by the organism Corynebacterium diphtheriae. knee. are rather diverse. 2 gm IV qd for 2–4 weeks. fever. or AIDP pattern. with different patients demonstrating symptoms and signs that suggest a distal peripheral neuropathy.1182 The nerve conduction studies are essentially normal. Adult patients with other types of peripheral neuropathy are treated with intravenous (IV) penicillin. 50–80 mg/kg/day IV for 2–4 weeks. but an underlying common electrophysiologic thread. possibly resulting in profound loss of function. plus probenecid. encephalitis and meningitis can be observed. In stage 2 disease. Adults with facial nerve palsies secondary to Lyme disease are treated with amoxicillin. for 30 days. mild fever. localized adenopathy.977. lassitude.1248 After exposure to the organism. headache. for example.543.1431 Pericarditis and heart block can be detected with cardiac infection. should be given for 2–4 weeks. Axonal degeneration and secondary demyelination can be seen. The organism spreads throughout the patient with a particular preponderance for the skin.974 — PART IV CLINICAL APPLICATIONS symptoms of generalized fatigue. During the later portion of the second stage (weeks to years after the first inoculation). patients may be misdiagnosed with AIDP. nervous.693a. representative of the peripheral nervous system as a whole. the electrophysiologic findings are usually confirmatory of the preferential nerve involvement suspected clinically.d. 100 mg PO b. F-wave latencies in the lower and occasionally upper limb nerves (peroneal/tibial and median/ulnar) are prolonged. all of these presentations have a number of accompanying findings.. for 2–4 weeks.542–545.544. The peripheral nerve manifestations of the disease. radiculopathy. immunocompromised people usually demonstrate systemic “flu-like” symptoms of generalized myalgias. symptoms and signs of peripheral neuropathy.i. If allergic to penicillin. Additional skin lesions may be detected about the body.923. Similarly.1175. painful polyradiculitis/plexitis.544 Various nerves are preferentially involved in different patients. In patients with an overt clinical presentation consistent with mononeuropathy multiplex. or ceftriaxone. DIPHTHERITIC NEUROPATHY Clinical Features. These symptoms eventually resolve with good return of function. With respect to peripheral nervous system manifestations. The neuropathy may result from an indirect immunologic response and/or some form of vasculopathy. heart.1010. Asymmetric polyradiculoneuropathies.1094. children can be treated with erythromycin. even in patients who present with preferential loss of seventh nerve function (i. accompanied by overt fatigue in some patients. reduced CMAP and SNAP amplitudes as well as membrane instability suggest axonal loss.e. 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. 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. in addition to the confirmatory electrophysiologic evidence of a focal peripheral nerve lesion. Rarely.1325. Histopathology. A concomitant mild reduction in sensory nerve conduction velocity is also detected. although it tends to be bilateral in about one-half of cases (rare in idiopathic Bell’s palsy).i.1011. Adults who are allergic to penicillin should receive doxycycline. doxycycline. Therefore. wrist. entrapment neuropathy (carpal tunnel syndrome). Reductions in proprioception and vibration are found in the feet as well as reduced deep tendon reflexes. 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. Needle EMG examination demonstrates an alteration in MUAPs as characterized by short-duration. Rarely. Some patients experience muscle weakness and cramps. 20–40 mg/kg/day in 4 divided doses for 2–4 weeks. With neurologic involvement. thus defining the second stage of the illness. and painful neck motion can be observed. or ceftriaxone. mononeuropathy multiplex. where active spirochetes may be readily cultured.419. cranial mononeuropathies can be documented. 100 mg PO b.839. The spirochete has not been demonstrated within the peripheral nerves themselves. 20–24 million U/day for 10–14 days. Facial nerve dysfunction is believed to be the most commonly observed disorder with respect to cranial neuropathies and can resemble Bell’s palsy.977. a distal glove-and-stocking distribution of altered sensation and accompanying paresthesias can be noted in roughly one-half of patients.1431 The same findings generally apply for all of the above disorders. Antibodies directed against the spirochete can be measured using immunofluorescent or enzyme-linked immunoabsorbent assay (ELISA).1095.542.807.544 Specifically. Children less than 4 years of age can be treated with amoxicllin.1094.839.543. Additional cranial nerves can be affected but less frequently than the facial nerve. possibly prolonged distal motor latency. chills.544 In patients with suspected Lyme disease. plexopathies or multiple mononeuropathies also can occur. with increased numbers firing rapidly at low levels of force.1258. False-positive reactions are not uncommon. The pathogenic mechanism for Lyme neuropathy is unknown. headache.737..d.807a.732. Children with Lyme neuropathy can receive IV penicillin G 250. 500 mg q.1258. and possible irritability within 1 week to . and epineurial blood vessels without clear necrotizing vasculitis. In stage 3. If the patient is allergic to penicillin.732 However. 30 mg/kg/day in 4 divided doses for 2–4 weeks. These distinct patterns may be more apparent than real. A somewhat bluish discoloration of the skin is located primarily on the distal limb regions (acrodermatitis chronica atrophians). most patients revealed evidence consistent with a primarily axonal neuropathy. an absent or asymmetric tibial H-reflex can be found.

250. with an asynchronous or differential slowing of neural conduction. relatively late in the course of the disease).g. As a result.419 However.807a The distal motor latencies are only mildly to moderately prolonged in most cases. HUMAN IMMUNODEFICIENCY VIRUS At least 20% of patients with HIV develop some form of polyneuropathy during the course of their illness. Electrophysiologic Findings.421. may ensue. In patients with a less fulminant form of the disease. Considerable information is available from animals. CMV-related). but they were absent in the median nerve. . The above findings are certainly anticipated from the histologic demonstration of primary demyelination with some degree of axonal loss.737 Motor nerve conduction studies reveal about a 45% reduction in the mean nerve conduction velocity expected for both upper and lower limbs.255 Histopathology. there is also a suggestion that conduction block is likely across the demyelinated segment. In most countries. CSF protein can be elevated with or without lymphocytic pleocytosis.306.421. treatment does not appear to alter the natural history of the associated peripheral neuropathy.959 Although not described in humans.Chapter 23 ACQUIRED NEUROPATHIES — 975 10 days of exposure. Hoarseness or dysarthria. cardiomyopathy).834. F-waves were attempted.e. but they can persist for more than 1 year in patients with profound weakness and muscle wasting. Muscle weakness may progress over a period of weeks to the degree that the patient is unable to ambulate independently.1024. a generalized peripheral neuropathy may manifest 2 or 3 months after the initial infection. The net result is an increase in the temporal dispersion of arriving motor impulses with the MUAP not summating temporally.857. but the abnormalities tend to maximize by 5–8 weeks.. In humans.438. In a single patient. By about the third or fourth week. In most patients. Nerve conduction studies may be abnormal by 2 weeks after onset of symptoms suggestive of a neuropathy.e. vasculitis. 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. In profound disease. Treatment.897. However. The CMAPs not only are reduced in amplitude but also show significant temporal dispersion. Deep tendon reflexes are diminished or absent throughout. however.244. and (6) sensory ganglionitis. patients complain of blurred vision. and this finding has not been observed in humans. because diphtheria toxin is an excellent manner in which to study demyelination experimentally. Hand intrinsic strength is commonly well preserved until the disease has progressed to affect more proximal leg muscles (i.764. Pathogenesis. At the same time. There is usually a disparity between the severity of nerve conduction studies and clinical presentation. (3) mononeuropathy multiplex (e. The diphtheria toxin binds to Schwann cells and inhibits synthesis of myelin proteins.1024 HIV-related Distal Symmetric Polyneuropathy Clinical Features.708. Laboratory Features. the nerve conduction studies have normalized by 33 weeks after the initial clinical neurologic manifestations. DSP is perhaps the most common form of peripheral neuropathy associated with HIV infection and usually is seen in patients with AIDS. autonomic disturbances of heart rate and vascular tone may progress to cardiac arrhythmias and eventual death. a considerable reduction in the CMAP amplitudes with proximal stimulation has been demonstrated in animals. Resolution of the symptoms may take several months in severely affected patients. along with diaphragmatic weakness.665. and (2) increased phase cancellation with positive and negative phases of motor units summating to cancel each other. criteria have not been applied to animal studies. given the pathology.1278 Six major types of peripheral neuropathy are associated with HIV infection: (1) distal symmetric polyneuropathy (DSP). 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. This finding implies that nerve conduction slowing is not uniform.. there is a paucity of information about the electrodiagnostic medicine findings in patients with diphtheria.75. A whitish. In animal studies. Physical examination reveals a reduction to all sensory modalities in the distal upper and lower limbs. 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.834.. the limited number of investigations have demonstrated absent SNAPs.255. Severely affected fibers are found in close proximity to well-preserved nerve fibers. (5) autonomic neuropathy.923. (2) inflammatory demyelinating polyneuropathy (including both AIDP and CIDP). The primary sites of pathologic reaction in the nervous system are the dorsal root ganglia and the nearby ventral nerve root and spinal nerve. after which there is a slow and steady recovery. Antitoxin and antibiotics should be given within 48 hours of symptom onset to reduce the incidence and severity of complications (i. patients may begin to complain of difficulty in swallowing with a demonstrable reduction in palatal sensation. It is also possible for the organism to produce the above symptoms after entrance through a wound in the body. a similar finding of reduced conduction velocities with prolongation of the distal motor latencies is noted. Some patients are asymptomatic but are found to have diminished sensation to all modalities on examination. the more distal segments of the peripheral nerves are also affected. Rarely. particularly when looking at near objects.1098 This is certainly likely.1221 Patients often complain of numbness and painful paresthesias of the hands and feet.539. Computer models support the above assertions that temporal dispersion and phase cancellation result in a reduction in CMAP amplitude. Manual muscle testing reveals reduced strength in the hand intrinsics and ankle dorsiflexor/plantar flexor muscles. A small degree of axonal loss and active degeneration also is noted. Pupils react to light but fail to accommodate. Additional cranial nerves also may become involved.278. Additionally.1060 Demyelination is believed to result from failure to replace myelin proteins during normal metabolic turnover. Segmental demyelination is the major observation with relatively good preservation of axons. Atrophy and mild weakness in foot intrinsic muscles may be noted. (4) progressive polyradiculopathy (usually CMV-related). Although nerve conduction studies worsen by 5–8 weeks. This temporal dispersion is attributed to segmental demyelination. urethral and anal sphincters become compromised.600. the patient begins to demonstrate clinical recovery. Deep tendon reflexes are reduced at the ankles but are relatively preserved at the knees and in the upper limbs. membranous exudate may be present in the throat region with or without cervical lymph node involvement. the reduction of morbidity and mortality due to diphtheria occurred before the development of sophisticated electrophysiologic techniques.737. About 20–70% of patients develop a peripheral neuropathy.

DSP can occur in patients not previously exposed to antiretroviral agents.837 Vitamin B12 deficiency has been noted in some series.284.338. Axonal regeneration and secondary demyelination are more prominent at the more proximal levels of the nerves. sedation.242. dizziness.075% cream Route Oral Motor nerve conduction velocities are usually not altered to a great degree. The histologic features are identical to those of AIDP and CIDP.61.895.90.762. A helpful feature in distinguishing idiopathic AIDP or CIDP from HIV-related AIDP/CIDP is the presence of pleocytosis in the CSF. SNAPs in the lower limbs are no longer obtainable with routine techniques. The neuropathy may be immune-mediated. the hand intrinsic muscles can demonstrate similar findings.025–0. whereas CIDP can occur at any point in the course of the infection but is more common in patient with AIDS.976 — PART IV CLINICAL APPLICATIONS Laboratory Features. along with elevated protein levels. Treatment is largely symptomatic (Table 23-9).e.570..438.. Treatment of Painful Sensory Neuropathies Dose 10–100 mg qhs Side Effects Cognitive changes.1085 A loss of cell bodies in the dorsal root ganglia can be seen in addition to degeneration of the dorsal columns.953.1221. Laboratory Features. Histopathology. leukopenia.1222 AIDP can occur at the time of seroconversion. and there is a reduction in upper limb SNAP amplitudes with a slight prolongation in the latency.762.g. elevations in duration.242. Some degree of centrofascicular loss also can occur. Patients with HIV infection can present with symptoms and signs similar to those of AIDP and CIDP. amplitude. perhaps caused by the release of cytokines from surrounding macrophages. dizziness. suggesting motor unit remodeling (i.82.5%/pylocaine 2. 436. urinary retention.435.1347 Histopathology. Occasionally. It is probably not due to actual infection of the peripheral nerves.683 but other studies have suggested that vitamin B12 metabolism does not play a significant role in the neurologic complications of HIV infection. Needle EMG examination can reveal positive sharp waves and fibrillation potentials in the foot intrinsic muscles that progress to the leg muscles.774. As noted above. Electrophysiologic Findings. vitamin B12 deficiency may contribute to some cases but is not a major cause of most cases.1110. Therapy First-line Tricyclic antidepressants (e. and phases). A small degree of perivascular inflammation (mainly macrophages and T-cells) can be observed. sedation Cognitive changes. regardless of the stage of the infection and the presence or absence of peripheral neuropathy.1237. Antiretroviral agents have no demonstrable affect on the course of DSP.1323 However. Autopsy studies and nerve biopsies have demonstrated a reduction in the total number of both myelinated and demyelinated axons due to axonal degeneration.897.895 There is no way to discriminate histologically idiopathic AIDP/CIDP from HIV-related AIDP/CIDP.1242.1074 Reduced motor and sensory conduction velocities are evident.211.211. Conduction block and temporal dispersion can be seen. F-waves are unobtainable or prolonged. Skin biopsies may demonstrate a reduced density of small myelinated nerve fibers in the epidermis. The detailed discussions of the electrophysiologic findings in idiopathic AIDP and CIDP should be reviewed.574 Pathogenesis.77. With disease progression. Neurontin may be beneficial in reducing the painful symptoms. Various antiretroviral agents (e.684 However. The electrodiagnostic medicine examination reveals evidence of a symmetric.1278 Sural and superficial peroneal SNAP amplitudes are reduced with only mildly prolonged latencies. along with evidence of increased cytokine expression. dideoxycytidine. a randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection demonstrated no significant benefit. The alterations noted for sensory and motor fibers in idiopathic AIDP and CIDP are also operational for cases associated with HIV infection. constipation Cognitive changes. nortriptyline) Gabapentin Second-line Carbamazepine Phenytoin Tramadol Third-line Mexiletine Other agents Lidocaine 2. dry eyes and mouth. amitriptyline.421.212.g. stavudine) are also neurotoxic and can cause a painful sensory neuropathy. Electrophysiologic Findings. CSF can reveal both increased protein and mild lymphocytic pleocytosis in patients with HIV infection.5% cream Capsaicin 0. dideoxyinosine.. Treatment. The pathogenic basis for DSP is unknown. axonal polyneuropathy that affects sensory more than motor nerves.338. The upper limb sensory studies are normal or only mildly affected early in the course of AIDS. liver dysfunction Cognitive changes.61. especially when evaluated in the foot. The MUAPs are reduced in numbers and recruitment with alterations in morphology.685 HIV-related Inflammatory Demyelinating Polyradiculoneuropathy Clinical Features. liver dysfunction Cognitive changes. but the CMAP amplitude may be reduced.436. Table 23-9. GI upset Arrhythmias Oral Oral Oral Oral Oral Apply cutaneously Apply cutaneously 300–1200 mg tid 200–400 mg q 6–8 hr 200–400 mg qhs 50 mg qid 200–300 mg tid qid qid Painful burning skin .

along with the loss of myelinated nerve fibers in the peripheral nerves. vidarabine). The clinical presentation and biopsy findings suggest the type of abnormalities anticipated on electrodiagnostic medicine examination. Electrophysiologic Findings.799. Plantar responses are flexor. The pathogenic basis for autonomic neuropathy is unknown but probably multifactorial. These findings are most evident in the lumbar regions. which usually are asymmetric. F-waves are hard to obtain and latencies can be prolonged. In addition. CMV retinitis) Laboratory Features.Chapter 23 ACQUIRED NEUROPATHIES — 977 Treatment. It is difficult to draw firm conclusions about treatment options. As expected from the lesion location. a progressive decline in the CMAP amplitudes is noted.1222 Patients have severe numbness. 242. and urine. Laboratory Features. one expects to find decreased amplitudes or absence of SNAPs. confirming the primary pathology as axonal loss with little demyelination. However.254 Treatment.899 However. or α-interferon. Patients with HIV-associated AIDP or CIDP can be treated with IVIG or plasmapheresis.1244 The clinical features are similar to those of idiopathic sensory neuronopathy or ganglionopathy. Examination is similar to that for other causes of multiple mononeuropathies. most patients with this complication die within several weeks or months.825 Prednisone also can be effective. Some patients with HIV infection. An elevated CSF protein with some degree of mononuclear cells is common. the prognosis in most patients is poor.278 The pathogenic mechanism is not known.372. They also note a reduction in perineal sensation with painful paresthesias. blood.254.898. HIV-related Multiple Mononeuropathies Clinical Features. although secondary demyelination also may be seen. there are limited discussions of the electrophysiologic features. The neuropathy may be caused by deposition of HIV antigen-antibody complexes in the walls of blood vessel. usually those with AIDS. Autopsies have demonstrated degeneration of neurons and inflammatory infiltration in the dorsal root ganglia. Histopathology. Single or multiple cranial nerve dysfunction also has been described. the cranial nerve root exit from the brainstem may be involved with a minimal degree of adjacent myelitis. Electrophysiologic Findings.278.897. There may be a limited response to ganciclovir or foscarnet in some patients. In some cases. Some cases may be related to vasculitis due to concomitant hepatitis B or C infection and antigenemia. The sensory neuronopathy may be the presenting manifestation of HIV infection.. Histopathology. the CSF can reveal pleocytosis and increased protein.228. Occasionally. Short courses of prednisone and cyclophosphamide may be used. Patients may have evidence of CMV infection in other parts of the body (e. Occasionally.774. treatment with ganciclovir or foscarnet should be initiated. Nerve biopsies can reveal perivascular inflammation or frank necrotizing vasculitis. If CMV is suspected. and weakness in the legs. Because of the rarity of the disorder.. Diminished or absent deep tendon reflexes in the legs can be found. The polyradiculopathy is caused by the direct infection of neurons by CMV. HIV-related Progressive Polyradiculopathy Clinical Features. In addition.1160. There are no distinguishing laboratory features.1165 It is not uncommon to find electrophysiologic evidence of a generalized symmetric distal polyneuropathy due to overlapping mononeuropathies.429. There is a profound reduction in MUAPs (reduced recruitment) with some muscles demonstrating a complete absence of MUAPs. Treatment. Concomitantly. Electrophysiologic Findings. The pathogenic basis for this disorder is probably multifactorial.g. antiviral agents (e. CMV inclusions have been demonstrated in endothelial cells and macrophages on nerve biopsy specimens.1158 Pathogenesis. The above combination of findings is quite distinct from findings in both CIDP and DSP and helps to differentiate the various disorders.1222 They have weakness and reduced sensation and paresthesias in a distribution suggestive of multiple peripheral nerve involvement. CSF glucose concentration may be decreased. Only symptomatic treatment of autonomic problems is currently available. needle EMG examination reveals profuse fibrillation potentials and positive sharp waves.g. Treatment. HIV-related Sensory Neuronopathy/Ganglionopathy Sensory ataxia due to ganglionitis is a rare complication of HIV infection. coincident with the progressive loss of axons and ensuing Wallerian degeneration.897. Patients with multiple mononeuropathies and hepatitis B or C infection can be treated with plasma exchange. usually those with AIDS.762. diarrhea. Laboratory Features. and bladder dysfunction.1158 Pathogenesis.898.798 The autonomic neuropathy often occurs in patients who also have DSP. Pathogenesis.1159 Axonal degeneration is prominent. Patients with advanced AIDS can develop an acute. Most patients have the electrodiagnostic features noted above for DSP. The conduction velocities are normal until there is a complete absence of the motor CMAPs or sensory SNAPs.1132. given the scarcity of relevant literature. There are no reports of histopathology data in patients with autonomic neuropathy due to HIV infection. Biopsies of the ventral and dorsal root regions demonstrate significant degrees of inflammatory infiltrates associated with varying degrees of axonal loss. . impaired sweating. the upper limbs and cranial nerves become involved. HUMAN T-LYMPHOCYTE TYPE 1 INFECTION HTLV-1 infection can cause a peripheral neuropathy. also can develop an autonomic neuropathy. which manifests as orthostatic hypotension. 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.1243 When the ventral roots are affected. CMV inclusions were evident in endothelial cells and macrophages on the nerve biopsy specimens. pain. CMV can be cultured from the CSF. CMV infection probably plays a role in some cases of multiple mononeuropathy. Histopathology.898. As with any patient with HIV infection.1132. develop multiple mononeuropathies. These abnormalities extend to essentially all muscles in the lower limbs bilaterally. as in DSP.689. HIV-related Autonomic Neuropathy Clinical Features.279. autonomic function testing is usually abnormal. Incontinence of urine and stool are common. The electrodiagnostic medicine findings are similar to those described with other forms of multiple mononeuropathies caused by vasculitis. progressive lumbosacral polyradiculopathy secondary to cytomegalovirus (CMV) infection.218. impotence. but the most common manifestation is the tropical spastic paraparesis. CSF reveals an increased protein and neutrophilic pleocytosis. Patients with HIV infection.

no matter what aspect of the peripheral nervous system is affected. Of course. proximal to the bifurcation of the spinal nerve into the ventral and posterior primary rami). Electrophysiologic Findings. Unilateral phrenic nerve involvement can lead to hemidiaphragmatic paralysis.1138 HEPATITIS VIRUSES Hepatitis B and C can cause multiple mononeuropathies. the potentials’ amplitudes may be reduced or. Ramsay-Hunt syndrome) has the highest likelihood of being affected. The most commonly affected region of paresis involves the cranial nerves. the virus can be reactivated with the above symptoms. roughly 25% of affected patients have significant residual pain. In a large series of patients. a loss of strength is noted in the corresponding myotomal distribution. confirming the impression that the lesion is at least as proximal as the spinal root level (i. in severe disease. if the facial nerve is involved. Physical examination reveals the expected loss of sensation and hyperpathia in the dermatomal distribution of the disease.1296 Cervical (C2–C8) eruptions are the least frequently encountered. or CIDP.978 — PART IV CLINICAL APPLICATIONS which is discussed in detail in Chapter 16. as discussed above.526. After initial infection. Of note is the rarely appreciated possibility of developing concomitant involvement of the associated motor nerves. and fibrillation potentials/positive sharp waves may be observed.24 This complication is more common in older patients. called postherpetic pain. CYTOMEGALOVIRUS CMV can cause an acute lumbosacral polyradiculopathy or multiple mononeuropathies in patients with HIV infection. the prognosis for most patients with any type of focal motor involvement is relatively good. reduced recruitment of MUAPs. HERPES VARICELLA ZOSTER VIRUS Clinical Features. cranial neuropathies.673 The same findings can occur if the virus damages a . brachial plexopathy. however. and sensory neuronopathies. When regions of the body are affected with available peripheral nerves amenable to SNAP measurements.1128. variable degrees of positive sharp waves and fibrillation potentials can be observed. HTLV-1 infection also can cause on inflammatory myopathy (discussed in Chapter 28). CSF may demonstrate a mild to moderate protein elevation with variable pleocytosis. where it appears to be insulated from the host’s immune defense mechanisms.1149.460. Cervical weakness. the vesicular skin lesions are clear but form a crusty mass by 2 weeks and heal with dermal scar formation. Initially. and secondary facial paralysis can appear to be Bell’s palsy if ear lesions are missed. 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. which at times can be clearly abnormal or reduced toward the lower limits of normal. Thoracic weakness is difficult to determine and most likely accounts for only 3% of patients with motor paresis. Motor paresis is postulated to develop when the virus causes local neuritis in the spinal nerve and subsequently gains access to the motor axons. severe infections can result in the destruction of dorsal root ganglion cells with secondary loss of posterior column fibers.1296 The weakness usually develops within the first 2 weeks of the skin eruption but can vary between several hours to 1 month.e. patients with a typical skin eruption develop AIDP. A variable degree of pain is associated with the skin lesion.904. as anticipated for a primarily axonal insult.24 Pain and paresthesias in the dermatome region may precede the vesicular rash by 1 week or more. which can be quite disabling.346. Two-thirds of infections are manifested by dermal zoster.1296.448. when the thoracic dermatomes are involved. a reduced CMAP from a facial muscle.497. it is not possible to evaluate a corresponding SNAP. When the thoracic myotomes are involved. Pathogenesis.298. may be associated with phrenic nerve dysfunction. the facial nerve (herpes zoster oticus.524. protrusion of the abdominal wall can suggest an abdominal wall hernia. Herpes varicella zoster (HVZ) infection can result from reactivation of latent virus or from primary infection.904. particularly with upper myotomal involvement.000 population. The basic pathologic neural reaction is axonal degeneration with some degree of secondary segmental demyelination. mononeuropathy multiplex.70 After a reduction in the immune system’s capacity. depending on the extent of axonal loss in the examined muscle. approximately 50% experienced the eruption in the thoracic region (T1–T12) with an equal number developing skin lesions in the first division of the trigeminal (18%) and L2–S4 aspects of the lumbosacral (18%) regions.524. HZV travels down the sensory nerves and results in the typical skin lesions. The virus is difficult to culture from the CSF. Histopathology. Rarely. With motor paresis.448. Examination of the paraspinal regions also demonstrates membrane instability. HZV migrates up the sensory nerves and resides in the sensory ganglia. but polymerase chain reaction can be used to confirm the presence of the virus in the CSF. The findings of relatively preserved nerve conductions and evoked response latencies apply equally. The incidence of HVZ infection is approximately 480 persons per 100.1149 SNAP distal sensory latencies and conduction velocities are only mildly affected.70 The peak age of developing the disease is between 55 and 75 years of age.1149 Nerve conduction velocities may be mildly reduced and distal motor latencies little affected.448. little change in distal motor latency.1399 After the appropriate period. For example. EPSTEIN-BARR VIRUS EBV has been implicated as causing some cases of AIDP. completely absent. Motor nerves affected by the infection demonstrate reduced CMAP amplitudes.. Decreased or absent deep tendon reflexes are also expected in the appropriate regions.521 Laboratory Features. lumbosacral radiculoplexopathy. if at all.1166 Additional neurologic manifestations of herpes zoster infection include encephalitis and stroke. From 5–30% 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. Primary acquired HVZ infection is frequently associated with severe disseminated zoster in immunocompromised patients. AIDP.1034 Herpes zoster oticus begins with vesicular eruption in the ear canal.904. With respect to the sensory system. However. Cervical and lumbosacral myotomal regions are equally likely (26% each) to be affected. The needle EMG examination demonstrates a reduction in the number of voluntary MUAPs in the affected myotome.483 Fortunately.489.

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 2–4 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 polyradiculoneuropathy—CIDP) • 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

Diabetes mellitus (DM) is the most common metabolic disease with a prevalence of 1–4%.362,1129 DM is categorized into two major categories: (1) insulin-dependent diabetes mellitus (IDDM or type 1 DM) and non–insulin-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 5–66%.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

980 — PART IV


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-α, interleukin (IL)-1α, IL-1β, 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., 15–30% 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

Chapter 23


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 300–400 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 1–3 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

74. Pathogenesis. Alternatively.241. electrophysiologic features of a generalized axonal sensorimotor polyneuropathy. Histopathology. This may allow patients to undergo physical therapy. as described above.627. examination reveals weakness of both proximal and distal lower limb muscles.177. particularly the distal muscles. 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.1033. similar findings can be seen in DSPN and diabetic amyotrophy.1162. A stocking-glove sensory loss to all modalities can be demonstrated along with reduced deep tendon reflexes. In many cases. symmetric proximal and distal weakness evolving over weeks to months. Remember that the natural history of the disorder is spontaneous improvement. are occasionally present. Some have suggested an increased risk of CIDP in diabetics. As with idiopathic CIDP. In contrast to classic diabetic amyotrophy. demyelinated fibers and onion-bulb formations are evident. Most biopsy specimens do not demonstrate frank vasculitis. which is often asymmetric between and within nerve fascicles. scant perivascular mononuclear inflammatory cells may be demonstrated in the perineurium and epineurium.1392 The pain can radiate from the posterolateral chest wall anteriorly to the abdominal region with associated loss of sensation anterolaterally. Thoracic mono. the disorder may be a distinct form of diabetic neuropathy.74 A mild stocking-glove sensory loss secondary to superimposed DSPN is sometimes noted.627. patients with this form of diabetic polyradiculopathy do not usually have severe back and proximal leg pain and the motor weakness is relatively symmetric.1444 Anecdotally.665a. of these immunotherapies on the polyradiculoneuropathy is not known. the distal latencies of the SNAPs are normal or slightly prolonged. is more common. SNAPs are absent or low in amplitude.1033. distal dysesthesias.1033 Such spontaneous improvement is not the natural history of other forms of “true” vasculitis. the arms are generally affected.1272.1106. The pathogenic basis for this form of polyradiculoneuropathy is quite controversial.217. Nevertheless.368. it is possible to observe abdominal wall protrusion secondary to muscle weakness. Laboratory Features.138. Occasionally. Small retrospective studies have reported that IVIG.1322 This form of polyradiculoneruopathy resembles idiopathic CIDP. MRI scans of the lumbosacral roots and plexus can reveal inflammatory changes. Likewise. More studies are necessary to unravel the pathogenic nature of diabetic amyotrophy.74. thinly myelinated. When obtainable. On rare occasions. Laboratory Features.or polyradiculopathies also can present with or without involvement of the lumbosacral roots/ plexus. and lateral femoral cutaneous nerve biopsies reveal a loss of myelinated nerve fibers. Finally.729. but it is not specific for vasculitis. In fact. 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 perhaps due to a superimposed cervical polyradiculoneuropathy/brachial plexopathy.1415 Recruitment of MUAPs is reduced in weak muscle groups.368.1415 As expected. are more prone to developing .215.74. some patients develop weakness in the upper limbs.217.982 — PART IV CLINICAL APPLICATIONS 18 months have been documented.627.43. In addition. The histopathology and presumed response to immunomodulating therapies has led some to suggest an immune-mediated microangiopathy as the basis for diabetic amyotrophy. CMAPs are diminished in amplitude in affected muscles.1444 This may be the case. Treatment.375.1263.729.43.479. placebo-controlled trials are necessary to define the role of various immunotherapies.215. However. Most patients gradually improve over time regardless of treatment. long-duration. F-waves are unattainable or slightly increased in latency.177.1272. Weakness is most prominent distally and in the lower limbs.1161. perhaps secondary to a superimposed DSPN.1026. Asymmetric loss of axons between and within fibers certainly is seen with ischemic neuropathies.1267. we have been impressed that short courses of corticosteroids can help to ease the pain associated with severe polyradiculoneuropathy. however.688. large-amplitude. superficial peroneal. but cell count is normal. residual weakness is significant.1273.729. regenerating fibers can be seen. and sural nerve biopsies. In addition. which can be asymmetric.999 Histopathology. whereas distal latencies are normal or slightly prolonged. as noted above.1260.729. Electrophysiologic Findings.1263. Conduction velocities in the affected limbs are normal or mildly slow. 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. proximal leg and upper limb muscles also are affected. however.1033. polyphasic MUAPs can be appreciated.74 There is an erroneous misconception that only proximal muscles are affected.1261. The histologic abnormalities are not specific for vasculitis or ischemia. Although even less common.627.1033 Needle EMG demonstrates positive sharp waves and fibrillation potentials in proximal and distal muscles in the affected limbs and paraspinal muscles. Prospective.24a. CSF protein concentration usually is increased. these nerve biopsy abnormalities are not specific for symmetric diabetic polyradiculopathy or CIDP. Diabetic Polyradiculoneuropathy Clinical Features. This second major group of diabetic polyradiculoneuropathy presents with a progressive. Mild perivasuclar inflammation. and adrenergic functions. Autonomic studies usually reveal abnormal sudomotor.1444 Active axonal degeneration and clusters of small.479.665a Pathogenesis. It may be that patients with DM.1261.729. which is a nonspecific abnormality.688. Sural.74.1033. However. superficial peroneal.627. double-blinded. especially those with autoimmune type I DM. are evident.810. The nerve conduction studies and EMG of diabetic amyotrophy reflect multifocal axonal damage to the roots and plexus.1033. relatively painless.24a The neuropathy may represent the coincidental occurrence of CIDP in patients with DM. As reinnervation occurs over time. cardiovagal. if any. However. Sural nerve biopsies have demonstrated a loss of large and small myelinated nerve fibers. the natural history of this neuropathy is gradual improvement so the actual effect.1267. Mild perivascular inflammation of epineurial and perineurial blood vessels have been noted on some nerve biopsies. In patients with underlying DSPN. and other forms of immunosuppressive therapy are effective in patients with diabetic amyotrophy. Deep tendon reflexes are reduced in the affected leg.627. CSF protein concentration usually is elevated. but much more information is needed. Painless. it may represents a spectrum of diabetic amyotrophy. Eventually the disorder stabilizes and slow recovery ensues.1033 A polymorphonuclear small-vessel vasculitis associated with IgM and complement deposition on affected epineurial vessels has also been reported. Findings suggesting microvasculitis have been described in lateral femoral cutaneous. Symmetric. This type of polyradiculoneuropathy occurs in both type I and type II DM but may be more common in the latter.1322 Axonal degeneration and clusters of small regenerating fibers are seen. prednisone. Erythrocyte sedimentation rates may be increased.

Histopathology. cubital tunnel. however. A number of retrospective studies have demonstrated that various forms of immunotherapy (i. The common presentation is a generalized sensorimotor peripheral neuropathy (i. Correction of the hypoglycemic problem usually results in clinical improvement. axonal loss.894. fourth nerve palsies. however. Ischemia is the primary cause for the dysfunction. some patients appear to benefit from various immunotherapies. motor weakness may develop. less frequently.1033. The authors believe that painless. Some of the more frequently encountered isolated limb neuropathies include carpal tunnel syndrome.627. Focal limb mononeuropathies are commonly observed in diabetic patients superimposed on a more mild generalized peripheral sensorimotor peripheral neuropathy. 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. It must be recognized. Diabetic Mononeuropathies or Multiple Mononeuropathies Patients with DM are particularly prone to both focal neuropathies and multifocal neuropathies.80. In many instances. Manual muscle testing can reveal significant muscle wasting in the distal aspects of the legs and hand intrinsic muscles.Chapter 23 ACQUIRED NEUROPATHIES — 983 CIDP.627.479. it is a useful clinical designation because it is quite descriptive of the patient’s symptoms and signs. and adrenergic functions. It has been suggested that the axonal loss associated with concurrent DSPN may account for the diminished response to immunosuppressive agents. indicating a superimposed focal lesion.551. Furthermore. The clinical features.e.1322 This observation has led to the belief that this type of diabetic neuropathy is immune-mediated and perhaps represents CIDP in diabetic patients. however.g.. Double-blind. The median and ulnar nerves are the most commonly affected. 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.e.1033. demyelination. Few nerve biopsies have been performed on affected patients with modern histologic techniques.24a. The nerve conduction studies demonstrate absent or reduced SNAP and CMAP amplitudes combined with slowing of nerve conduction velocities. placebo-controlled trials are needed for better assessment of treatment options.1261 The needle EMG examination reveals fibrillation potentials and positive sharp waves diffusely. 1033. accompanied by weakness. peroneal neuropathy at the fibular head. more work needs to be done to unravel the pathogenic nature of this form of neuropathy. There is usually complete loss of function within hours to one day. the complete absence of multiple responses can make it virtually impossible to define separate nerve lesions by electrophysiologic means. oculomotor.479. diabetic polyradiculoneuropathy.1322. electrophysiologic features (see below). and absent or prolonged latencies of Fwaves. followed by peroneal mononeuropathy at the fibular head.426.626. femoral. IVIG. and cranial (e.1322 Obviously.628.479. Although this “form” of neuropathy is not a single disease entity.12.1033 Occasionally. Deep tendon reflexes are generally reduced. patients with long-standing muscle wasting and weakness may have less than satisfactory recovery..1412 Conduction block and temporal dispersion are uncommon but may be seen.. Clinical delineation of individual peripheral nerve insults can be difficult. abducens. The extraocular nerves also can be affected: a focal lesion of the third nerve is the most common. and prolonged distal latencies) can be expected out of proportion to the more generalized neuropathy. PE. Abnormalities consistent with axonal loss (reduced or absent SNAP and CMAP amplitudes. because they can improve spontaneously without treatment.479 In addition. a seventh nerve palsy is most common. that the primary lesion is axonal loss primarily affecting the large myelinated fibers.242.627.729. facial) nerves are affected less frequently. femoral neuropathy. it is by no means certain that this form of polyradiculopathy is immunemediated. cubital tunnel syndrome. foot drop. These mononeuropathies may occur with or without concomitant significant clinical or electrophysiologic evidence of a generalized peripheral neuropathy.80. others may be unusual cases of diabetic amyotrophy or caused by a distinct metabolic neuropathy related to the DM.729. sparing of pupillary function is common. and resolution is noted by 3–5 months. creating a clinical presentation of mononeuropathy multiplex. increased CSF protein.. DSPN) associated with one or more focal mononeuropathies such as carpal tunnel. especially with respect to the subjective sensory symptoms. and lateral femoral cutaneous neuropathies. Any of these isolated nerve insults can occur in combination within a similar time frame. Electrophysiologic Findings. Of some help in better defining all of the individual and combined peripheral nerve dysfunctions is a carefully performed electrodiagnostic medicine examination. thus limiting the available information. the nerve histopathologic abnormalities.1261. In profound disease. but there are generally more axonal abnormalities than in idiopathic CIDP.1453 Of the cranial mononeuropathies.627. the magnitude of the response is not as robust as in idiopathic CIDP. The apparent response to various types of immunotherapies does not imply that patients have CIDP. There is a suggestion. symmetric diabetic polyradiculoneruopathy is likely to be multifactorial with some cases representing CIDP. patients with symmetric.1033 Treatment.628 Segmental demyelination is not a .286.566a. Over a variable course of time. however.45. 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. mild reduction in conduction velocities) as well as demyelination (reduced conduction velocities. However.637 One of the focal neuropathies likely to be observed in diabetics is a cranial mononeuropathy.e. that at times doubt may persist as to the true nature of the patient’s complaints because of the limited manner in which the peripheral nervous system reacts to insult (i. however.1033 Therefore.1412 Autonomic studies demonstrate abnormalities in sudomotor. HYPOGLYCEMIA/HYPERINSULINEMIA Clinical Features. prolongation of distal latencies. corticosteroids. including immunohistochemistry. temporal dispersion. are not specific for this form of diabetic polyradiculopathy and have been noted in DSPN and diabetic amyotrophy. and histopathology can be indistinguishable from idiopathic CIDP. cardiovagal.242. followed by sixth nerve palsies and.1261. diabetic polyradiculoneuropathy also can improve spontaneously without treatment. cyclophosphamide) appear to be beneficial in the symmetric.479.926 Patients may note progressive numbness and paresthesias in the hands and feet.658 Sciatic. the electrophysiologic features fulfill research criteria for demyelination. or both). The electrodiagnostic medicine examination reveals a significant generalized sensorimotor polyneuropathy. including multiple levels of the paraspinal musculature. or oculomotor palsy. The electrodiagnostic medicine evaluation should include a generalized evaluation of the peripheral nervous system in addition to the focal problem.

1056. early recruitment). combined with prompt recognition of the disorder. primarily in the intrinsic foot and hand muscles. HYPOTHYROIDISM Clinical Features. CMAP amplitudes are relatively well preserved.312. Pathogenesis. Some patients develop mild distal weakness. or generalized sensorimotor polyneuropathy. Appropriate medical treatment usually arrests progression of the peripheral neuropathy with variable degrees of compensation.1056 Several different types of peripheral neuropathies also may occur.628.984 — PART IV CLINICAL APPLICATIONS prominent feature.1062. The small number of patients reported in the past.1076 Less common are symptoms and signs suggestive of tarsal tunnel syndrome. In some cases. 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. is less frequent. the distal latencies may be prolonged and conduction velocities are slow. proximal muscle examination can demonstrate short-duration.681a. the bony overgrowth in or about the spinal canal and neural foramens can result in spinal cord compression.322. Teased nerve fiber preparations demonstrate changes suggestive of axonal degeneration and segmental demyelination. The cause of the neuropathy in patients with acromegaly is not clear.321. mono/polyentrapment syndromes.415. Treatment. Data about the response of peripheral neuropathies associated with acromegaly to treatment are insufficient.1186 A few series of cases suggest that generalized peripheral neuropathies also can complicate hypothyroidism.817 Pathogenesis. two major forms of peripheral nerve dysfunction can be observed as well as proximal myopathy. The cause of the generalized neuropathy associated with hypothyroidism is not known.1306 The most common mononeuropathy in acromegaly is carpal tunnel syndrome. Carpal tunnel syndrome most likely results from reduced space within the flexor retinaculum as a result of associated edematous changes.286.880. ACROMEGALY Clinical Features. Nerve biopsy demonstrates primarily segmental demyelination with small onion-bulb formation over time in untreated patients. The CMAP amplitudes are slightly decreased in the distal muscles of the hands and feet. The basis for the polyneuropathy is not known but is felt to be directly attributable to reduced glucose levels in neurons. In patients with hypothyroidism. Needle EMG reveals reduced recruitment with MUAPs suggesting chronic motor unit remodeling in the distal limb muscles. Both central (encephalopathy) and .1063 The most common form of peripheral nerve disease is carpal tunnel syndrome. Electrophysiologic Findings. Nerve biopsies in patients with generalized polyneuropathy are abnormal. small-amplitude potentials firing at rapid rates during low levels of force production (i.880.930.1210 A general reduction in large myelinated fibers may be seen.926 Fibrillation potentials and positive sharp waves often accompany these changes. as anticipated. depending on the amount of peripheral nerve reserve at the time of medical intervention.312. Histopathology. Histopathology. Motor nerve conduction velocities are normal or only mildly reduced.322.838. The little available information has shown a generalized reduction or absence in sensory nerve responses. Documentation of frank weakness is less common despite the concurrent complaint of sensory symptoms. Reduced sensation in a glove-and-stocking distribution is noted as well as reduced or absent ankle reflexes. Some investigators have suggested an associated anterior horn cell disorder. Patients are treated for the underlying cause of the hyperinsulinemia. When clinical and electrophysiologic studies are combined.346a. A reduction in myelinated and unmyelinated nerve fibers also is evident. there may be slightly prolonged distal latencies and slow motor conduction velocities. F-waves are prolonged in both upper and lower limbs. but pathologic evidence of this supposition is lacking. amplitudes of SNAPs.956. Electrophysiologic evaluation demonstrates evidence consistent with carpal tunnel syndrome. Needle EMG examination reveals variable degrees of fibrillation potentials and positive sharp waves.346a. Nerve conduction studies in patients with generalized polyneuropathy demonstrate reduced NEUROPATHIES ASSOCIATED WITH SYSTEMIC DISEASE UREMIC NEUROPATHY Clinical Features.817 Finally.681a.1210 Motor nerve conduction velocities are usually 70–80% of the lower limit of normal with mild prolongation of distal motor latencies. the neuropathy may be attributable to superimposed DM. or cauda equina compression. with some degree of reduction compared with normal mean values in most patients.838. Pathogenesis.e. The amplitudes of the CMAPs are usually normal.349.92621 There are insufficient long-term electrophysiologic studies to define resolution after appropriate medical intervention.943 Patients develop symmetric painful paresthesias and dysesthesias in both hands and feet. but by no more than 30% of the lower limit of normal.817 When SNAPs are obtainable.346a.943 In patients with a generalized neuropathy. has limited the number of patients available for detailed electrodiagnostic testing.817. characterized by reduced sensation and paresthesias beginning in the feet and progressing to the hands. polyradiculopathies.346a.681a.817 showing an increase in endoneurial and subperineurial connective tissue and an overall increase in the fascicular area. Electrophysiologic Findings. Electrophysiologic Findings.. Treatment.1306 These hypertrophic changes may render the nerve fibers more susceptible to pressure and trauma. In patients with myopathies.628 When present.679. as are H-reflexes in the lower limbs. There are a number of neuromuscular manifestations of acromegaly.956. given the overt muscle wasting. Treatment.551.1056 A proximal myopathy can be readily found in acromegalic patients with long-standing disease and lack of treatment (see Chapter 28).1062.817. However.1181 A generalized sensorimotor peripheral neuropathy. the SNAP amplitudes are reduced and may have mildly prolonged latencies.681a.349. evidence of carpal tunnel syndrome is noted in 82% of patients and a generalized sensorimotor peripheral neuropathy in 73% of patients. 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. Evidence of mild degrees of active axonal degeneration also can be found in some patients. the sensory conduction velocity is reduced. and this observation tends to be supported by electrodiagnostic findings (see below).551.

and when about 6 ml/minute is reached. The most common mononeuropathy in patients with chronic renal failure is carpal tunnel syndrome. In one study. Patients may note muscle cramps in the distal legs and occasional restless leg syndrome.959. which is normally catabolized by the healthy kidney. the adverse effects on the peripheral nervous system are minimal. and feet that are extremely sensitive to normally nonpainful stimuli. but these symptoms are most likely not related to the neuropathy. F-waves are usually absent or demonstrate delayed latencies. but according to one theory.632 Evidence of active axonal degeneration is more prominent in the distal than proximal regions of the peripheral nervous system. primarily because of ease of performance and relatively good intertrial reproducibility. even when the lower limb motor studies are considered normal. Segmental and paranodal demyelination also can be prominent but generally is believed to be a secondary result of axonal degeneration.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. a number of mononeuropathies can occur. the proximal nerve conduction does not appear to be as affected as the more distal segments.1298 Median and ulnar nerve conduction velocities tend to be abnormal later in the course of the disease process compared with lower limb conductions.1130 Motor conduction studies have been the mainstay of electrodiagnostic evaluation of uremic patients for years. because the distal muscles of the lower limbs are the first to demonstrate abnormalities. With disease progression. The primary pathophysiology of the uremic neuropathy remains unknown.121. nerve conduction studies become abnormal. In general.630. In addition to the sensorimotor peripheral neuropathy. particularly early in the course of the disease. The mean CMAP amplitudes for uremic patients are within the low normal range. Ischemic monomelic neuropathy.. The amplitudes become abnormal and eventually disappear in the lower limbs and decrease much later in the upper limbs. with particularly adverse consequences when deposited in the carpal tunnel about the transverse carpal ligament. affecting the median.538. Because of their general debilitation.227. When only short segments are used in patients with obvious clinical neuropathy.113. The Cuprophan membrane fails to remove completely a small ß2 microglobulin. the sural SNAPs were abnormal in 100% of patients examined.597 However.1057 Somatosensory evoked potential studies reveal slowing of neural conduction along both peripheral and central pathways. reduced recruitment becomes evident in the affected muscles. 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 transplant—an interval too brief for remyelination or axonal regeneration. soleus. tingling. When the tibialis anterior demonstrates easily obtainable membrane instability. as measured through F-waves and H-reflexes. and radial nerves.47.512. the electrophysiologic findings in uremic patients tend to follow the clinical symptoms and signs.713. Some patients display temporally dispersed SNAPs with an increase in phases. Positive sharp waves and fibrillation potentials of varying degrees are evident first in the foot intrinsic muscles and later in the gastrocnemius.Chapter 23 ACQUIRED NEUROPATHIES — 985 peripheral (peripheral neuropathy) nervous system abnormalities can result from renal failure. This syndrome is related to a particular type of hemodialysis instrument that uses a Cuprophan membrane. particularly large myelinated nerve fibers. provided good technique is used. much like AIDP. Some evidence suggests that as long as the glomerular filtration rate exceeds roughly 12 ml/minute.1292 . Studies using disparate methods have arrived at opposite conclusions—i. which may predispose patients to tissue damage. damage to the brachial plexus or peripheral nerves may result from improper limb positioning or traction. Patients usually complain of bilateral numbness. such as ulnar neuropathy at the elbow and peroneal nerve injury about the fibular head.118.1019 This discrepancy most likely results from a more diffuse metabolic process that is not detectable over the short nerve segments that are routinely used.350. Sural nerves in patients with generalized sensorimotor polyneuropathy demonstrate a loss of nerve fibers. Degeneration of the fasciculus gracilis at the cervical level also has been noted.958 A few patients may develop a clinical syndrome that is rapidly progressive.835. and sensory conduction velocities are slow.962 Most patients have either prolonged or absent H-reflexes.118. and distal latencies. The sural SNAPs are reduced in amplitude or. If mild disease is present. median and ulnar SNAP abnormalities are detectable with respect to conduction velocities. Whether the Schwann cell or the axon is the primary target of the essential metabolic or toxic abnormality in uremia is still debated. Pathogenesis.1410 Histopathology. Electrophysiologic Findings.273. A small number of patients also experience a reduction in the thermal threshold. 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. When present.3 In the upper limbs. At glomerular filtration rates below this value. and tibialis anterior muscles. especially the foot intrinsic muscles in early disease.4. Of interest. no difference and more proximal than distal slowing. may result from ischemia to the nerve(s) secondary to the creation of an arteriovenous shunt in the arm for dialysis.1123 Approximately 60% of patients with renal failure develop a peripheral neuropathy. again first in the lower and then with upper limb muscles. the intrinsic hand muscles begin to show the same abnormal potentials.216. There is some debate about whether the proximal portions of the peripheral nerves are affected to a greater degree than the distal aspects.1123 Physical examination demonstrates an early depression or abolition of the ankle reflexes with an accompanying reduction in the foot vibratory threshold.15 The lower limbs are more involved than the upper limbs. more commonly. especially as the neuropathy progresses.121. respectively. Proximal and distal muscles in the upper and lower limbs should be examined.974. and improves with an increase in renal dialysis or transplantation. several single-fiber investigations of uremic patients demonstrate that fiber density is relatively normal. motor nerve conductions still may vary to some degree. the distal latencies are prolonged. the proximal segments. Needle EMG findings support a generalized axonopathy. patients begin to demonstrate clinical signs of peripheral nerve dysfunction. During renal transplant surgery. Carpal tunnel syndrome is the end result of this form of amyloid accumulation.47.118 This substance forms a type of amyloid deposit throughout the body. unobtainable. amplitudes.785. 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.957. ulnar.e. appear to be preferentially involved. patients with renal failure are also prone to developing other mononeuropathies.

If CMAPs are present.654.114.1364b Histopathology. .978 Later (months to 1 year or more). 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.528a. basal ganglia. and increases in amplitude. and ataxic gait.1046 Patients with gluten intolerance can develop neurologic complications related to vitamin B12 or vitamin E deficiencies caused by malabsorption.986 — PART IV CLINICAL APPLICATIONS Essentially normal fiber density is an important finding because it implies that the peripheral nervous system’s compensatory mechanism of collateral sprouting is ineffective or inoperative. Patients complain of distal paresthesias and some loss of sensation associated with gait ataxia.1384 Generalized sensorimotor polyneuropathy. Spasticity and upper motor neuron weakness can be seen in patients with subacute combined degeneration related to vitamin B12 deficiency. results in a malabsorption syndrome (weight loss. when collateral sprouting is defective. the MUAP parameters (amplitude and duration) should not be as abnormal as in the more commonly observed axonal loss lesions. Romberg sign.696. The most likely pathologic insult to the peripheral nervous system is axonal degeneration of the large myelinated fibers. Severe ischemia resulting in infarction leads to delayed and incomplete recovery. After renal transplantation a biphasic mode of functional gains occurs.233. For this reason. even in nerves with significant amplitude reductions.528. Needle EMG demonstrates a marked reduction in MUAPs with abundant positive sharp waves and fibrillation potentials along with decreased recruitment. steatorrhea). Electrophysiologic Findings. Physical examination demonstrates a distal muscle weakness.528.822a. the electrophysiologic findings are commensurate with the degree of ischemic neural insult.111. Of course. Limited electrophysiologic data are available for celiac disease. This is the likely explanation for reduced motor CMAP amplitudes relatively early in the disease process compared with other neuropathies. Dementia can be seen in some patients. Furthermore.961. hemodialysis apparently has the ability to stabilize and prevent further peripheral nerve functional deterioration.239. 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. If treated early enough.1310 The median. electrodiagnostic findings are compatible with focal demyelination and/or axonal loss. 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.110.239. In patients with mononeuropathies.1384 The pathogenic basis for the neuropathy is unclear but may be autoimmune.528a. One case has been described with neuromyotonia. Individual entrapment neuropathies also may improve.1046 In patients with vitamin B12 or vitamin E deficiency. the ability of the peripheral neuromuscular system to repair itself is limited. 1046. 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. Laboratory Features. mononeuropathy multiplex. When hemodialysis is instituted. but based on the presumably reduced ability of muscle fibers to be reinnervated. Autopsy studies have revealed atrophy of the cerebellum with loss of Purkinje cells. (2) blunting and flattening of jejunal villi. in patients with profound axonal loss and significant muscle atrophy. Diagnosis of celiac disease is based on the documentation of (1) malabsorption. As axons are lost. Motor conduction studies demonstrate a mild reduction in the nerve conduction velocity with preservation of distal motor latencies and CMAP amplitudes. Conduction block may be seen as well. improvement probably results from functional axonal regrowth and reinnervation of previously denervated muscle fibers by collateral sprouting.978 Patients demonstrate an increase in both motor and sensory nerve conduction velocities. Median neuropathy at the wrist related to amyloid deposition in the form of ß2 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.112. segmental demyelination.1054 Surgical release is helpful in patients with carpal tunnel syndrome.113. and brainstem are also apparent.785. reductions in distal latencies. replacement therapy may improve or stabilize the neuropathy.696 Cortical atrophy and degeneration of neurons in the thalamus. Intolerance to gluten. the CMAP amplitudes drop because the remaining axons do not reinnervate the denervated fibers. SNAP amplitudes are important indicators of axonal loss because there is no compensatory mechanism to repair the lost axons. a protein found in wheat and wheat products. There are few detailed quantitative needle EMG examinations in uremic patients. Needle EMG examination can demonstrate features typical of any other type of axonal neuropathy. absent deep tendon reflexes. Nerve biopsy reports are conflicting with respect to axonal loss vs. which can be in a mononeuropathy multiplex pattern or generalized. Sensory conduction velocity is only mildly reduced. depending on the degree and duration of ischemia.654 Electrodiagnostic medicine evaluation reveals a significant reduction in the SNAP amplitude or complete absence of the SNAP. motor neuropathy.960 Some nerve conduction parameters may improve after hemodialysis over a short time incompatible with remyelination. and ulnar SNAPs may be absent or reduced in amplitude. abdominal distention. This assumption remains to be documented. and amplitude is a good indicator of the total number of functional axons.1255 The peripheral neuropathy and electrodiagnostic abnormalities also improve after a successful renal transplant. the distal motor latencies are relatively normal. The neuropathy may be secondary to malabsorption of vitamins B12 and E. and neuromyotonia have been reported. degeneration of the posterior columns and corticospinal tracts has been described.528 Treatment. Positive sharp waves and fibrillation potentials are difficult to detect and may disappear completely. The neuropathy does not appear to be responsive to a gluten-free diet. and (3) clinical and histologic improvement after the institution of a gluten-free diet.528a. indicating an ischemia-induced conduction block rather than peripheral nerve infarction. as are the conduction velocities. Pathogenesis. However.309. Anti-gliadin and anti-endomysial antibodies are often detected in the serum of patients with celiac disease. the peripheral neuropathy and nerve conduction studies may not necessarily improve. If the patient has sustained an ischemic monomelic neuropathy. Treatment. motor and sensory symptoms can resolve quickly. In addition. and only minimal to modest gains may be made. radial. GASTROINTESTINAL DISEASES Celiac Disease (Gluten-induced Enteropathy or Nontropical Sprue) Clinical Features. However. some patients have no appreciable vitamin deficiencies.

patients with inflammatory bowel disease can develop weakness secondary to myasthenia gravis or myositis (including polymyositis. however. the neuropathy may be caused by bacterial infiltration and subsequent inflammatory involvement of the peripheral nerves. In addition to neuropathy. AIDP. it is not known whether antibiotic treatment improves or arrests the progression of peripheral neuropathy. most patients have hepatic failure secondary to other disorders.994 Whether hepatic failure itself can cause peripheral neuropathy is unclear. Electrodiagnostic medicine evaluations have demonstrated a reduction in SNAP amplitudes as the major abnormality. diarrhea. and other systemic involvement. Quantitative sensory testing is abnormal in 62% of patients in large series. replacement therapy should be started.812 The clinical. However. Obviously more work needs to be done before we can conclude that liver failure is the direct cause of associated peripheral neuropathies. and periaortic lymph nodes. Patients develop progressive liver failure. Hepatitis B and C can cause mononeuropathy multiplex (secondary to vasculitis or cyroglobulinemia). polyneuropathy can complicate Crohn’s disease as well as ulcerative colitis and may manifest as AIDP. insomnia. other autoimmune neuromuscular disorders. Alcoholics may develop neuropathy secondary to the direct toxic effect of alcohol or because of nutritional deficiencies. or CIDP. CNS involvement can result in dementia. it would not be surprising to find a CIDP-like neuropathy in PBC because autoimmune disorders frequently occur together.812 LIVER DISEASE Chronic Liver Disease Patients with chronic liver disease from various causes can develop a mild. mesenteric. oromandibular myorhythmia.655. such as myasthenia gravis.1198 Sural nerve biopsies reveal both segmental demyelination and axonal loss. There have been no reports of peripheral nerve or muscle histopathology in patients with suspected neuropathy or myopathy. and granulomatous myositis). need to be considered. and myositis. 6 developed a peripheral neuropathy (3 AIDP. if a vitamin deficiency is documented. In a large series of 638 patients with inflammatory bowel disease.541. Furthermore. 939 brachial plexopathy. proximal muscle weakness on clinical examination suggested a superimposed myopathic process.266.1229 Associated symptoms and signs include fever and peripheral lymphadenopathy. including a polymorphonuclear response and periodic acid-Schiff (PAS)-positive macrophages. Alternatively. Muscle strength is typically normal.210 Autonomic testing reveals dysfunction in nearly 50% of patients.Chapter 23 ACQUIRED NEUROPATHIES — 987 Whipple’s Disease Whipple’s disease is a rare disorder characterized by abdominal pain. Small bowel mucosa has PAS-positive macrophages containing the bacilli Tropheryma whippeli. Histopathology. generalized sensorimotor peripheral neuropathy characterized by numbness. malabsorption weight loss. Chloramphenicol and trimethoprim-sulphamethoxazone are efficacious in the treatment of CNS disease associated with Whipple’s disease. Single-fiber EMG failed to demonstrate significant abnormalities. demonstrated short-duration. it may result from malabsorption of necessary vitamins. Both disorders are thought to have an immunologic basis and are associated with various neurologic abnormalities. Liver function tests are obviously elevated. .1450 generalized axonal sensorimotor polyneuropathy. along with diminished proprioception.230. that can cause peripheral neuropathies. 1 mononeuropathy multiplex. The proximal muscles.210. The organism also can be identified in the CNS. histologic.812 All of the patients with neuropathy had ulcerative colitis. and polydipsia have been described.706.607. 1 bibrachial plexopathy. Motor nerve conduction studies are usually normal. Although documentation is poor. Treatment.712.1046. with some prolongation of sensory and motor distal latencies. whippeli.190. Some patients develop a sensorimotor polyneuropathy.471. laboratory.202. low-amplitude potentials consistent with a myopathic process. especially prominent in the lower limbs. including peripheral neuropathy. A detailed electrodiagnostic medicine report of a single patient with Whipple’s disease revealed evidence of a sensorimotor peripheral neuropathy.595. Antimitochondrial antibodies can be detected in the sera of some patients. and electrophysiologic features of the specific types of peripheral neuropathies associated with inflammatory bowel disorders are no different from the idiopathic forms.210. Intestinal mucosal changes lead to malabsorption. Obviously. Pain and temperature perception can be diminished to a minor degree in the most distal aspects of the limbs.266 Laboratory Features. accompanied by enlargement of the celiac. convergence nystagmus. T. Electrophysiologic Findings. Rarely.1046 MRI scan of the brain can reveal signal changes correlating with the sites of pathologic involvement and gadolinium enhancement suggestive of ependymitis. 1 recurrent facial nerve palsy). Although the pathogenic basis of the neuropathy is not known. hyperphagia. which yielded evidence suggestive of conduction block. Patients with PBC can develop a peripheral neuropathy characterized by distal numbness and tingling.1046 Because of the rarity of PNS involvement. arthralgias. Laboratory Features. Supranuclear ophthalmoparesis.812 and cranial neuropathies. EBV-related hepatitis can be associated with AIDP. Similar findings were noted for the motor nerves with the exception of the peroneal nerve. Inflammatory Bowel Disease Inflammatory bowel disease refers to ulcerative colitis and Crohn’s disease. Lambert-Eaton syndrome. Sensory nerve conduction revealed reduced SNAP amplitudes with mild impairment of conduction velocities.812 multiple mononeuropathies. The CSF examination in patients with CNS involvement typically demonstrate inflammatory changes.266 Additionally. which is often fatal. dermatomyositis. Toxins that could damage peripheral nerves may accumulate as a result of liver disease. myoclonus. tingling. Needle EMG examination demonstrated a reduced recruitment pattern distally with positive sharp waves and fibrillation potentials.73. and minor weakness primarily in the distal aspects of the lower limbs. Pathogenesis. Primary biliary cirrhosis (PBC) is an autoimmune disorder directed against the biliary ducts in the liver.210. However. patients exhibit proximal weakness and atrophy suggestive of a myopathic process. Primary Biliary Cirrhosis Clinical Features. Deep tendon reflexes may be reduced or absent.820 Physical examination demonstrates a reduced ability to perceive touch and vibration. Whipple’s disease is caused by a gram-positive actinomycete. When weakness is present. with cooling thresholds more abnormal than vibratory thresholds. such as alcoholism or viral hepatitis. although needle EMG examinations have not been well described.812.

patients with gout may develop a sensorimotor peripheral neuropathy preferentially localized to the lower limbs or neural entrapments at the wrist and elbow. it can be quite difficult to distinguish these disorders. Burn patients also may develop the complete critical illness polyneuropathy described above. The electrophysiologic and histopathologic findings support the clinical impression of a primary sensory neuropathy. Pathogenesis. 87% of patients with chronic obstructive pulmonary disease had electrophysiologic evidence of a subclinical sensorimotor peripheral neuropathy.1424 However. 17% of patients had needle EMG evidence of axonal loss as demonstrated by a combination of positive sharp waves.754. An electrodiagnostic medicine examination in critical care units is usually fraught with technical difficulties secondary to interference from multiple lifesaving and monitoring equipment. Electrophysiologic Features. Critical illness polyneuropathy occurs in patients in the ICU with sepsis and multiple organ failure.1099. loss of dorsal root ganglion cells. ultimately. whereas those in the upper limbs reveal reduced amplitudes with mild alterations of conduction velocity or distal latencies. weakness in critically ill patients in the ICU setting121a. fibrillation potentials. scattered muscle fiber necrosis and increased central nuclei. whereas in AIDP and CIDP in CSF protein is usually significantly increased. In addition. which are nonspecific myopathic features. The cause of peripheral nerve damage is unknown.1100 In the largest series involving 88 patients who developed weakness in the ICU.310.116. Patients may develop a mononeuropathy multiplex (69% of patients in one series). morbidity and mortality appear to be similar in critical illness neuropathy and critical illness myopathy. prolonged neuromuscular blockade. Histopathology. radial. prolonged neuromuscular blockade occurred in only one patient. Similar findings are noted for motor nerve studies. the elevated serum CKs may be secondary to critical illness myopathy rather than critical illness neuropathy. some patients have increased serum creatine kinase (CK) levels. 13%). Deep tendon reflexes are depressed in the upper limbs and absent in the lower limbs.76 From a clinical and electrophysiologic standpoint.572. The pathogenic basis of critical illness neuropathy is not clear. CRITICAL ILLNESS POLYNEUROPATHY As opposed to AIDP and myasthenia gravis. Nerve biopsy demonstrates a reduction in the large myelinated fibers without evidence of segmental demyelination.752–754. CSF is usually normal or only mildly elevated. Additional findings of long-duration. Nerve biopsies reveal significant axonal degeneration with little demyelination. although mild facial weakness may occur. ulnar. liver transplantation. Additionally. The motor conduction and needle EMG portions of the evaluation are normal.116. GOUT Rarely.1451 Electrophysiologic Features. Electrodiagnostic medicine evaluation demonstrates reduced or absent SNAPs.385 Only 17% of the total study population had clinical findings suggestive of a peripheral neuropathy. who also had AQM. AQM is usually associated with necrotic fibers and loss of myosin thick filaments.117. muscle strength recovers slowly over several months.988 — PART IV CLINICAL APPLICATIONS Histopathology. Nevertheless. possibly secondary to vascular insult of the vasa nervora. Physical examination can reveal a wide-based gait with a positive Romberg sign.1000. the neuropathy may be related to unknown toxins that accumulate as a result of liver failure. a loss of about one grade of strength may be documented in the distal lower limb muscles. see Chapter 28).1449a.1451 or critical illness myopathy (also known as acute quadriplegic myopathy [AQM].1451 Autopsies have demonstrated chromatolysis of anterior horn cells.1451 However. Deep tendon reflexes are absent or reduced. Neurologic examination can be limited by encephalopathy related to sepsis and organ failure. and peroneal nerves can result from poorly applied compression dressings or malpositioning of limbs. and reduced recruitment of MUAPs.833 Delayed paraparesis may result from electrical injuries (see Chapter 16).1452 or.1451 Of note. and axonal degeneration of motor and sensory nerves.1451 Muscle biopsies show grouped atrophy and targetoid fibers suggestive of acute neurogenic process. which are the most common neuromuscular causes for admission to intensive care units (ICU). also have been noted.776. Critical illness neuropathy was more common than critical illness myopathy in some series of ICU patients. CHRONIC OBSTRUCTIVE PULMONARY DISEASE In a single study. critical illness myopathy was three times as common as critical illness neuropathy (42% vs.754 In patients who survive the underlying sepsis and multiorgan failure.1424. Needle EMG studies have not been detailed in patients with gouty neuropathy. other institutions and the authors’ own anecdotal experiences suggest that critical illness myopathy is more common than critical illness neuropathy. One can speculate that circulating toxins and metabolic abnormalities associated with sepsis and multiorgan failure lead to axonal degeneration of the peripheral nerves.1451 However. high-amplitude potentials suggested chronic disease with motor unit remodeling.776.1449a. respiratory muscle involvement is prominent.115.1100. much less commonly. Sensory nerve conductions in the lower limbs can be absent. generalized weakness of the limb muscles can be appreciated.117.1185.174.115. It is often difficult to ascertain the degree of sensory loss and modalities if the patient’s mental status is altered. Decreased sensation to all modalities can be observed in the legs. PBC is treated with immunosuppressive therapy and.570. Pathogenesis. which were attributed to myocardial infarction in some cases.710 Laboratory Features. 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.1424.312a usually is secondary to critical illness polyneuropathy.776. perhaps by interfering with axonal transport mechanisms or mitochondrial function.1414.754 From a practical standpoint. Cranial nerve musculature is usually comparatively well preserved. As noted above.1164 Focal neuropathies of the median.121a. The neuropathy may have an immunological basis.833 A generalized sensorimotor peripheral neuropathy that is less severe than critical illness polyneuropathy may occur in 6–52% of burn patients . Whether transplantation affects the peripheral neuropathy has not been adequately addressed. units are located .569.308 Patients with peripheral neuropathies may complain of progressive loss of sensation in the feet with difficulty in walking. Clinical Features. Despite a lack of overt muscle atrophy.312a.1451 The peripheral neuropathy is often first suspected when the patient cannot be weaned from a ventilator. Treatment. Similarly.

604. the latencies are normal or only mildly prolonged. However.24 Estimating the frequency of peripheral neuropathies associated with malignancies is difficult because the frequency depends on a number of factors. both the neCMAP and dmCMAP would be expected to be very low.1099. the disorder is also called a ganglionopathy. If the SNAPs amplitudes are normal or only slightly reduced in comparison with loss of CMAP amplitudes. a large control group is needed to confirm the statistical value of this ratio. then stabilizes.1291. ovaries.7–5.192.382. if the muscle membrane excitability is reduced.919 Peripheral neuropathy is most common in carcinoma of the lung but also is associated with carcinoma of the breast.192 The onset can be acute or insidiously progressive. it is not unusal to be unable to recruit MUAPs.1151.24. discussion of the recruitment pattern often has been neglected.259. We obtain a chest CT scan. and other organs.1 or less) in a neuropathy or neuromuscular junction disorder.784. diabetes mellitus). Diminished touch.801 Furthermore. clinically evident peripheral neuropathy has been reported in 1. if one sees early recruitment of small-duration. The neuropathy generally evolves over a few months. AQM should be considered.263 The predominant symptoms—numbness.116. Paraneoplastic Sensory Neuronopathy/Ganglionopathy Clinical Features. the sensory conduction velocities are normal or only mildly reduced.115.1324.491–493.26. Despite these adverse conditions.121a. but when they are present. thus predisposing recording of electrical signals from radio and television stations. dysesthesia.874. they are often small and polyphasic in morphology. ovaries. nerve conduction studies have demonstrated peripheral neuropathy in 30–40% of patients with cancer. Deep tendon reflexes are diminished or absent.1313. the diagnosis of critical illness myopathy or motor axonal neuropathy must be considered. radiation.1435 These neuropathies result from indirect carcinomatous insult to the peripheral nervous system. F-waves may be unobtainable.191.1100 Direct muscle stimulation bypasses the distal motor nerve and neuromuscular junction. but the muscle weakness may be more related to the superimposed myopathy. good technique can demonstrates significant abnormalities in patients with critical illness polyneuropathy. Increased jitter on single-fiber EMG has also been noted. myopathic. including the type. Repetitive stimulation studies fail to reveal electrophysiologic evidence of neuromuscular junction failure. or the SNAPs may be abnormal secondary to an underlying condition (e.1424. 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.117. Direct muscle stimulation has been advocated to help distinguish critical illness neuropathy from myopathy. When MUAPs are recruited. but cases associated with carcinoma of the esophagus. polyphasic MUAPs. colon.262. bone marrow transplantation). When SNAPs are recordable.1264 PARANEOPLASTIC NEUROPATHIES The remote effects of carcinoma on the peripheral nervous system (so-called paraneoplastic neuropathies) are quite diverse. One would expect to see decreased recruitment of small MUAPs in a neurogenic process.876. as in AQM. mammogram. Symptoms begin in the arms in over 60% and are asymmetric in approximately 40% of cases. Symptoms of the neuropathy may precede symptoms of the cancer by several months or years. and antineuronal nuclear antibodies (anti-Hu) for all patients in addition to performing a complete physical examination.493.1313 of patients with malignancy. The SNAPs also should be significantly diminished in amplitude or absent.1414. or neuromuscular junction defect. In a neuropathic process or prolonged neuromuscular blockade. and the direct muscle stimulation CMAP (dmCMAP) theoretically should be near normal despite a low or absent nerve stimulation-evoked CMAP (neCMAP). Phrenic nerve studies often reveal absence or reduction of the diaphragm’s CMAP amplitude. and location of the cancer. Alterations in mental status.262. low-amplitude SNAPs do not necessarily imply that the patient’s weakness is secondary to critical illness neuropathy. duration of disease. and the distal sensory latencies are normal or only slightly prolonged. degree of malnutrition. Small cell lungcarcinoma (SCLC) is the most commonly associated malignancy. stomach.. Discovery of a sensory neuronopathy should lead to an aggressive evaluation for an underlying malignancy.1232. including the lymphoproliferative system. thus SNAPs would be abnormal.262. and cranial nerve abnormalities occur in about twothirds of patients as a result of a superimposed paraneoplastic encephalomyelitis.24. However. (2) a remote or paraneoplastic effect. In contrast.1366 The disorder is rare and most commonly affects women in late-middle life (mean age of onset: 59 years). In patients with severe weakness. Motor nerve conduction velocity and distal motor latency are normal or only slightly abnormal.172. and quantitative sensory testing can detect peripheral neuropathy in 12%. pelvic CT.283.312a. breast.1185 but increased jitter can be caused by remodeling of the motor terminal due to a neuropathic. (3) or an iatrogenic effect of treatment (chemotherapy. stage. There is no specific therapy for critical illness neuropathy other than supportive care and treatment of the underlying sepsis and organ failure. Of importance.602 Although most cases of sensory neuronopathy have only sensory abnormalities. rectum.312 Because the site of the lesion is at the level of the sensory cell body. Needle EMG examination reveals profuse positive sharp waves and fibrillation potentials.602.564.1449a.Chapter 23 ACQUIRED NEUROPATHIES — 989 on the upper floors of the hospital.1100 However. Patients with critical illness myopathy may have an age-related decrease in SNAP amplitudes. Unfortunately. immunosuppression. These small units have been attributed to early reinnervation. Rich and colleagues suggest that the ratio of neCMAP to dmCMAP should be close to 1:1 (> 0. patients may have a mixture of critical illness neuropathy and myopathy. not from direct nerve infiltration or compression. the muscle membranes should retain excitability. Furthermore. autonomic dysfunction. pinpoint. and neurotoxic effects of various therapies. .1185.g. Treatment.876. Subacute sensory neuronopathy was the first neuropathy described as a complication of carcinoma.876.261.5%261. and kidney and lymphoma also have been reported.776.1099.1183.261. There is no conduction block or increased temporal dispersion.1451 CMAPs are profoundly reduced in amplitude or absent. and paresthesia—begin distally and spread proximally. and temperature sensation and prominent loss of vibratory and position sense result in sensory ataxia and pseudoathetosis.163.580. mild weakness is occasionally evident and may reflect an associated sensorimotor neuropathy or a superimposed myasthenic (Lambert-Eaton) syndrome.9) in a disorder of muscle membrane inexcitability and approach zero (0.

Paraneoplastic Autonomic Neuropathy Autonomic dysfunction can occur as an isolated disturbance or as part of the spectrum of the anti-Hu–associated encephalomyelitis-neuropathy syndrome.283.172. ovary. whereas 10 seconds of exercise or fast rates of repetitive stimulation (20–50 Hz) may demonstrate facilitation of CMAP amplitudes. The cause of the neuronopathy is unclear. The CMAP amplitudes may be reduced in the intrinsic muscles of the hands and feet. but rarely—in widespread cases—the distinction may be difficult. decreased recruitment. can be demonstrated in serum and CSF in patients with small cell carcinoma of the lung complicated by paraneoplastic sensory or sensorimotor polyneuropathy.1435 Sensory nerve conduction studies show absent or low-amplitude SNAPs with normal or borderline-slowing conduction velocities and slightly prolonged distal latencies. in which sural SNAPs are affected earlier and more severely than upper limb SNAPs. the cause of sensory or sensorimotor polyneuropathy complicating cancer remains unknown or idiopathic. CSF may be normal or demonstrate mild lymphocytic pleocytosis and elevated protein.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.492 The antibodies are directed against a 35–40 kD nuclear protein and are highly specific for SCLC. Perhaps an antigenic similarity between proteins in tumor cells and neuron cells leads to an immune response directed against both. Some patients with subclinical motor nerve involvement may have a few positive sharp waves and fibrillation potentials in the distal limb musculature. and kidneys.1307. and phases).777 CRYPTOGENIC SENSORY OR SENSORIMOTOR POLYNEUROPATHY Clinical Features. Motor conduction studies reveal low normal or mildly slowed velocities.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. but many patients have motor involvement.214. mild weakness is evident in many patients.876. This feature suggests a ganglionopathy as opposed to the much more common length-dependent axonopathies.564. pancreatic malignancy. Of importance. Pathologic features of the disease include inflammation and degeneration of the dorsal root ganglia with secondary degeneration of sensory neurons and the posterior columns. 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. The distal motor latencies can be mildly prolonged. and fibrillation potentials and positive sharp waves of varying degrees. Perhaps an immune response is directed at both sensory and motor components of peripheral nerves. with low rates of repetitive stimulation (2–3 Hz). encephalitis. Nerve conduction studies in pure sensory neuronopathy reveal low-amplitude or absent SNAPs with normal CMAPs.1291. Electrophysiologic Findings. In a study of 71 patients with anti-Hu–associated encephalomyelitis-sensory neuronopathy syndrome.and T-lymphocytes. dry eyes and mouth. In particular.639. variability in MUAP morphology and increased jitter may be seen in patients with superimposed Lambert-Eaton syndrome.491.1366 Electrophysiologic Findings.262. distal.52 Motor conduction studies are normal in pure sensory neuronopathies. low-amplitude CMAPs. is actually uncommon.1313. Treatment. Needle EMG findings usually are normal. intestinal pseudo-obstruction. A paraneoplastic basis for the sensorimotor polyneuropathy. kidney.602 Type 1 antineuronal nuclear antibodies (ANNA-1). and 28% had varying degrees of dysautonomia during the course of the illness. Sensorimotor polyneuropathies also may have an immunologic pathogenesis as part of a paraneoplastic syndrome. symmetric numbness. Needle EMG examination may reveal evidence of long-standing motor unit remodeling (increased MUAP amplitudes.1357.491.1313. The neuropathy in most patients manifests clinically with slowly progressive.283. In most cases.558.172. beginning in .263.262. 10% presented with severe orthostatic hypotension. endometrium.262. constipation.846. Furthermore. the SNAPs can be asymmetrically affected. Treatment of the underlying cancer may prolong survival but generally does not affect the course of the underlying neuronopathy.602 A small reduction in the sensory conduction velocity may result from loss of large myelinated nerve fibers. testes.24 From a clinical and electrophysiologic standpoint. although often suspected. and cerebellar degeneration.194 The inflammatory infiltrate is comprised of both B.985.283. some patients have superimposed Lambert-Eaton syndrome.1430 Histopathology.580.491. Blink and masseter reflexes are generally normal.1127.26.283.1245 The autonomic neuropathy may manifest as orthostatic hypotension. Furthermore. 876.26. durations. Although sensory symptoms predominate in the paraneoplastic anti-Hu syndrome. prostate.1435 Perivascular inflammation as well as changes due to necrotizing vasculitis have been described within peripheral nerves. and pupillary dysfunction. it is usually easy to distinguish neuropathy caused by direct tumor infiltration from a paraneoplastic or idiopathic variant by its local character. Pathogenesis.564. Paraneoplastic Sensorimotor Polyneuropathy Clinical features. Thus. The pathogenic basis of the neuropathy is not known.443. Cryptogenic sensory or sensorimotor polyneuropathy complicating cancer is much more common than paraneoplastic neuropathies. one can see abnormal SNAPs in the hand when they are normal in the legs. Sural nerve biopsies may demonstrate perivascular inflammation. also known as anti-Hu.283.26. and Hodgkin’s lymphoma. urinary retention. and gastrointestinal tract. Patients with a generalized sensorimotor peripheral neuropathy demonstrate findings consistent with the above histopathologic observations. testicular cancer.564 The polyneuropathy is more common in patients with SCLC but also can complicate carcinoma of the breast.580. and adenocarcinoma of the lungs. reflecting clinical involvement.283 Remission after treatment of the tumor is rare.51.1366 Pathogenesis.283 Multiple mononeuropathies attributed to paraneoplastic vasculitis are described in patients with lymphoma.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.1214. uterus.453.1291. autopsies reveal degeneration and inflammation involving neurons in the brainstem and limbic system.24. The causes of sensorimotor neuropathy in malignancy is multifactorial. SCLC.739.629 In addition. can reveal a decrement.777.990 — PART IV CLINICAL APPLICATIONS Laboratory Features. Histopathology. Lennon reported autoantibodies directed against a nuclear antigen of myenteric neurons in patients with this syndrome.

revealing increased protein.24.1364 The CNS and skin are the most common sites of involvement. Nerve conduction studies demonstrate features of a length-dependent.263. the response rate is much lower in other types of tumors. polyradiculopathies. Lymphomatoid granulomatosis is an angiocentric. Multiple cranial neuropathies may result from spread of a local tumor (i.1418 There is a predisposition for evolution into lymphoma. Electrophysiologic Findings. where divisions of the lower trunk of the brachial plexus are located. occuring in approximately 85% of patients. axonal. mononeuropathy multiplex. Cancers in the apices of the lungs may grow into the paravertebral space and posterior chest wall and invade the extraspinal C8–T3 mixed spinal nerves.24. Symmetric peripheral neuropathy is unusual but has been described. There is no specific treatment for the neuropathy other than treating the underlying malignancy and maintaining adequate nutrition.256 The neuropathy may respond to corticosteroids and treatment of the underlying leukemia.263. distal latencies and conduction velocities of motor and sensory nerves are normal or only slightly prolonged or slow. Cranial Neuropathies and Radiculopathies Almost any type of cancer has the potential to invade the leptomeninges. and nerve roots. or chronic progressive. The most common symptom. polyradiculopathy. It may take several weeks for evidence of active denervation to appear on EMG. Patients with leukemia and lymphoma may respond to irradiation and intrathecal chemotherapy. metastatic tumor was responsible for the plexopathy in 78%. plexopathy. EMG may reveal mild denervation changes distally. Approximately 24% of patients have involvement of the spinal cord or roots. that occur with malignancies may be responsible for the neuropathy. a sensory or sensorimotor polyneuropathy can occur in untreated people with cancer.725. Electrophysiologic studies suggest an axonopathy.876.e. fifth.312.” characterized by numbness of the lower lip and chin. Histopathology. peripheral neuropathy may be the presenting clinical manifestation of leukemia or lymphoma or the heralding feature of a relapse.876 Metabolic disturbances. Pancoast tumor).443. The sixth and fifth cranial nerves are most commonly affected in nasopharyngiomas.262. CSF may be abnormal. However. and segmental demyelination. cranial nerves. followed by the third. and the stellate ganglia (see Chapter 19). MRI with gadolinium may demonstrate enhancement or compression of the nerve roots by the tumor. such as an alteration in protein and fat metabolism.24 The onset and course of the neuropathy can be acute.786 Intravascular vascular and endoneurial lymphocytic infiltration (primarily B-cells) is evident on nerve biopsy. with the possible exception of breast cancer.1403 Mononeuropathy or mononeuropathy multiplex may result from hemorrhage or leukemic infiltration into cranial or peripheral nerves and spinal roots. nasopharyngioma) or by metastasis.1068. Angiotrophic largecell lymphoma is a rare malignancy characterized by intravascular .1313 Sensory studies reveal decreased or absent sensory nerve action potentials. or even generalized symmetric distal or proximal and distal polyneuropathy. which are driven by Epstein-Barr infected T-cells. sensory or sensorimotor polyneuropathy. Deep tendon reflexes are diminished or absent distally.262. an increased cell count. are well documented. Brachial Plexopathy Damage to the brachial plexus usually results from metastasis.Chapter 23 ACQUIRED NEUROPATHIES — 991 the feet and later progressing to the hands. Widespread involvement can mimic a generalized sensorimotor polyneuropathy.876 Pathogenesis. Laboratory Features. lymphoid B-cells.g. immunoproliferative disorder with a pleomorphic lymphoid infiltrate of blood vessels.. Nerve biopsies can demonstrate leukemic infiltration of the nerve.1362. There are no specific laboratory abnormalities. and hypo.717 The most common tumors are lung or breast carcinomas. mononeuropathy multiplex. Leukemia. the peripheral nerves can be invaded directly by the tumor. Distal symmetric polyneuropathy. Upper motor neuron dysfunction can also occur. and malignant cytology. subacute.24.24 In a series of 100 patients with cancer and brachial plexopathy. whereas the sixth cranial nerve. Nerve biopsies and post-mortem tissue analysis most commonly reveal axonal degeneration and regeneration. which may somehow result in axonal degeneration. and 5% have mononeuropathies. but the prominent sensory ataxia that is seen in sensory neuronopathies is generally not observed. but segmental demyelination and remyelination have been reported. proliferation of large.261. weakness. Although various chemotherapies are toxic to peripheral nerves. Electrophysiologic features are consistent with an axonal sensorimotor polyneuropathy. and chronic sensorimotor polyneuropathies complicating chronic leukemia. and cranial neuropathies occur in 10–15% of patients. but patients may not appear cachectic or malnourished when neuropathy initially manifests.662.1269. malignant cells are absent in the peripheral blood or lymphoid tissues. axonal degeneration. or radiation-induced injury. Treatment. particularly leukemia and lymphoma.168. Of importance. Acute.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..24 Polyradiculopathy due to malignant invasion of the nerve roots manifests as radicular pain and sensory loss. is pain in the shoulder area that radiates into the NEUROPATHIES RELATED TO TUMOR INFILTRATION Mononeuropathy Multiplex Occasionally. Vasculitis also has been suggested as a cause of peripheral neuropathy in hairy cell leukemia. resulting in mononeuropathy. atypical. Compound muscles action potentials are normal or only mildly reduced in amplitude. is particularly worrisome for malignant invasion of the mental or alveolar branches of the mandibular nerve. Mild distal weakness of the distal lower and upper limbs may be noted. and seventh. The cancer most often spreads via the lymphatics to the region of the lateral group of axillary lymph nodes. Peripheral neuropathy has been reported in up to 5.5% of cases of leukemia. is most commonly affected in metastatic processes. vitamin supplementation is of no benefit. if the spinal cord is compressed. regional spread of a local tumor (e.24 The infiltrate is composed of reactive T-cells.876 The pathogenesis may be related to toxic factors released by the tumor. The pathogenic basis is not known.786. The so-called “numb chin syndrome. Of note.1134. Weight loss frequently accompanies malignancies. subacute.1313 Furthermore. the sympathetic chain.558 Angiotrophic Large-cell Lymphoma. Likewise. Asymetrically prolonged or absent F-waves may be a sensitive early indicator of nerve root involvement. especially chronic lymphocytic leukemia.876.564 All sensory modalities can be affected.or areflexia. Lymphomatoid Granulomatosis.

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. but the relationship between neuropathy. the absence of myokymia doses not exclude radiation plexopathy. sarcoma. A few patients have lymphedema of the affected arm.885 Antibodies directed against myelin-associated glycoprotein (anti-MAG) are present in at least 50% of patients with IgM monoclonal gammopathies and peripheral neuropathies. what role.803. bone marrow biopsy and aspirate. Incontinence or impotence develops in less than 10% of patients. The lumbar plexus is involved in 31%. and the entire lumbosacral plexus in 18% of patients with malignant invasion of the plexus. lymphoma. and surgical exploration and biopsy are required for definitive diagnosis. Bowel and bladder incontinence may result from radiation-induced proctitis or cystitis.170. Sensory loss and weakness are usually present in the distribution of the lower trunk.768. the lumbosacral trunk in 51%. suggest epidural extension of the tumor. Serum protein electrophoresis (SPEP) is a useful screening test. there is usualy no notable improvement in strength. and diffuse plexus involvement is seen in 23% of patients. At times noninvasive testing cannot differentiate between metastatic and radiation disease.5% of patients with peripheral neuropathies secondary to other diseases. Both lower limbs are typically involved.877 However. along with hematologic studies.1361 If a monoclonal gammopathy is detected.704. weakness. pain is present in only one-half of patients and typically is not as severe.24 NONINFILTRATIVE PERIPHERAL NEUROPATHIES ASSOCIATED WITH LYMPHOPROLIFERATIVE DISORDERS AND MONOCLONAL GAMMOPATHIES Neuropathies associated with monoclonal gammopathies are discussed under immune-mediated neuropathies. other studies have reported that the entire plexus is more commonly involved than just the upper trunk.1064. monoclonal gammopathies. if any. sympathetic blockage. In IgA and IgG monoclonal gammopathies. and malignancy deserves further comment. and breast cancers.1381 Sensorimotor neuropathy can complicate both Hodgkin’s disease (HD) and nonHodgkin’s lymphoma (NHL). However. or dorsal rhizotomies has been disappointing.669. no underlying disease is found. Paresthesias and lymphedema are present in 55% and 45% of patients.270. at times.1269.768 However. numbness. Signs and symptoms attributable to involvement of the upper and middle trunk of the brachial plexus are much less common and.1064 Lymphoma Clinical Features. Myokymia is evident in over 50% of patients with radiation-induced lumbosacral radiculoplexopathy. immunoglobulin deposition is generally not seen on nerve sheaths. and a causal link is much less established. because a small monoclonal protein may not be apparent. Although myokymic discharges on EMG are highly suggestive of radiation-induced damage. multiple myeloma. cryoglobulinemia. The presence of monoclonal gammopathies should lead to an aggressive work-up for amyloidosis. osteosclerotic myeloma.270. these antibodies play in the pathogenesis of peripheral neuropathies is unknown.671.1368 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. urine protein electrophoresis and immunoelectrophoresis should be performed.383. All patients with peripheral neuropathies of unknown etiology should be tested for the presence of monoclonal gammopathies.916 MRI or CT scan may demonstrate malignant invasion of the plexus and perhaps extension to the epidural space.921. 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.1151 or motor1183 .816. The upper plexus is involved in 77%. Bilateral lower limbs are involved in approximately 25% of cases.768.921 but more commonly occurs as a remote effect of the cancer.620 The most comon tumors are colorectal.1381 The incidence of peripheral neuropathy is generally thought to be lower in patients with lymphoma (approximately 1–2%) than in patients with SCLC.262.727. such patients are designated as having a monoclonal gammopathies of undetermined significance (MGUS). and lymphoma. Serum IEP or IFE should be performed to identify the nature of monoclonal proteins and in patients suspected of having a myeloproliferative disorder. extension of the tumor into the epidural space. Neuropathy in patients with lymphoma may be secondary to direct endoneurial infiltration or direct compression of nerves by lymphoma24.747. pain occurs in only 15% of patients and usually is not as severe. Waldenström’s macroglobulinemia. In most patients with monoclonal gammopathies. 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%).24 Unlike plexopathy secondary to tumor invasion. EMG reveals fibrillation potentials in the paraspinal muscles in approximately 50% of patients with radiation-induced damage. Horner’s syndrome due to involvement of the sympathetic chain or stellate ganglia is evident in most patients. leukemia. when present. An increased incidence of monoclonal gammopathies has been observed in patients with peripheral neuropathy. respectively. 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.24. Neoplastic invasion of the brachial plexus can be treated with radiation therapy.661.702.877.921. although asymmetrically. Although patients may experience pain relief. even with a normal SPEP.123. cervical. a prospective study reported clinically evident neuropathy in 8% and electrophysiologic evidence of neuropathy in 35% of patients with lymphoma. MRI or CT of the lumbosacral spine and pelvis can demonstrate tumor invasion of the lumbosacral plexus and. The neuropathy may be purely sensory602. Radiation-induced lumbosacral plexopathy manifests 1–31 years (mean: 5 years) after completion of treatment as slowly progressive weakness.768 In addition.803.1381 The clinical presentation is variable.668. suggesting the disorder is more appropriately termed a radiation radiculoplexopathy. Treatment of the pain with transcutaneuous stimulation.620 Patients present with insidious onset of pain.717 Unlike metatastatic plexopathy.992 — PART IV CLINICAL APPLICATIONS medial aspect of the arm and the fourth and fifth digits of the hand. peripheral neuropathies may be more common in patients with monoclonal gammopathies than in the general population.767. and edema of the lower limb. and a radiographic skeletal survey. and distal muscles are affected more than proximal muscles. but it is not as sensitive as immunoelectrophoresis (IEP) or immunofixation (IFE). About 10% of patients with idiopathic peripheral neuropathies have monoclonal gammopathies compared with 2.744.

Likewise. Nerve conduction studies reveal low-amplitude or absent SNAPs with normal or only mildly abnormal distal latencies and conduction velocities. and weakness of the distal lower limbs.1381 It may be symmetric. The most common cause is primary amyloidosis with infiltration of the nerves. Skeletal survey typically reveals osteolytic lesions.702. Diagnosis of multiple myeloma requires the demonstration of at least 10% plasmacytes on a bone marrow biopsy. Osteosclerotic myeloma occurs in less than 3% of patients with myeloma.295. anemia. Electrophysiologic Findings.1269 chronic progressive.702. Monoclonal gammopathy. CMAP amplitudes are reduced in patients with weakness.992.667.1380 Less frequently. Osteosclerotic Myeloma (POEMS Syndrome) Clinical Features. ascitis. or multifocal.877. The lower limbs have more profound changes than the upper limbs.1380 Most patients have a distal.1380 Figure 23-9. nerve biopsies reveal prominent axonal degeneration along with mild segmental demyelination/remyelination consistent with reinnervation.262. The sensory modalities mediated by large fibers are most affected. testicular atrophy with impotence in men. However. Recruitment of long-duration..667 Others may be due to the metabolic or toxic effects of the systemic consequences of multiple myeloma or amyloidosis (e. Some patients can have POEMS syndrome without osteosclerotic myeloma. In addition.921. Monoclonal proteins consisting of γ or µ heavy chains or κ light chains are usually identified in the serum or urine.877.670 Systemic manifestations are common and include hepatosplenomegaly.921 Laboratory Features. (Paraffin section.702 In up to 20% of patients. rectal. and hypercalcemia. Amyloid deposition may be responsible for up to two-thirds of neuropathies in patients with multiple myeloma. Organomegaly. These alterations are bilateral and symmetric.748.1269 subacute. Many patients are anemic.1381 or relapsing and remitting. indicating possible subclinical peripheral neuropathy. including interleukin (IL)-1β. Skin changes) (Table 23-7).170.803. unlike multiple myeloma.921. no tumor is ever detected. Laboratory Features. In still others. a demyelinating polyradiculoneuropathy may develop.Chapter 23 ACQUIRED NEUROPATHIES — 993 but most commonly is sensorimotor. various cytokines.1269 Multiple Myeloma Multiple myeloma is the most common hematologic malignancy associated with a monoclonal gammopathy. Autonomic dysfunction also may occur. and hypercalcemia is evident on routine chemistries. Laboratory Features.667.803.69.749.1380 Pathogenesis.128 Epidural cranial and spinal root compression by expanding plasmacytomas is common and may be superimposed upon and overshadow the peripheral neuropathy. Lymphoma. Peripheral neuropathies associated with multiple myeloma are uncommon.1355 Patients may display all or none of these features. large-amplitude polyphasic MUAPs may be reduced in the motor and sensorimotor forms of the disease but not in pure sensory neuropathy. The peripheral neuropathy is usually present for several years before the correct diagnosis is established. renal failure) Electrophysiologic Findings. Other patients usually have Castleman’s disease (angiofollicular lymphadenopathy).727.g. The treatment of the underlying multiple myeloma usually does not affect the course of the neuropathy. and ammenorhea in women.1381 Histopathology. 934. The mechanism of the neuropathy in multiple myeloma is multifactorial.123. H&E stain). The needle EMG examination demonstrates positive sharp waves and fibrillation potentials in the distal limb muscles. Endocrinopathy. and vascular endothelial growth factor. cutaneous pigmentation. The paraneoplastic neuropathy associated with lymphomas is presumably autoimmune. hypothyroidism. bone pain. occurring in 3–13% of cases. 23-9).668. hypertrichosis. Pathogenesis.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. may be detected in 40% of cases. In patients without amyloidosis. are elevated in the serum of patients . edema. Treatment. however. asymmetric. Treatment. axonal. Nerve conduction studies may reveal changes compatible with an axonal sensorimotor neuropathy1381 or demonstrates features of prominent demyelination270. polyneuropathy is present in almost one-half of cases of osteosclerotic myeloma.803. Histopathology. extramedullary plasmacytomas. with decreased but relative sparing of pain and temperature sensation.667. The disorder typically manifests in the fifth-to-seventh decade of life with fatigue. This complex constitutes the Crow-Fukase or POEMS syndrome (Polyneuropathy.262. sensory or sensorimotor neuropathy.921.270.1269 similar to that seen in AIDP and CIDP.1380 Electrophysiogic abnormalities.170.1355. The neuropathy may respond to treatment of the underlying lymphoma. which gradually progresses proximally in the lower limbs and upper limbs like CIDP.1151.667 Abdominal fat pad. The course may be acute. finger clubbing. or a solitary lytic plasmacytoma. tumor necrosis factor-α.727. but the exact antigen(s) and triggers for the immune attack are not known.170.1381 Inflammatory cells within the endoneurium may be demonstrated in both infiltrative and presumed paraneoplastic neuropathies complicating lymphoma (Fig. gynecomastia. The cranial nerves and respiratory muscles are usually spared but can be affected. CSF may reveal lymphocytic pleocytosis and elevated protein. The neuropathy manifests as tingling. numbness. leukonychia. The presence of a monoclonal population of inflammatory cells within the nerve fascicles suggests infiltration of tumor cells rather than an immunologic paraneoplastic etiology. IL-6. Sural nerve biopsy demonstrates marked lymphomatous infiltration of endoneurium. pleural effusion. Nerve biopsy may reveal axonal degeneration along with segmental demyelination. Most patients have a IgG or IgA lambda-chain monoclonal gammopathy. the monoclonal protein is demonstrated in the urine but not in serum. or sural nerve biopsy should be performed to look for amyloid deposition.

670.702.. Occasionally. Familial amyloidosis is caused by mutations in the genes for transthyretin. with some patients approaching 50–60% of the lower limits of normal. hence the term AL amyloidosis. and few inflammatory cells are noted. Pathogenesis. These findings are worse in lower than upper limbs and more pronounced in distal than proximal muscles.1073. which produce an IgM monoclonal protein. Immunoglobulin deposition similar to that seen in IgM-MGUS neuropathy has not been demonstrated in patients with POEMS syndrome. or gelsolin. Castleman’s Disease (Angiofollicular Lymph Node Hyperplasia) Castleman’s disease (angiofollicular lymph node hyperplasia) is a lymphoproliferative disorder characterized by lymphoid hyperplasia associated with capillary proliferation. with or without some other form of chemotherapy.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. these skeletal lesions. a mononeuropathy multiplex pattern of involvement is seen.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.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. the above-noted abnormalities become manifest. Sural nerve biopsy demonstrates a combination of segmental demyelination and Wallerian degeneration. Pathogenesis. These findings are prominent in the distal muscles of the upper and lower limbs. The neuropathy also may improve with the usual treatment given to patients with idiopathic CIDP (e. Approximately 5% of patients with Waldenström’s macroglobulinemia develop a symmetric sensory or sensorimotor peripheral neuropathy. The disease is characterized clinically by insidious onset of progressive fatigue. Hepatomegaly and splenomegaly are commonly found on physical examination. Antibodies directed against MAG can be detected in the serum in as many as 38% of patients. The electrodiagnostic medicine examination is consistent with a demyelinating or mixed axonal and demyelinative sensorimotor peripheral neuropathy. The angiofollicular lymph node hyperplasia is characterized by marked vascular proliferation.702.1388 CSF protein levels are often elevated. When patients are examined early in the course of the disease. usually with a κ light chain.702 In 50% of cases.388 Waldenström’s Macroglobulinemia Waldenström’s macroglobulinemia is an uncommon disorder responsible for about 2% of cases of monoclonal gammopathy. Familial amyloidosis is discussed in Chapter 22. Distal motor latencies are normal to increased. lymphadenopathy. as in CIDP.1073. chlorambucil.1. Waldenström’s macroglobulinemia most commonly occurs in men aged 50–70 years. or plasma exchange. The disorder is distinguished from IgMmyeloma by the absence of lytic bone lesions and hypercalcemia and by the presence of hepatosplenomegaly and lymphadenopathy. but not on the compact myelin. or ribs. some patients have features more consistent with an axonal sensorimotor neuropathy. Treatment. Patients initially complain of numbness and paresthesias that begin in the feet.994 — PART IV CLINICAL APPLICATIONS with POEMS syndrome. Over 80% of the monoclonal proteins are associated with a κ light chain. which is similar clinically.702. are multiple.295. electrophysiologically.481. but an autoimmune mechanism is likely. As the disease progresses. In one series of 38 patients. Some neuropathies are caused by secondary amyloidosis or nerve fiber ischemia related to serum hyperviscosity. which may be related to increases in serum cytokine levels and vascular endothelial growth factor.323.702 Skeletal survey reveals characteristic sclerotic (two-thirds of cases) or mixed sclerotic and lytic bony lesions (one-third of cases). almost 50% reported that the neuropathy responded to radiation and prednisone. weight loss.323 Castleman’s disease may be associated with POEMS syndrome (absence of the osteosclerotic lesions). anemia. less dramatic changes are noted in proximal muscle examination.750.g. or chemotherapy. Secondary amyloidosis (AA) is seen in patients with rheumatoid arthritis and other chronic inflammatory diseases and is associated with the accumulation of protein A. with a shift of fiber sizes toward the smaller end of the spectrum. and also affect the hands.1363 The disorder is caused by a malignant proliferation of lymphoplasmacytoid cells. Primary amyloidosis can occur in the setting of multiple . although a causal relationship has not been established.481. and histologically to IgMMGUS neuropathies. As with IgM-MGUS. progress proximally in the lower limbs. The pathogenesis of POEMS syndrome is not clear. usually in the vertebral bodies. corticosteroids). Nerve conduction studies most commonly reveal a demyelinating sensorimotor polyneuropathy indistinguishable from IgM-MGUS neuropathy. surgical excision of the isolated plasmacytoma. prospective. only a mild generalized peripheral neuropathy may be present. Primary amyloidosis (AL amyloidosis) is the designation given when the amyloid is composed of light chains. which represent focal plasmacytomas. Electrophysiologic Findings. with few needle EMG abnormalities.964 Histopathology. hemorrhagic diathesis (especially nosebleeds). along with reduced fine motor coordination of the hands. Needle EMG examination can demonstrate fibrillation potentials and positive sharp waves with reduced recruitment of MUAPs of long duration and increased amplitude. The neuropathy may respond to radiation. The CMAP amplitudes are markedly reduced or absent in the lower limbs and mildly to moderately reduced in the upper limbs. Some patients reportedly benefit form corticosteroids.964 However.992 The number of myelinated fibers is reduced. blinded. Histopathology. ACQUIRED AMYLOIDOSIS Amyloidosis is a relatively nonspecific name for a heterogeneous collection of various disorders.667. The mechanism of the neuropathy is unknown.964. and weakness.613. Progressive difficulty in ambulating independently may occur. the neuropathy and plasmacytoma can recur even in patients with an initial positive response to treatment.326. Peripheral neuropathy is uncommon in secondary amyloidosis. the neuropathy may be related to anti-MAG antibodies. Laboratory Findings. apolipoprotein A-1. However.181.743. Electrophysiologic Findings. pelvis. controlled trials have not been performed. all with amyloid deposition in different organs.613. Diagnosis requires demonstration of an IgM monoclonal protein in a concentration greater than 3 gm/L. Motor conduction studies demonstrate variable reductions in velocity. 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.575. However. Treatment.

the lower limbs tend to be more severely affected than the upper limbs.27. approximately 10–20 nanometers in diameter. constipation. As discussed in the CIDP section.750 Immunohistochemistry is helpful in demonstrating that the amyloid is composed of λ or. Treatment. the median survival is 2 years. Motor unit remodeling results in the eventual demonstration of long-duration.344. and electrophysiologic features.1168a.Chapter 23 ACQUIRED NEUROPATHIES — 995 myeloma. and transthyretin are required to distinguish histologically among the various forms. Cranial nerves also may demonstrate significant loss of axons. and loss of bladder control.972. When obtainable. Motor nerve conduction velocities are in low normal range or slightly reduced. impotence. elevated jitter. Degeneration of the large myelinated nerve fibers is less pronounced but obvious.128.152. Metachromasia is seen when they are stained with methyl violet or crystal violet. diarrhea. hoarse voice (amyloid deposit in vocal cords).969.348. Waldenström’s macroglobulinemia.661. high-amplitude. Primary (AL) amyloidosis is a systemic disorder that typically affects men after the sixth decade of life. whereas the sensory system does not have this capability to a significant degree.750 Histopathology. Electrophysiologic Findings.1235 Patients usually describe numbness and tingling in both upper and lower limbs. other plasmacytomas or lymphoproliferative disorders. and macroglossia. or colchicine. Amyloid deposition also can be demonstrated in the sympathetic and dorsal root ganglia.750 Enlarged peripheral nerves are a rare finding. Peripheral neuropathy occurs in 15–30% of patients with AL amyloidosis and may be the presenting manifestation in onesixth of cases.1168.1234. all sensory potentials may be absent. and eventually symmetric weakness develops. Nerve biopsies may reveal amyloid deposition in either a globular or diffuse pattern within epineurial and endoneurial connected tissue and blood vessel walls. discriminatory sensory loss. In general. beginning in the distal regions and progressing proximally. Fasciculation potentials also may be observed in upper and lower limb muscles. whereas in multiple myeloma κ light chains are more common. Although the peripheral nerve symptoms are annoying. Lambda (λ) is more common than κ light chain (2:1) in AL amyloidosis.702.666. Chemotherapy with melphalan.745. protein A. with amyloid deposition the most likely cause. the electrophysiologic findings are the same as those anticipated for preferential slowing of median nerve conduction across the carpal tunnel region. Single-fiber EMG examination also demonstrates findings consistent with denervation and subsequent motor unit remodeling (i. Organs that commonly are rendered dysfunctional include the kidney (nephrotic syndrome). neuropathies associated with an IgM monoclonal protein are typically demyelinating.666 Laboratory Features..1217.672. and weight loss. and conduction velocities are similarly normal or mildly reduced. less frequently κ. The amyloid is composed of the complete or variable portion of the monoclonal light chain. The clinical and electrodiagnostic findings are essentially the same in patients with primary amyloidosis and other lymphoproliferative disorders. the distal sensory latencies are normal or only mildly prolonged. 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. skin. The distal motor latencies are normal or only moderately prolonged in the upper limbs and usually prolonged in the lower limbs. all of which reduce the concentration of monoclonal proteins. The general physical examination can demonstrate limb edema. pain). resulting in painful dysesthesias along with diminished pain and temperature sensation. laboratory. 1218. Amyloid is a proteinaceous substance composed of nonbranching fibrils. syncope.750 NEUROPATHIES ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE Clinical Features.671. lymphoma. The generalized sensorimotor peripheral neuropathy in all forms of amyloidosis demonstrates variable degrees of SNAP abnormalities. Needle EMG usually reveals significant degrees of positive sharp waves and fibrillation potentials in the distal muscles of the lower limbs. The fibrils are not soluble in aqueous solutions and are quite resistant to proteolytic decomposition.666 This later age of onset is helpful in distinguishing between AL and familial amyloidosis. Amyloid eventually damages the various organs and peripheral tissues in which it is deposited. The SNAP amplitudes are diminished or absent. light chains. MGUS neuropathy is heterogeneic in its clinical. and fiber density). Patients with a demyelinating neuropathy can present with typical features of CIDP. renal or cardiac failure is more serious and has lethal consequences. polyphasic potentials. in long-standing and severe disease.1216. blocking. gelsolin. CMAP amplitudes are normal or only mildly reduced during early disease and not as severely affected as the SNAP.128. Such findings usually are not observed in the upper limbs until late in the disease process. Active axonal degeneration and severe loss of small myelinated and unmyelinated fibers are observed. gastrointestinal disturbance. gastrointestinal tract (nausea. fatigue. whereas IgG and IgA monoclonal gammopathies may be axonal or demyelinating in nature.e. hepatomegaly. beginning in the distal lower limbs and accompanied by large-fiber. however. Despite the various different types of amyloidosis. Patients with peripheral nervous system involvement commonly complain of weakness.1064. 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. impaired sweating. lungs. The neuropathy is slowly progressive.750 Initially small-fiber modalities are affected. heart (congestive heart failure). Primary Amyloidosis Clinical Features. and peripheral nervous system. similar histopathologic alterations form the foundation for the rather common electrodiagnostic medicine findings.750 Death generally results from progressive congestive heart failure or renal failure. or without any other identifiable disease.702.1299 In patients with carpal tunnel syndrome. prednisone. Significant reductions in sensation conveyed . Carpal tunnel syndrome occurs in 25% of patients and may be the presenting manifestation. This finding is understandable when one considers that collateral sprouting maintains the CMAP amplitude until it can no longer compensate for lost axons.768 The neuropathies can be either demyelinating or axonal.702. generally has been unsatisfactory.666.745.746–748. Reduced recruitment is noted in affected muscles. Patients with AL amyloidosis may present with symptoms attributable to the major organ systems preferentially affected. The prognosis of patients with primary amyloidosis is poor. with a β-pleated sheet structure. Most patients develop autonomic involvement with postural hypertension.

CMAP amplitudes can be normal or reduced. demyelination predominates. or mixed pathogenic process. the higher the dose and the longer the time of exposure.996 — PART IV CLINICAL APPLICATIONS by large myelinated fibers are noted. CMAP amplitudes are at least minimally reduced and often considerably reduced. radiation. Nerve biopsy demonstrates a reduction in the myelinated nerve fiber population with relative sparing of unmyelinated fibers. The electrophysiologic findings depend on the pathogenic basis of the neuropathy. hence conduction velocities are variably reduced. Age alone is probably not a major factor that predisposes patients to develop . 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. demyelinating. As previously noted.1256. The demyelinating sensorimotor polyneuropathies associated with IgG-MGUS and IgA-MGUS are more amenable to treatment than the IgM-MGUS neuropathies.329. Endoneurial injection or passive transfer of serum from patients with IgM antiMAG antibodies into animals leads to conduction block and demyelination.768. nerve conduction studies are often normal. When symptoms first begin. Another important cause of peripheral neuropathy in patients with BMT is graft-versus-host disease (GVHD).699 Ultrastructurally. However. Distal accentuation of demyelination and thus slowing of conductions are reflected by the lower terminal latency index (TLI) in patients with IgM-MGUS neuropathy.969.293.533.275. Motor nerve conduction studies reveal markedly prolonged distal latencies with moderate slowing of conduction velocities.885.1235 Lower limb nerves are usually considerably more involved than upper limb nerves.1235 The location of the abnormality obviously depends on the severity of disease. Laboratory Features. along with a reduction in the ability to perceive pain and temperature.669.275.1089. C3d. and an immune-mediated response may be directed against peripheral nerves.942.661. A combination of segmental demyelination and remyelination as well as axonal loss is found.152.152. docetaxel) (Table 23-11).942. but distal latencies and conduction velocities are normal or only mildly affected. Patients with IgG-MGUS and IgA-MGUS neuropathies are more likely to have symmetrical proximal and distal weakness typical of idiopathic CIDP.1234.748.972. long-duration potentials predominating in distal muscles and variable degrees of changes in more proximal muscles. with variable degrees of abnormal spontaneous activity in more proximal muscles.21. 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. F-wave latencies are characteristically prolonged and sometimes hard to elicit with every supramaximal stimulus. Clinical. Histopathology.911 although in some patients the presence of C5b9 deposits cannot be confirmed. whereas in others axonal loss may be somewhat more significant. with large-amplitude.21 Chronic GVHD has features associated with a variety of autoimmune disorders. abnormalities eventually occur but again may differ with the various chemotherapy drugs. vinca alkaloids (vincristine). the neuropathy responds to increased immunosuppressive therapy and resolution of GVHD. SNAPs are reduced in amplitude or absent. and taxanes (paclitaxel. Some cases of GBS have been attributed to chemotherapy.1038 or CIDP21 have been well described.24 The clinical manifestations of neuropathy are somewhat different for various agents.931. and electrophysiologic features are indistinguishable from idiopathic sensory or sensorimotor polyneuropathies. and sepsis with multiorgan failure in critically ill patients. Treatment.21 TOXIC NEUROPATHIES CHEMOTHERAPY The commonly used anticancer drugs that can cause neuropathy fall mainly into three groups: platinum agents (cisplatin).748.1256 Elevated CSF levels are common in patients with a demyelinating neuropathy. laboratory. Patients can develop a variety of cranial neuropathies.329.947.500 sensorimotor polyneuropathy. toxicity from immunosuppressive medications. immunosuppressive agents. IgG and IgA MGUS neuropathies can be either axonal or demyelinating.972 Latencies are usually prolonged. As described earlier.1234 The remaining myelinated fibers are usually of small fiber caliber.22.24 Cranial and peripheral neuropathies1425 are most frequently related to herpes zoster infection or previous chemotherapy. the more likely a neuropathy will occur. At least 50% of the patients with IgMMGUS neuropathy have antibodies directed against myelin-associated glycoprotein (MAG). Patients with an axonal neuropathy present with distal sensory loss in a length-dependent fashion. Weakness also can develop but usually is restricted to the distal limbs in IgM-MGUS neuropathies. In demyelinating MGUS neuropathies. IgM-MGUS is usually associated with a demyelinating neuropathy.969. These agents generally produce neuropathy in a dose-dependent relationship. Patients with MGUS neuropathy who fulfill clinical and electrophysiologic criteria for CIDP can improve with immunotherapy (discussed in greater detail in the CIDP section).360 Electrophysiologic Findings.488 multiple mononeuropathies.1234. the myelin sheaths appear to be separated and IgM deposits can be demonstrated in zones of myelin splitting.748. CMV.702.1425 Neuropathy may be due to hemorrhage within the nerve or plexus. A positive Romberg sign may be present.327. and C5b-9) along the myelin sheath also has been demonstrated.1168a.661. Deep tendon reflexes are reduced or absent throughout.942.488 or IVIG. or Campylobacter jejuni infections and have improved with plasma exchange79. The pathogenic relationship of the monoclonal protein to the neuropathy is not clear. The IgM-MGUS neuropathies are typically demyelinating. In some patients. Electrophysiologic studies may be consistent with a primary axonal.668.1425 and severe generalized peripheral neuropathies resembling GBS79. MUAPs suggest extensive motor unit remodeling. When axonal loss predominates. Needle EMG quite commonly reveals positive sharp waves and fibrillation potentials in the hand and foot intrinsic muscles. including loss of olfactory and gustatory sensation.669.533 In some patients. histopathology. 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. Other potential causes of neuropathy include carcinomatous or infectious meningitis with infiltration of nerves.1361 Deposition of complement (C1q. or infection and perhaps to an autoimmune response directed against the peripheral nerves. With further doses. the SNAP amplitudes are reduced or absent in most patients. C5.1168. Pathogenesis.1064. malnutrition.

g. pyridoxine). Collins MP: Neuropathies associated with malignancy. particularly vibratory perception Vinca alkaloids Interfere with axonal microvincristine. with permission. demyelinating. withdrawal leads to some improvement of the neuropathy. It is often a difficult to decide whether to stop chemotherapy drugs in the setting of neuropathy if the tumor is responding to therapy. temporal dispersion) Loss of myelinated nerve fibers Axonal degeneration Segmental demyelination No inflammation None described Axonal..Chapter 23 ACQUIRED NEUROPATHIES — 997 Table 23-11. Occasionally. 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. Toxic Neuropathies Caused By Chemotherapy Drug Mechanism of Neurotoxicity Clinical Features Symmetric. 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.g.18:125–144. nitrofurantoin. a neuropathy secondary to chemotherapy. Neurotoxicity is more common and severe in patients with a preexisting neuropathy (e. isoniazid. 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. prolonged distal Occasional epi. The mechanism by which degeneration of the ganglion cells or axons occurs is different for various agents.. sensory predominant PN Autonomic neuropathy Abnormalities consistent with axonal S-M PN S-M = sensorimotor. diabetic neuropathy) and patients taking other potentially neurotoxic drugs (e. some symptoms and signs may persist. QST = quantitative sensory testing. In general. After significant cumulative doses.and endoneulatencies and F-wave rial inflammatory cell latencies. 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. particularly vibratory perception Taxanes (paclitaxel. axonal degeneration slow CVs. Charcot-Marie-Tooth disease. vindesine. particularly vibratory perception Suramin Axonal PN Demyelinating PN Unknown ? Inhibition of neurotrophic growth factor binding ? Neuronal lysosomal storage Unknown ? Immunomodulating effects Symmetric. S-M. conduction infiltrates block. disulfiram. However. The pathologic process in chemotherapy-induced neuropathies is either distal axonopathy due to axonal degeneration or ganglionopathy. EMG = electromyography. Semin Neurol 1998.g. NCS = nerve conduction studies. GBS = Guillain-Barré syndrome From Amato AA. especially mild distal sensory . PN = polyneuropathy. vintubule assembly blastine.. docetaxel) Promotes axonal microtubule assembly Interferes with axonal transport Symmetric. complete resolution of symptoms and signs is more likely if the drug is stopped in the early stages of the peripheral neuropathy. predominantly sensory PN Large-fiber modalities affected more than small-fiber Axonal sensorimotor PN Distal denervation on EMG Abnormal QST. a dose reduction can ameliorate some of the neuropathy symptoms or stop them from progressing.

Cisplatin given to rats produces changes in the dorsal root ganglion and axonal degeneration on both central and peripheral nerve processes. Weakness occurs in only 2% of patients. Autonomic nerves can become involved.290.1155. the neuropathy is severe in only 1% of patients.503. autonomic neuropathy is less frequent. The loss of ankle reflexes commonly precedes the subjective loss of sensation.136.1112. Pathogenesis. The most common symptoms are distal sensory loss and paresthesia. 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. segmental demyelination. Pathogenesis.1009 Distal latencies and conduction velocities were normal. predominantly sensory polyneuropathy occurs in 4–10% of patients. but nerve conduction studies and needle EMG show changes consistent with an axonal sensorimotor polyneuropathy. Sural nerve biopsies reveal axonal degeneration and loss of myelinated and unmyelinated nerve fibers.913. Vincristine.24.1167 Cranial neuropathies.1112.67. hearing loss. Motor nerve conduction studies and needle EMG are usually normal. or VP16.390. creating interstrand and intrastrand cross-links. VP16 causes degeneration of cell bodies within the dorsal root ganglion. facial weakness.24 Histopathology. but a dose-related peripheral neuropathy has been reported in 20–50% of patients. Sensory and motor nerve conduction studies reveal diminished amplitudes or absent responses.1304. distal weakness of the hands and feet occurs in 25–35% of patients.1144. and orthostatic hypotension. and pseudoathetoid movements.1066.or areflexia. Binding of the drug to neuronal DNA may inhibit transcription of important proteins and impair axonal transport.1014. Although the drug may be eliminated from the blood stream.998 — PART IV CLINICAL APPLICATIONS loss and hypo. and testicular cancer. resulting in paresthesia. leukemia. Vinorelbine Clinical Features.724. are rare.869 Scattered clusters of regenerating axonal sprouts may be seen. Deep tendon reflexes are reduced or absent at the ankles in most patients after 12 cycles of chemotherapy. As with vincristine.1339 A subclinical or mild neuropathy develops in up to 85% of patients after 3–7 cycles at doses of 135–200 mg/m2.24 Electrophysiologic Findings. Cisplatin covalently binds DNA.24. The neuropathy gradually improves over several weeks or months after discontinuation.496.1304 Axonal degeneration. Etoposide (VP16) Clinical Features. but they do not commonly return to pretreatment levels. histopathology has not been described in humans with the neuropathy. The amplitudes of the sensory and compound muscle action potentials improved after discontinuation of vinorelbine.1383 Large-fiber modalities are preferentially affected.802. The MUAP recruitment is reduced in the distal limb muscles. in patients treated with doses between 250–350 mg/m2. diminished deep tendon reflexes.592. the most commonly used vinca alkaloid. impotence. Nerve growth factor and other neurotrophins may be beneficial in the future for preventing or treating chemotherapy-induced neuropathies. Cisplatin produces a predominantly sensory neuronopathy (ganglionopathy) at cumulative doses of 225–501 mg/m2. Of interest.592. Presumably. Electrophysiologic Findings.1304 Quantitative sensory testing has demonstrated that vibratory perception is a sensitive indicator of early cisplatin-induced neuropathy.179.1105. loss of vibratory perception and proprioception with gait ataxia. Vinca alkaloids inhibit microtubule formation by binding to tubulin. However.1105. It produces a dose-dependent.869. Stopping the drug results in improvement of SNAP and CMAP amplitudes.206. Detailed descriptions are lacking.187.1096. and bladder cancer.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. Histopathology.1009 Histopathology.724. A severe neuropathy occurs in 2% of patients at this lower dose range. is a semisynthetic derivative of podophyllotoxin and is used to treat patients with lymphoma. These symptoms have been reported as early as 2 weeks after a single dose of 2 mg/m2.611 Severe autonomic dysfunction can result in orthostatic hypotension and gastroparesis.24. urinary retention. as many as 40% of patients can develop Lhermitte’s sign.912. Nerve pathology has not been reported. and regenerating axonal sprouts also may be evident. Pathogenesis.1155 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.775. It is less neurotoxic than vincristine. bladder.422.1328.808. including optic neuropathy. produces a sensorimotor and autonomic neuropathy.503. The pathogenesis is presumably similar to that of vincristine-induced neuropathy.1009 However.808. SCLC.146.462. Over time. A moderate to severe distal. and head and neck as well as lymphoma. Deep tendon reflexes are reduced or diminished throughout. axonal. In mice. Cisplatin is used widely for the treatment of ovarian.808 Sural nerve biopsies reveal a predominant loss of large myelinated nerve fibers. its toxic biologic effects on the peripheral nervous system can continue. testicular. Electrophysiologic Findings. A prospective study using serial nerve conduction studies demonstrated a dose-dependent reduction of sensory and compound muscle action potentials. Fibrillation potentials and positive sharp waves reflecting active denervation can be seen in distal muscles. Pathologic and electrophysiologic studies suggest that neuronal cell bodies in the dorsal root ganglion are preferentially affected.529.373 Vincristine Clinical Features. The impairment in the microtubules interferes with axoplasmic transport and subsequently causes cytoskeletal disarray and axonal degeneration. leading to constipation.1167 Normal or only mildly prolonged distal latencies and slow conduction velocities are evident.513. breasts. VP16 also produces its neurotoxic effects by inhibiting microtubule function. Vinorelbine is a semisynthetic vinca alkaloid recently approved for treatment of various types of cancer.529. Etoposide.1156.724.24 Cisplatin Clinical Features. With further dose accumulation. motor unit remodeling leads to large-amplitude. Paclitaxel is used for treatment of cancer of the ovaries. Weakness can develop after 3–6 months of treatment.136. much like vincristrine.1167 The earliest symptoms are paresthesias and numbness. perhaps due to demyelination and edema of the posterior columns.1136.912. oculomotor palsies.67.1004.611 Paclitaxel (Taxol) Clinical Features.48. predominantly sensory neuropathy. However. hypesthesia. long-duration MUAPs.1112. Histopathology.24. lungs. Pathogenesis.869.1014. neuropathy develops after the first or second cycle—sometimes within 24 hours . and laryngeal paralysis. which at times occur in the fingers before the toes.

1250 Suramin appears to cause two distinct types of neuropathy: (1) a dose-dependent.208.581. unless these risk factors are present. Vibratory perception is impaired more than pain and temperature sensation.1066. but regenerating axonal sprouts are uncommon.1268 or induce a form of lysosomal storage disease. and secondary axonal degeneration. and vibratory perception are noticeable on examination.422. The mechanism of neurotoxicity is unknown.. There are only a few pathologic descriptions of paclitaxel-induced neuropathy. followed by symmetric weakness (proximal > distal).422. The neuropathy can continue to progress for 1 month or more after the drug has been discontinued because of the coasting effect. paresthesias. but weakness can occur in patients with an underlying neuropathy or other risk factors (e.24. distal. Sensory nerve biopsy in one patient revealed a loss of large myelinated fibers with scattered fibers undergoing axonal degeneration. However.206.g.g.208. Fibrillation potentials and large-amplitude. Sensory nerve conduction studies demonstrate unobtainable or very low-amplitude potentials. toe extensors) and diminished ankle refelxes can be seen. reflecting an axonal neuropathy. exposure to greater than 200 µg/L for more than 25 days per month.1136 Cumulative doses above 1500 mg/m2. Plasma exchange has been tried in an uncontrolled fashion with mixed results. Electrophysiologic Findings.271 Electrophysiologic Findings. was used initially for treatment of trypanosomiasis and onchcerciasis and more recently for various cancers.1156 Docetaxel (Taxotere) Clinical Features. Deep tendon reflexes are absent at the ankles in one-half of patients.1136. most patients improve 1–2 months after cessation of chemotherapy.206.1250 Symptoms typically begin with numbness and paresthesias of the distal limbs or face. preexisting neuropathy. Sural nerve biopsies have been performed in a few patients with the subacute demyelinating polyradiculoneuropathy. which is also used in the treatment of various malignancies. Mild proximal and distal weakness can be seen in 5–19% of patients. Paclitaxel may have a toxic effect on the neuronal cell body.766.1250 Diminished light touch.. axon. Suramin may inhibit the interaction of neurotrophic factors with peripheral nerve receptors1145. Needle EMG may show fibrillation potentials in the distal limbs.802. Laboratory Features. Electrophysiologic Findings. As many as 25% of patients become bedridden and require mechanical ventilation. peripheral neuropathy develops in 11–50% of patients.951 Motor nerve conduction studies reveal diminished amplitudes with mild slowing of conduction velocities. Recovery occurs over a few months. axons.208. the sensory symptoms persist.951 Pathogenesis.1328 Quantitative sensory testing reveals impairment of vibratory perception more often than abnormal thermal thresholds. Suramin Clinical Features. a hexasulfonated naphthylurea.802. which disassemble microtubules. A subacute sensorimotor demyelinating polyradiculoneuropathy develops in 10–20% of patients after 1–5 months of treatment. although two cases with demyelinating features have been reported.422.24.766. This process leads to aggregation and accumulation of abnormal bundles of microtubules in dorsal root ganglia.1156. Electrophysiologic studies have been reported in detail in only a few patients.208. The reported incidence of peripheral neuropathy ranges from 25–90%. Mild weakness of the distal limbs (e.24. Distal motor weakness is uncommon. although some patients have residual numbness and weakness. demyelination and remyelination. the taxanes promote microtubule assembly by increasing tubulin polymerization.802. Distal latencies and conduction velocities are usually normal. axonal sensorimotor polyneuropathy and (2) a subacute demyelinating polyradiculoneuropathy. and some patients develop sensory ataxia. Docetaxel is a semisynthetic analog of paclitaxel.1250 Biopsies demonstrated loss of large and small myelinated nerve fibers. Paclitaxel produces both sensory and motor nerve conduction abnormalities and denervation potentials in distal muscles.1136. Neurotoxicity is the dose-limiting side effect. As many as 70% of patients have severe neuropathy after high doses.951 Large-fiber modalities are more commonly affected.1250 Quantitative .1339 The electrophysiologic motor involvement is more likely to be subclinical and occur later in the course of the neuropathy. diabetic neuropathy).1328 Histopathology. predominantly sensory.1066. and Schwann cells. CSF protein has been elevated in some patients with a subacute demyelinating polyradiculoneuropathy.1066. Patients can continue to deteriorate for 1 month after suramin discontinuation.24 The distal axonopathy is more common and manifests with distal numbness and paresthesias. The more common distal axonopathy is associated with decreased amplitudes of sensory and compound muscle action potentials.208. but with further therapy.457 The demyelinating neuropathy may be related to the immunomodulating effects of suramin. The neuropathy is reversible with suramin discontinuation. As with paclitaxel.1339 Reduction in amplitudes of the sensory nerve and compound muscle action potentials correlate with the cumulative dose. and prior or concurrent exposure to neurotoxic agents are additional risk factors for developing a severe neuropathy. Suramin. long-duration polyphasic MUAPs showing decreased recruitment can be appreciated in distal muscles. The pathogenic mechanism is presumably similar to that of paclitaxel (see above).208. The weakness progresses over 2–21⁄2 months.766. Histopathology. The subacute demyelinating polyradiculoneuropathy is much more severe and is associated with peak plasma concentrations of over 300 µg/L. or both. or cumulative dose of 40. with patients complaining of distal numbness.208 Pathogenesis. EM has demonstrated accumulation of tubular and membranous structures within the axons.000 mg/hr/L.1156. a dose-dependent.1136 The neuropathy manifests with numbness.802.Chapter 23 ACQUIRED NEUROPATHIES — 999 of the initial infusion.430.1328.1339 Symptoms can resolve before the next scheduled dose. although severe symptoms develop in only 4% of patients.1328. Autonomic neuropathy is uncommon.1328 Sural nerve biopsies reveal a greater loss of large. Deep tendon reflexes are decreased or absent throughout. Axonal degeneration with secondary demyelination and remyelination may be seen.1137 Axoplasmic transport may be disrupted by the mechanical obstruction caused by the abnormal accumulation of microtubules.206. Some patients describe pain in the hands and feet and also have Lhermitte’s sign. and dysesthesias that begin in the feet and later involve the arms and face. Epineurial and endoneurial mononuclear inflammatory infiltrates were present in two biopsies.430.24 In contrast to vinca alkaloids.1156.206.1250 Histopathology. pain. The neuropathy may continue to worsen for several months after discontinuation of the drug.1156 Pathogenesis. even with large cumulative doses.than small-diameter myelinated nerve fibers.

metronidazole is a member of the nitroimidazole group. the antimetabolite action of cytosine arabinoside C inhibits proteins important in myelin production or axonal transport. Perhaps. A few patients also may demonstrate evidence of a reduction in strength in the distal muscles of the lower limbs.124. As in the distal axonopathy. Electrodiagnostic and histopathologic data are lacking. slow conduction velocities.208. Needle EMG demonstrates increased amplitudes. EM may reveal an accumulation of neurofilaments with axonal swellings. Serum CK levels are usually elevated because of the superimposed myopathy. Deep tendon reflexes are preserved.1003 Histopathology. The CMAP amplitudes are typically well preserved throughout. Sural nerve biopsies demonstrate a reduction in the large myelinated fibers with evidence of axonal degeneration and segmental demyelination/remyelination. Symptoms gradually resolve but recur if patients are rechallenged with chemotherapy. but occasional symptom onset in the hands rather than the feet suggests a ganglionopathy. Chloroquine is a quinoline derivative used for treating malaria. Electrophysiologic Findings. Patients with chloroquine myopathy develop slowly progressive.1040 After approximately 3–5 weeks of administration (total dose > 18 gm). Alternatively.1250 Prolonged distal latencies and F-waves. and a few cases have been reported in which patients developed an axonal peripheral neuropathy with primarily sensory symptoms.636 Needle EMG may reveal active denervation changes in distal muscles. its immunomodulating effects may lead to dysinhibition of autoreactive lymphocytes and an immune attack against the peripheral nerves.369. painless. The neuromyopathy is reversible after discontinuation of the medication. Several types of peripheral neuropathy have been reported with cumulative doses of 60–36g/m2.137. Chloroquine Clinical Features. Sensation is diminished in some patients secondary to a superimposed neuropathy. Ambulation may become impaired by a combination of sensation loss in the feet and pain. Pathogenesis. The distal sensory latencies and conduction velocities are normal or mildly abnormal. Electrodiagnostic studies may be compatible with a primary axonal1038 or an acquired demyelinating sensorimotor polyneuropathy.843 Chloroquine can cause a toxic myopathy (discussed in Chapter 28).1003. and motor conduction velocities are at the lower end of normal values.1282 Like misonidazole.827. The pathogenic basis of the neuropathy is not known. but a number of patients continue to have residual deficits.124. Pathogenesis. proximal weakness and atrophy. The pathophysiologic mechanism for the neuropathies is not well understood. and rheumatoid arthritis. 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. Sural nerve biopsies may reveal demyelination or axonal degeneration. Laboratory Features.381. Pathogenesis. Deep tendon reflexes may be diminished particularly at the ankle. Electrophysiologic Findings. temporal dispersion. Increased CSF protein has been demonstrated in patients with a severe neuropathy resembling GBS. scleroderma. Chloroquine has amphiphilic properties because it contains both hydrophobic and hydrophilic regions.1003. Compound muscle action potentials are well preserved. Histopathology. A reduction in motor unit recruitment can be seen in weak limb muscles. In addition to vacuolar myopathy. Cytosine Arabinoside (ARA-C) Clinical Features. Neuropathy has been reported in patients receiving a total dose of 14 g/m2 or more. OTHER MEDICATIONS Misonidazole Clinical Features. durations. Deep tendon reflexes are well preserved except for a reduction at the ankles.949. Sensory nerve conduction studies demonstrate a mild to moderate reduction in upper limb nerves with significant reduction to complete absence of lower limb SNAPs.638. Cases of brachial plexopathy1179 and severe sensorimotor polyneuropathy resembling GBS124. sarcoidosis. Cessation of the drug usually results in symptom improvement. some patients may begin to complain of painful paresthesias in the feet. Cardiomyopathy also may occur.882. Cytosine arabinoside C is an antimetabolite used in the treatment of leukemia and lymphoma.1000 — PART IV CLINICAL APPLICATIONS sensory testing has demonstrated increased vibratory and cooling thresholds. quantitative sensory testing shows increased vibratory and cooling thresholds. affected. which are worse in the legs than in the arms.208 Fibrillation potentials and neurogenic MUAPs may be noted in distal muscles with needle EMG. Histopathology.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. Histopathology.766. The major manifestations are hyperalgesia and hypesthesia in a glove-and-stocking distribution. systemic lupus erythematosus.1038 have been attributed to the drug. but vibration sensation and pain/temperature discrimination are significantly . Motor conduction studies reveal normal nerve conduction velocities and distal motor latencies in the upper limbs with borderline abnormal values in the lower limbs. Nerve biopsies demonstrate evidence consistent with axonal loss.1038 Pathogenesis. Needle EMG findings have not been reported. 1037 Numbness and painful paresthesias begin in the hands and feet 10–14 days after treatment. Electrodiagnostic studies in the subacute sensorimotor polyradiculoneuropathy reveal features of demyelination. 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. Nerve conduction studies reveal reduced or absent sural SNAPs with low-amplitude upper limb SNAPs.638 Ifosfamide Ifosfamide is a cyclophosphamide analog. Electrophysiologic Findings. followed by similar symptoms in the hands. nerve biopsies also demonstrate autophagic vacuoles. The pathogenic basis of the neuropathy is not known. Metronidazole Clinical Features. These neuropathies may begin hours or weeks after treatment.253. and conduction block have been reported. Muscle strength is usually normal throughout. Metronidazole is used in the treatment of various protozoan infections as well as in Crohn’s disease. The distal sensory latencies are usually at the upper limits of normal. Laboratory Features. and polyphasia of MUAPs.

734. others mildly or moderately. Nerve biopsies demonstrate significant segmental demyelination with variable degrees of Wallerian degeneration. pigmentary skin changes.619. The drug-lipid complexes are resistant to digestion by lysosomal enzymes. Of note.793. but not exclusively. combined with distal sensory loss. The H-reflex may be of help in demonstrating mild abnormalities of conduction in patients with early disease. Perhexiline maleate has antiarrhythmic properties and was used in the past to treat angina.Chapter 23 ACQUIRED NEUROPATHIES — 1001 These properties account for the ability of the drugs to interact with the anionic phospholipids of cell membranes and organelles. Histopathology. Distal motor latencies are mildly prolonged in some patients or increased by 100% in others. Hydroxychloroquine Hydroxychloroquine is structurally similar to chloroquine and also produces a neuromyopathy.201. fibroblasts.425. and peripheral neuropathy with elevated CSF protein. Colchicine. Pathogenesis. Alterations of MUAP morphology suggesting motor unit remodeling can be anticipated in the distal limb muscles. Muscle biopsies demonstrate autophagic vacuoles with myeloid inclusions. Amiodarone Clinical Features.381 Weakness and histologic abnormalities are usually not as severe as in chloroquine myopathy. Weakness is present in the distal regions of both upper and lower limbs.1042 The sural SNAPs are usually markedly reduced in amplitude or reduced with some degree of nerve conduction slowing. Later weakness becomes apparent in the distal lower limb muscles.1189. weight loss. Muscle biopsies reveals a vacuolar myopathy. Needle EMG reveals fibrillation potentials and positive sharp waves in patients with severe disease as well as reduced recruitment of MUAPs.g. can have motor conduction velocities as low as 11–12 m/s in the lower limb. particularly in distal muscles. and endothelial cells. Electrophysiologic Findings.391. The peripheral neuropathy is a generalized sensorimotor type manifesting with an initial reduction in sensation and paresthesias in the feet. Amiodarone is an antiarrhythmic medication that causes a neuromyopathy similar to chloroquine. The pathogenesis is presumably similar to other amphiphilic medications (e. Needle EMG examination usually detects fibrillation potentials and positive sharp waves in the hand and foot intrinsic muscles with reduced recruitment.131. affects the legs more than the arms. Within several months. accompanied by a tendency to fall and cramping in some leg muscles. Some patients. whereas sensory nerves demonstrate axonal degeneration. Neurogenic atrophy also can be appreciated. The drug is known to have a number of adverse effects including tremor.843 Patients with only the myopathy usually have normal motor and sensory studies. The SNAP and CMAP amplitudes are significantly reduced only in patients with long-standing disease of a severe nature. which results in the accumulation of autophagic vacuoles in muscle and nerves. significant weakness and muscle wasting are noted in the legs with progressive loss of strength and coordination of the hands. provided that profound muscle wasting has not already occurred. but EM usually demonstrates the abnormal accumulation of myeloid and curvilinear bodies. and parotid gland hypertrophy. Histopathology. The neuropathy may develop over months to years.840. with some minor loss of pain and. and similar sensory disturbances are noted in the hands.1408 The nerves are affected to different degrees—some profoundly. difficulty in ambulation may be noted.735 . Electrophysiologic Findings. in the proximal limb muscles. Physical examination demonstrates a reduction in sensation to all modalities as well as absent deep tendon reflexes. The disruption of the microtubules probably leads to defective intracellular movement or localization of lysosomes. Myotonic potentials may be seen despite a lack of clinical myotonia. it is now rarely used. Colchicine Clinical Features. thus resulting in the formation of the autophagic vacuoles filled with myeloid debris. with some degree of numbness and tingling in the distal lower limbs and occasionally the hands. and the mechanism of neuropathy may be similar to other such agents (see above). Electrophysiologic Findings. however. Pathogenesis. hepatitis. rarely. Perhexiline Maleate Clinical Features. Perhexiline is an amphiphilic drug. These lipid membrane inclusions in muscle and nerve biopsies have persisted for as long as 2 years after discontinuation of the medication.1042 Severe proximal and distal weakness. Sural nerve biopsies demonstrate a combination of segmental demyelination and axonal loss. Pathogenesis. Its exact incidence is unknown. hypoglycemia. pulmonary fibrosis. Nerve conduction studies reveal variable findings among different nerves in the same patient.131.1408 Because of its significant side effects.381. temperature sensation in the distal limbs.1189. thyroid dysfunction. With time. inhibits the polymerization of tubulin into microtubules. such as liver dysfunction.1104 Patients usually present with complaints of inability to climb stairs and arise from a low chair. chloroquine). whereas distal latencies may be increased by up to 100% of the upper limit of normal. Patients with neuropathy demonstrate mild slowing of both motor and sensory nerve conduction velocities associated with a mild to moderate reduction in the amplitudes. especially at the ankle. Histopathology. Voluntary MUAPs are significantly decreased in amplitude and duration with a predominance of polyphasic MUAPs. Cessation of the drug leads to significant clinical improvement in most patients.425.840. The initial complaint is reduced sensation and paresthesias in the feet with burning pains and a feeling of coldness. colchicine is capable of generating both a significant myopathy and a mild to moderately severe polyneuropathy. keratitis.735. Sensation to touch and vibration and position sense may be reduced. Peripheral neuropathy usually occurs in patients taking the medication for over 2–3 years.1157 Osmiophilic inclusions are evident in Schwann cells. Vacuoles are typically absent on biopsy. which is used primarily to treat patients with gout. Physical examination demonstrates significant weakness in the proximal limb muscles with a lesser degree of strength reduction in the distal limb muscles.369 EMG reveals an increase in insertional activity with significant amounts of positive sharp waves and fibrillation potentials primarily.793. Most patients demonstrate a mild reduction (within the 70–80% range of the lower limit of normal) in nerve conduction velocity throughout. Deep tendon reflexes are reduced particularly at the ankles. EM reveals myeloid inclusions in muscle and nerve biopsies.. Nerve conduction studies may demonstrate a reduction in both motor and sensory conduction velocities to less than 60–70% of the lower limit of normal.881.

1002 — PART IV CLINICAL APPLICATIONS Electrophysiologic Findings. and other uncomfortable paresthesias in the feet and hands.909. vomiting.126. Muscle weakness may be noted in a proximal distribution with some wasting in severely affected patients. Patients may have residual deficits. which develops in 10–100 % of patients.908.995. The neuropathy gradually improves after discontinuation of the podophyllin.28. burning. Unfortunately. Fasciculations also can be observed.93. Needle EMG is commonly normal. Sensation is reduced primarily in a stocking distribution with later development of significant muscle weakness. EM reveals an accumulation of neurofilamentous material within the myelinated and unmyelinated axons. as many as 50% patients continue to have significant symptoms. Histopathology. muscle weakness. like colchicine. A few patients may demonstrate absent F-waves in the lower limbs. with muscle cramping in the legs. The neuropathy may be secondary to carbon disulfide. liver function abnormalities and renal insufficiency also may be noted on routine laboratory work-up. but improvement can take from several months to more than 1 year. Sensory nerve conduction studies reveal absent SNAPs or reduced amplitudes. CSF protein levels can be elevated. The distal limbs are affected more than the proximal limbs and the legs more than the arms. as expected in length-dependent axonopathies. Pathogenesis. The pathogenic basis of the neuropathy is not known.414. the same type of abnormal membrane instability can be observed. and peripheral neuropathy. The primary abnormality is a reduction or complete absence of SNAPs. Motor nerve conduction studies are expected to reveal normal distal motor latency. however. The neuropathy can progress for a few months even after the medication is stopped. the conduction velocity remains relatively well preserved.909. the MUAPs are reduced in number with longer duration and higher amplitude than normal. Nerve biopsies demonstrate axonal degeneration. Nausea.903.1015 Patients with peripheral neuropathy can display symptoms reflective of axonal loss within 10 days to 18 months of starting the drug. Histopathology.28.1067 It is effective in some dermatologic conditions. Distal latencies and conduction velocities of the CMAPs are relatively spared.1228 Systemic side effects include gastrointestinal paresis. Peripheral nerve biopsy reveals axonal degeneration of the large-diameter myelinated fibers with little evidence of demyelination. Electrophysiologic Findings. causing psychosis. although both large and small fibers can be equally affected.1039 Electrophysiologic Findings. Pathogenesis. orthostatic hypotension. such as discoid lupus erythematosus and prurigo nodularis. conduction velocities are normal or mildly slow.909 Axonal degeneration is the predominant feature. the better the prognosis for return of function.1104 The distal motor and sensory latencies may be normal or slightly prolonged. pancytopenia.414 The distal latencies and conduction velocities of the SNAPs are normal or only slightly impaired. and F-waves. 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. although the latter follow the lower limb abnormalities rather closely.995. which is a neurotoxin and can have adverse effects on both the peripheral and central nervous systems. Electrophysiologic Findings.1067 When the SNAP is present. paresthesias.756.440. altered consciousness. but segmental demyelination also may be seen. The lower limb SNAPs appear to be affected first and more profoundly than those in the upper limbs. as well as graft-versus-host disease and leprosy and multiple myeloma. Podophyllin Clinical Features. Thalidomide is a rarely used immunomodulating agent because of its profound teratogenic effects. conduction velocity. Podophyllin toxicity can also involve the central and peripheral nervous systems.171. CMAP amplitude. Podophyllin binds to microtubules.715. urinary retention. It is important to be aware of these neurotoxic effects because the sooner the medication is stopped.93. urinary retention. leading to axonal swelling. and H-reflexes may be prolonged or absent. Nerve conduction studies reveal low amplitude SNAPs and CMAPs.439.440. Patients complain of significant pain. Sural nerve biopsy demonstrates a loss of all myelinated fibers with some preference for the large-diameter fibers. Thalidomide Clinical Features. It is metabolized to carbon disulfide.225. F-waves can be expected to be significantly prolonged.735. Deep tendon reflexes are usually diminished or absent. and SNAP latencies are not significantly affected. A few autopsy studies also have documented degeneration of dorsal root ganglion cells. even after stopping the drug for 4–6 years. Pathogenesis.126. Some patients present with bilateral foot drop.756. and liver and renal dysfunction. and diminished deep tendon reflexes. Likewise. Vibration and position sense usually are reduced. ileus. Physical examination demonstrates an erythematous hue to the palms of the hands as well as increased fragility of the finger and toenails. and tachycardia may result from involvement of the autonomic nervous system. and probably inhibits axoplasmic flow. Drug cessation does not lead to a normal fiber profile.783 A similar axonal neuropathy characterized by accumulation of neurofilaments occurs with carbon disulfide toxicity. This combined pattern of electrophysiologic alterations is consistent with a proximal myopathic and distal neurogenic process. Needle EMG may demonstrate fibrillation potentials and positive sharp waves in distal limb muscles along with decreased recruitment. The electrodiagnostic medicine findings are consistent with the histopathologic findings of an axonal neuropathy. but may demonstrate reduced amplitudes. a metabolite of disufiram. Some particularly sensitive patients also experience proximal muscle weakness and atrophy. Podophyllin resin is a topical agent used to treat condylomata acuminata. Disulfiram Clinical Features. The neuropathy appears to be dose-dependent and occurs after a total dose of 40–50 gm in most patients.1206 One of its major dose-limiting side effects is peripheral neuropathy. Motor conduction studies are less affected. Laboratory Features. Systemic toxicity has resulted from topical exposure and oral ingestion. Pancytopenia. leading to axonal degeneration. Needle EMG examination demonstrates short-duration. Disulfiram (Antabuse) is used in the treatment of alcoholism.439. In the distal muscles of the upper and lower limbs. The neuropathy is characterized by slowly progressive sensory loss. whereas those in the upper limbs are reduced in amplitude.28.1015 The SNAPs in the lower limb are usually absent or markedly reduced.93. Histopathology. Loss of sensation is variable. The conduction velocities . low-amplitude MUAPs in the proximal limb muscles accompanied by positive sharp waves and fibrillation potentials.

Conduction velocities are moderately reduced in severely affected patients. particularly in the hands. but peripheral neuropathy also may occur. with more severe effects on dorsal than ventral roots. motor unit remodeling results in large-amplitude. Pathogenesis.1438 Similarly. The most common side effects are anemia and methemoglobinemia. although a few patients with profound disease can have reductions approaching 70% of the lower limit of normal. Patients also may exhibit a wide-based gait secondary to sensory ataxia. long-duration MUAPs. and people can develop a rather significant peripheral neuropathy from consuming as little as 116 mg/day. it is not as harmless as once thought. The primary initial symptoms are difficulty in walking secondary to sensory ataxia.792 Pathogenesis. the nerve conduction velocity is reduced by no more than 80–90% of the lower limit of normal.1225 Segmental demyelination also is noted. Dapsone Clinical Features. Sural nerve biopsy has demonstrated significant loss of large myelinated fibers with signs of active Wallerian degeneration. Objective tests of sensation are relatively normal except for minor alterations in a few patients. Electrophysiologic Findings. Deep tendon reflexes are reduced or absent. The CMAP amplitude is borderline normal or reduced in the upper limb and considerably reduced or absent in the lower limb. particularly at the ankles. Over time.285. with an occasional return to normal for the lower limbs. numbness. Unfortunately. Cessation of the drug usually results in recovery. Reflexes are usually preserved but may be diminished in some patients. Plantar responses are flexor.376.1306.1087. Sural nerve biopsy also can reveal a loss of myelinated nerve fibers. Occasional fasciculation potentials may be observed.598. Physical examination demonstrates weakness with accompanying muscle wasting in the distal upper and lower limbs. Distal sensory and motor latencies may be mildly prolonged. long-duration MUAPs.Chapter 23 ACQUIRED NEUROPATHIES — 1003 are usually mildly reduced. An autopsy study has shown degeneration of the spinal roots. 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.1376 Symptoms of a primarily motor neuropathy manifest within 5 days to as late as 5 years after starting the drug. Motor nerve conduction studies demonstrate a mild prolongation in the distal motor latencies for the lower limbs with good preservation in the upper limbs. Electrodiagnostic medicine evaluation documents absent SNAPs or severely attenuated amplitude and slightly reduced conduction velocity.1306. secondary to sensory loss. Needle EMG commonly reveals fibrillation potentials and positive sharp waves in the distal muscles of the lower limbs with significant reductions in recruitment. The CMAPs are either absent or profoundly reduced in amplitude in the foot muscles. and chromatolysis of the anterior horn cells. Electrophysiologic Findings. and some patients are rendered completely quadriparetic. and deep tendon reflexes are reduced or absent. Histopathology.522. Sensory nerve conduction studies usually demonstrate normal or slightly reduced amplitudes. the CMAP may be unobtainable. 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. 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. the same findings are noted in the more proximally located limb muscles. after cessation of the medication.1087. Physical examination reveals decrease of all sensory modalities in the distal regions of the upper and lower limbs. particularly in the distal limb muscles.7. Patients who are elderly or have any degree of renal dysfunction are particularly sensitive to nitrofurantoin.522. although all sensory modalities can be reduced.598.1192 Sensory nerve conduction velocities are normal or only mildly slow. A few patients have mainly a sensory neuropathy with minimal motor involvement.814. Pyridoxine has become a “fad vitamin” in that megadoses (600 mg–3 or 4 gm/day) is supposed to be beneficial for all types of ailments. Histopathology.939. In chronic cases. In the upper limbs. and 41% of patients have initial motor symptoms in both hands and feet. This symptom is especially problematic during eye closure or at night. Physical examination reveals impairment in vibratory perception and proprioception. Pyridoxine is an essential water-soluble vitamin that acts as a coenzyme for multiple transamination and decarboxylation reactions within the body. The hip girdle muscles may be preferentially affected in some patients. In patients with reduced CMAPs. Nitrofurantoin Clinical Features. motor unit remodeling leads to large-amplitude. F-wave latencies can be moderately prolonged with a number of stimuli resulting in no response. The nerve conduction studies usually improve to some degree after medication cessation. Needle EMG usually demonstrates high degrees of fibrillation potentials and positive sharp waves in association with markedly reduced recruitment. Pyridoxine (Vitamin B6) Toxicity Clinical Features. in patients with weakness present for some time.1438 These symptoms can occur as early as 9 days after treatment initiation. the CMAP amplitudes are usually normal or only borderline reduced. Motor nerve conduction studies demonstrate that the distal motor latencies are prolonged by about 10–30% above the upper limit of normal and that conduction velocity is normal or not less than 80–90% of the lower limit of normal. The pathogenic basis of the neuropathy is not known. . and difficulty in walking as well as manipulating objects with the hands. Biopsy of the motor nerve terminal at the extensor brevis muscle has demonstrated axonal atrophy and Wallerian degeneration of the distal motor nerve terminals. In profound disease. Dapsone is used world-wide in the treatment of leprosy and various dermatologic conditions. Roughly 29% of patients note the progression of weakness first in the hands. The pathogenic basis of the neuropathy is not known.797. All abnormalities improve to varying degrees.1225. Sensory loss can begin and be more severe in the upper limbs than in the lower limbs. tingling. It has been reported to result in the development of an acute and profound peripheral neuropathy in which patients complain of pain. Strength is normal.1192. but a complete return to normal may not be achieved. H-reflexes are either absent or mildly prolonged. 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 (Lhermitte’s sign).14.13. 24% of patients first describe some form of weakness in the feet.7.1176 It generally is considered quite safe with a minimum recommended daily allowance of 2–4 mg in adults.939. Fine motor control is impaired.

peripheral nerve biopsies reveal axonal loss of all fiber diameters. and. Ethambutol is another antituberculous medication that can cause a toxic peripheral neuropathy as well as severe optic neuropathy. and deep tendon reflexes are reduced in the legs. impairing HIV replication. Pathogenesis. Furthermore. painful neuropathy. Detailed histopathologic descriptions in humans with nucleoside-induced toxic neuropathies are lacking. Hyperpathia and calf tenderness can be noted. If the INH is stopped early.1177 Typical doses (3–5 mg/kg/day) are associated with a 2% incidence of neuropathy. Motor conduction studies are usually normal.90. A decreased number of myelinated nerve fibers due to axonal degeneration has been noted in human and animal studies. Histopathology. Of importance. Patients describe mild numbness in the hands and feet. Sensory examination reveals a mild loss of all modalities. Isoniazid (INH) is used for treatment of tuberculosis.18 mg/kg/day) are associated with a subacute onset of severe burning and lancinating pains in the feet and hands. diminished pinprick and temperature sensation.106 The QST abnormalities.338 Chloramphenicol This antibiotic also can cause a distal sensory polyneuropathy and optic neuropathy.847 Pathogenesis. lamivudine (3TC). Nerve conductions studies reveal absent or significantly reduced SNAP amplitudes.1083 The neurotoxicity is now rare but occurred more commonly in the past with prolonged courses and large doses. to a lesser degree.338. Examination reveals hyperpathia. symmetric.1083.917.1432 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. which is the suspected pathogenic basis for the neuropathy. Electrophysiologic Findings. Phenytoin Clinical Features. didanosine (dideoxyinosine [ddI]).1084 Most patients treated with . In humans. It can be prevented by coadministration of pyridoxine. and antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) are used in the treatment of HIV infection. The initial symptoms are numbness and tingling in the distal upper and lower limbs. Nucleoside analogs inhibit reverse transcriptase. Recovery at this stage can take months and may be incomplete. Nerve conduction studies are remarkable for diminished amplitudes of the SNAPs with normal sensory distal latencies and conduction velocities. Sensory nerve conductions reveal decreased amplitudes or absent responses. Motor conduction studies are usually normal. The pathogenic basis for the neuropathy is not known. 100 mg/day. Isoniazid Clinical Features.730.847 Nucleosides Clinical Features. the sensory loss spreads proximally and dysesthesias occur. a reduction of the dose leads to improvement in most patients after several months (mean time: about 10 weeks). INH inhibits pyridoxal phosphokinase resulting in pyridoxine deficiency. impaired touch and vibratory perception. Ethambutol Clinical Features.1346 EMG demonstrates fibrillation potentials and positive sharp waves in distal muscles along with decreased recruitment of large. Deep tendon reflexes are diminished distally. if the medication is continued. which usually occur after 6 months of treatment with smaller doses but may begin within a few weeks with large doses.338.1352 Zalcitabine is the most extensively studied nucleoside analog. length-dependent.13.06 mg/kg/day).1023. They also inhibit mitochondrial DNA polymerase.1177 The neuropathy usually occurs in patients receiving prolonged doses in excess of 20 mg/kg/day. Electrophysiologic Findings. Electrophysiologic Findings.14. Histopathology. The pathogenic basis of the neuropathy is not known. diminished deep tendon reflexes.90. precede clinical symptoms or standard nerve conduction abnormalities. polyphasic MUAPs. Nevertheless. patients may continue to worsen even 2–3 weeks after stopping the medication. However. Mild weakness at the ankles and in foot intrinsic muscles is seen in a few patients. Sural nerve biopsies reveal axonal degeneration and loss of both myelinated and unmyelinated nerve fibers. Impaired temperature and vibratory thresholds have been noted on QST.1352 Distal latencies and conduction velocities of the SNAPs are normal. One of their major dose-limiting side-effects is a predominantly sensory. Histopathology.03 mg/kg/day) develop a toxic neuropathy after 1–51 weeks (mean: 16 weeks) after starting the medication.975 Autopsy studies have demonstrated degeneration of the dorsal columns. although unobtainable CMAPs have been described. The neuropathy is characterized by numbness and paresthesias in the feet.1177 Slower acetylation also can occur with age. The CMAP amplitudes are normal or borderline small. 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.103.731 Pathogenesis. Acetyl-carnitine deficiency may contribute to the neurotoxicity. stavudine (d4T).106. the symptoms resolve after a few days or weeks. There are no detailed descriptions of the histologic or electrophysiologic findings. distal muscle atrophy and weakness. Weakness is uncommon.1176. The nucleoside analogs zalcitabine (dideoxycytidine [ddC]). INH is metabolized by acetylation.975. The neuropathy occurs in most patients even at lower doses (0. neuropathy develops in at least 17% of patients taking in excess of 6 mg/kg/day. Needle EMG demonstrates reduced recruitment in distal muscles with occasional fibrillation potentials and positive sharp waves in some patients. The neuropathy is thought to be related directly to INH-induced pyridoxine deficiency. Examination reveals loss of all sensory modalities. The peripheral neuropathy gradually improves after discontinuation of the medication. High doses of ddC (> 0.643.1177 The neuropathy is more likely in the elderly and malnourished patients and so-called slow acetylators. Electrophysiologic Findings. although it is less severe. particularly vibratory perception.1177 Pathogenesis.1176 The sensory nerve conduction velocities are minimally reduced when they can be recorded. and occasionally ataxia. a coasting effect can be demonstrated. distal weakness and aching of the calves may develop. motor conduction velocities and distal latencies are usually spared or only mildly abnormal. Examination reveals a loss of large fiber modalities and reduced reflexes distally.933. Insufficient data are available. The upper limbs usually are spared.997. One of its most common side effects is peripheral neuropathy. As many as 34% of patients taking even lower doses of ddC (0. but recovery of the optic neuropathy is more variable.90. Phenytoin is a commonly used antiepileptic medication.1004 — PART IV CLINICAL APPLICATIONS Histopathology.

INDUSTRIAL AND ENVIRONMENTAL AGENTS A number of known toxic substances are used in the manufacturing process of multiple materials. The CMAP amplitudes in most patients are normal. However. . sweating. The pathogenic basis of the neuropathy is not known. with some normalization of the nerve conduction studies and needle EMG abnormalities. myalgia. arthralgia.1195.567. but conduction velocities may be normal or significantly slow. accompanied by evidence of vasculopathy and angioneogenesis. Eosinophilia-Myalgia Syndrome Clinical Features.1316 Other patients developed a severe peripheral neuropathy simulating Guillain-Barré syndrome567. Similar findings have been demonstrated in animal studies. the SNAP amplitudes are reduced in both upper and lower limbs with mildly to moderately reduced conduction velocities. Pathogenesis. most patients respond well to lowering the phenytoin levels. F-waves are either present but prolonged and not present after each stimulus. appropriate precautionary measures can be instituted to protect workers. mainly mononuclear with occasional eosinophils and often perivascular. multiple people all too often become impaired before a substance is recognized as hazardous to human health.780. The CMAPs amplitudes may be profoundly reduced or absent in the lower limbs with mild to moderate amplitude reduction in the upper limbs. The absolute eosinophil count is elevated (>1 × 109 cells/L).e. cough.1317 Usually they present with central nervous system toxicity.1152. Needle EMG demonstrates positive sharp waves and fibrillation potentials in the distal limb muscles with reduced MUAP recruitment and increased potential amplitude and duration. and vibration as well as diminished or absent deep tendon reflexes at the ankles. endoneurium.1'-ethylidenebis tryptophan (EBT). in the epineurium. Lithium Clinical Features. fibrillation potentials and positive sharp waves are found in the distal muscles of the upper and lower limbs. overt symptoms of numbness and tingling as well as difficulty in ambulating may be present. and the distal motor latencies are normal or only mildly prolonged. Electrophysiologic Findings. Autoantibodies are absent and ESR usually is normal.856 The mechanism by which the contaminant resulted in the disorder is unknown.1231 or mononeuropathy multiplex. and/or perineurium.160. the disorder has all but disappeared. peripheral edema. polyphasic MUAPs is reduced.925. loss of sensation distally. Some patients consuming the offending L-tryptophan presented with progressive symptoms of fever.1084 Pathogenesis. or proximal and distal distribution with accompanying myalgias. Nerve biopsy demonstrates a loss of large myelinated fibers with little demyelination. rare patients develop symptoms and signs of a mild. 330. Laboratory Features. Pathogenesis.1316 The distal sensory latencies usually are normal. Electrophysiologic Findings.Chapter 23 ACQUIRED NEUROPATHIES — 1005 phenytoin do not complain of symptoms suggestive of peripheral nerve compromise. Needle EMG in most patients is normal. Conduction block is also evident in some cases.1275 Histopathology. early recruitment of MUAPs with reduced durations and amplitudes). Lithium can result in central nervous system toxicity with findings of tremor. Treatment. and seizures.567. skin rash.1152.1231. dysarthria. in about 20% of patients taking only phenytoin.952. Histopathology. Once they are identified. confusion. or simply absent.567. Sural nerve biopsy may reveal loss of the large myelinated axons with some accompanying segmental demyelination and subsequent evidence of remyelination. The few reported electrodiagnostic medicine studies demonstrated absent SNAP and CMAP responses in the lower limbs with reduced amplitudes.1316 Significant axonal degeneration is also appreciated. Such patients may demonstrate a mild degree of weakness in the distal muscles of the upper and lower limbs.1152. and depressed or absent deep tendon reflexes. as well as electrocardiographic and electroencephalographic abnormalities. Distal motor latency usually is well preserved.567. but patients may demonstrate weakness. In patients who are clinically toxic with elevated blood levels. primarily sensory neuropathy. primarily through the production of a distal axonopathy. Deep tendon reflexes usually were depressed in the upper limbs and absent in the lower limbs. in persons with significant toxicity.1131 After identification and removal of the contaminant. affecting primarily the sensory fibers. Needle EMG examination revealed positive sharp waves and fibrillation potentials as well as complex repetitive discharges. however.1231. Several industrial agents are known to affect the peripheral nervous system adversely. and occasional alopecia. Two trace adulterants have been identified as the possible toxins: 3-phenylamino alanine (PAA) and 1. but relatively normal conduction velocities in the upper limbs. Electrodiagnostic medicine findings may reveal alterations suggestive of a mild peripheral neuropathy. Histopathology. About 30% of patients also had symptoms and signs suggestive of a progressive sensorimotor peripheral neuropathy. suggesting a major demyelinating component. obtundation. Phenobarbital can result in a peripheral neuropathy with similar findings.1212 In patients with definite symptoms and signs of a peripheral neuropathy. Fortunately. a number of patients also had a primary myopathy or combination of myopathy and peripheral neuropathy. but eosinophilia and eosinophilic infiltrate in tissues suggest some form of allergic reaction. A few patients have developed significant sensorimotor peripheral neuropathies after lithium administration. Motor conduction velocities are low normal or mildly reduced. The serum CK level may be normal or elevated.1212. Recruitment of large-amplitude. Patients demonstrate a progressive loss of strength in a proximal.. Some patients experience relapses after withdrawal of steroids. Nerve biopsies reveal inflammatory infiltrate. long-duration. position sense.1195. The pathogenic basis of the neuropathy is not known. Multimodality stocking-and-glove sensory loss was worse in the lower limbs. After drug withdrawal. Discontinuation of L-trytophan and treatment with high-dose corticosteroids usually are effective. The numbers of voluntary MUAPs were markedly reduced in the distal limb muscles.1195 In addition. Some patients have MUAP parameter alterations consistent with a myopathic process when proximal girdle muscles are examined (i. This interesting disorder arose from the ingestion of contaminated L-tryptophan in the latter part of the 1980s and early 1990s. Electrodiagnostic medicine evaluation reveals reduced or absent SNAPs in the lower limbs with diminished-amplitude SNAPs in the upper limbs.829. symptoms related to central nervous system toxicity resolve.1231. There is usually a loss of touch.1195. distal. Electrophysiologic Findings. Unfortunately.

Deep tendon reflexes are depressed in the upper limbs and markedly diminished or absent in the lower limbs. After elimination of acrylamide exposure. Sensory nerve biopsies reveal the loss of primarily. Carbon disulfide is used in the manufacture of viscose Rayon products and sheets of cellophane.1177 Pathogenesis. but not exclusively. despite clinical symptoms and signs. and none has included needle EMG. Distal weakness of the hands and feet is noted. and temperature sensation. electrophysiologic studies return to normal values. After cessation of the toxic exposure. but theories include (1) a chelating effect on enzyme function. After elimination of exposure to acrylamide. (2) direct inhibition of various enzymes. CMAP amplitudes are at the lower range of normal. gait difficulties. in patients exposed to large amounts. Histopathology.1356 Patients complain of distal numbness and tingling.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.418.269. pain. Needle EMG examination may reveal fibrillation potentials and positive sharp waves in the distal limb muscles. H-reflexes in the lower limbs are commonly absent.1177. Pathogenesis.782 Sensory nerve conduction velocities are normal or only slightly reduced. Detailed descriptions of the histopathology in humans are lacking.1170.609 After exposure. slow and clumsy alternating hand motions. and altered mentation. However. electrophysiologic data may improve in a few patients.782 Patients have a loss primarily of large fiber function.252. A few sural nerve biopsies reveal primarily axonal degeneration with loss of large myelinated fibers.441. Chronic low-level exposure may present with mental confusion and hallucinations in addition to weakness. with some evidence of intrinsic foot muscle wasting and a wide-based gait. optic tracts. Motor nerve conduction studies demonstrate well-preserved distal motor latencies and only an occasional mild reduction in conduction velocities. Heel-to-shin ataxia. but it is believed that acrylamide impairs fast bidirectional axonal transport as well as slow antegrade transport. Nerve conduction studies demonstrate a reduction in the SNAP conduction velocities and may be the only abnormality noted early in the disease. The pathogenic basis of the neuropathy is not known. Pain and paresthesia are uncommon. Only a small number of electrodiagnostic medicine examinations have been reported in humans. large myelinated fibers. Some degree of temporal dispersion of the CMAPs can be observed in patients exposed to high levels of the substance. a distal sensorimotor polyneuropathy develops. and occasionally urinary incontinence. The distal motor latencies may be normal or slightly prolonged. Acute exposure to high levels produces various psychotic disturbances. Ethylene oxide can act as an alkyating agent and bind with many organic molecules. Ataxia. The primary manifestations of human exposure are dermatologic lesions. vomiting. Motor conduction studies demonstrate comparatively less pronounced slowing of conduction. and electrophysiologic findings. A mild reduction in muscle strength can be detected in the intrinsic foot and distal lower limb muscles. Patients may be ataxic and demonstrate a positive Romberg sign.1177 Enlargement of the distal axons with subsequent axonal degeneration and segmental remyelination can be seen. No comments have been made about the CMAP amplitude during the disease process. nerve conduction studies are relatively normal. and the corticospinal tracts also can be found. Pathogenesis. and patients may not recover completely. People exposed to high levels can develop a severe sensorimotor peripheral neuropathy.509. function gradually returns. Shortly thereafter. especially in the lower limb. but SNAPs are usually markedly reduced in amplitude. patients develop contact dermititis with excessive sweating and peeling of erythematous skin over the same regions. primarily in the distal aspects of the lower limbs. but carbon disulfide can also be absorbed through the skin. The monomer is a white powder that can be absorbed through the skin or inhaled. Ethylene oxide is one of the most widely used industrial substances. mucosal membrane irritation. is an important industrial agent in the form of a white crystalline substance. 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. similar to that seen in acrylamide and hexocarbon toxicity.441. especially in the lower limbs. mamillary bodies. histologic. but many simply no longer progress and maintain a new steady state of neural conduction slowing. which resolve with elimination of exposure. experimental studies in animals have shown accumulation of 10-nm neurofilaments and axonal swellings. Acrylamide. A course tremor may be noted in the hands. In patients chronically exposed to low levels. The exact pathogenic basis for the neuropathy is not known.1354 The primary route of entry is through inhalation. and increasing irritability can be seen.742 Sensory conduction velocities are diminished but usually not below 80% of the lower limit of normal. Motor conduction studies demonstrate reduced . particularly in the health care setting. Distal muscle atrophy and weakness may be evident. The exact pathogenic basis is unknown.609. Histopathology. The polymerized form of the monomer produces a substance used as flocculators and in grouting agents. Electrophysiologic Findings.1252 Carbon Disulfide Clinical Features.1170.1177 Electrophysiologic Findings. a vinyl monomer.449 A few patients have been reported to become ill after exposure to water contaminated by acrylamide grouting of wells. Histopathology. dysarthria.1343 The amplitudes of the SNAPs have not been addressed in detail.1006 — PART IV CLINICAL APPLICATIONS Acrylamide Clinical Features. These modest abnormalities are usually observed only in patients suffering from acute intoxication. and (3) release of free radicals after cleavage of the carbon-sulfur bond with secondary axonal damage. nausea.609. spinocerebellar tracts.1177 Electrophysiologic Findings. including DNA. Electrodiagnostic medicine evaluation reveals reduced amplitudes or absence of sensory responses. Examination demonstrates a reduction in sensory modalities. usually beginning in the lower limbs and progressing to involve the upper limbs. Chronic low-level exposure can result in a peripheral neuropathy.53.1177. Patients with low levels of exposure usually do quite well. significant improvement may require a year or more. Ethylene Oxide Clinical Features. However. and diminished deep tendon reflexes are present.1184 Patients usually complain of acral hypesthesia and paresthesias accompanied by difficulty in walking and increased fatigability. Animal studies have verified a number of the above-noted clinical. Reductions in all sensory modalities can be demonstrated and accompanied by a diminution in deep tendon reflexes. Unmyelinated fibers as well as degeneration of the posterior columns. It is used for sterilizing heat-sensitive materials.

There are no onion-bulb formations or inflammation. at which time the upper limbs become numb. positive sharp waves. Rather. Toxic exposure to organophosphate esters can result in muscarinic. Weakness is also an early finding. but it is present throughout the CNS and PNS. Physical examination is commensurate with the above symptoms. Electrodiagnostic findings in the acute and subacute stages of the disease are consistent with neuromuscular dysfunction secondary to compromise of acetylcholinesterase. Symptoms and signs may progress to involve the hands. Organophosphates do not cause the toxic neuropathy by inhibiting acetylcholinesterase. Electrophysiologic Findings. Histopathology. Progressive loss of motor function ensues. Histopathology.608.719.1197. Supportive care is of primary importance to see the patient through the several weeks of crisis. Pain and temperature sensation are only mildly reduced. The . the CMAP amplitudes initially decrement but then recover. Pathogenesis. Needle EMG reveals a reduction in voluntary MUAPs. is the demonstration of repetitive firing of the CMAPs after a single neural stimulus. Sensory and motor evoked response amplitudes are reduced with only mild prolongation of the distal latencies.197.472.98. most patients note numbness and tingling in the feet.1177 In addition. It has been speculated that the neuropathy is due to hexacarbon interactions that lead to covalent cross-linking between axonal neurofilaments. Sphincter function usually is preserved. Central effects can produce anxiety. Needle EMG reveals significant reduction in voluntary MUAPs with attempts at muscle contraction and positive sharp waves and fibrillation potentials at rest. EM reveals that the swollen axons are filled with 10-nm neurofilaments. A profound subacute sensorimotor polyneuropathy progressing over the course of 4–6 weeks can develop secondary to hexacarbon toxicity. Motor nerve conduction velocities also are slightly decreased.300. Some patients with acute organophosphate toxicity later develop a distal sensorimotor peripheral neuropathy (organophosphate-induced delayed polyneuropathy [OPIDP]).224. and seizures. Acute intervention is directed at maintaining ventilation and circulation through the administration of atropine to counteract the muscarinic effects.1253.98. 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.695 Lower limb SNAPs are preferentially affected. the substance believed to be responsible for the toxic neuropathy. before the toxic neuropathy develops.1309 Some degree of demyelination also is noted. and bradycardia.1233. Nicotinic actions result in generalized weakness and fasciculations. The clinical manifestations can result from inhaling vapors or through skin absorption. the sensory and motor conduction velocities are usually at the lower limits of normal or mildly reduced. but in profound disease upper limb SNAP responses also may be markedly reduced or absent. pulmonary edema. altered mental status. Organophosphates Clinical Features. specific organophosphates cause OPIDP by binding to and inhibiting an enzyme called neuropathy target esterase (NTE). At both low (2–5 Hz) and high (20 Hz) rates of repetitive stimulation.1197. the prognosis is good.1374 OPIDP evolves several weeks after exposure and maximizes within several weeks.Chapter 23 ACQUIRED NEUROPATHIES — 1007 amplitudes or absent CMAP responses. approaching the baseline amplitudes. Electrophysiologic Findings. Of note. unconsciousness.18. The exact mechanism by which hexacarbons cause a toxic neuropathy is not known. The electrodiagnostic examination in OPIDP reveals findings consistent with an axonal sensorimotor polyneuropathy. proximal muscle and cranial nerve weakness can develop. During this period.1177. plastics. thus producing the acute clinical symptoms and signs. However. Both n-hexane and methyl n-butyl ketone are classified as hexacarbons and are metabolized in the body to 2. Needle EMG demonstrates fibrillation potentials. Likewise. Pathogenesis.583 The posterior columns and dorsal root ganglia appeared to be spared. In some patients an interesting decrement-increment phenomenon can be detected after a mild exposure or in the recovery phase. 23-10). and central effects.482. A flaccid weakness is accompanied by loss of deep tendon reflexes and position/vibration sense. Within 12–96 hours a so-called intermediate syndrome may become evident after the onset of acute muscarinic actions.1373 These compounds inhibit acetylcholinesterase and result in the accumulation of acetylcholine at cholinergic synapses (see Chapter 25). with impaired ambulation and decreased fine motor coordination skills.1309 Initially. emotional lability. but axonal loss is clearly the dominant finding.813. Death can result from respiratory failure and cardiovascular collapse.583.1376 Sensory and motor nerve studies are normal. The electrodiagnostic evaluation demonstrates decreased amplitude of the SNAPs with normal or only mild slowing of sensory conduction velocities or prolonged distal latencies.583. diarrhea. The nerve biopsy can demonstrate evidence of profound loss of myelinated as well as giant axons (Fig. and reduced recruitment of MUAPs. abdominal cramping. nicotinic. and petroleum products and as toxic nerve agents in biologic warfare.5-hexanedione. The muscarinic effects can cause nausea. however. Exuberant perspiration may be noted on the soles of the feet. The organophosphorous esters are used primarily in the production of insecticides. Accidental exposure in factories and intentional glue sniffing account for most peripheral neuropathies associated with these compounds. Inhibition of NTE is not sufficient for the development of OPIDP. as are swallowing and respiratory functioning. The MUAPs are increased in duration and amplitude as well as number of phases. Hexacarbons are water-insoluble industrial organic solvents with a high vapor pressure.482. Patients may note cramping in the calf muscles followed by burning or tingling in the feet. Weeks after the development of the peripheral neuropathy. and eventual axonal degeneration. In patients with mild peripheral neuropathy. 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.1344. Hexacarbons (Glue Sniffer’s Neuropathy) Clinical Features.1344.1196. whereby a lateral side-chain of NTE is cleaved. along with respiratory compromise. patients with significant peripheral and central nervous system insult generally are left with reduced abilities to perform activities of daily living.1177 Impaired transportation of cross-linked neurofilaments leads to aggregation.1177. A decrement can be observed in response to low rates of repetitive stimulation and persists for about 4–11 days. The organophosphate-NTE complex must age. swelling of the axons. A progressive loss of sensation in the proximal leg may occur.578. vomiting.813 The function of NTE is not known. Multiple instances of accidental and intentional intoxication by types of organophosphorus compounds have resulted in neurologic complications. superimposed signs of central nervous system dysfunction with increased tone and hyperreflexia may be seen.576. ataxia.

1241 Such cases are extremely rare.94. It is unclear whether the primary target of the toxic insult is the anterior horn cell or. a few nerves in both upper and lower limbs may demonstrate conduction velocities approaching 50% of the lower limit of normal.36. Alterations . Additional Agents Other agents reported to result in a preferential axonal sensorimotor peripheral neuropathy include dichlorophenoxyacetic acid and carbon monoxide. Laboratory Features.164 Pathogenesis. 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.470.1199. can produce primarily axonal Lead Clinical Features. With respect to the neuropathy. accompanied by varying degrees of constipation. batteries. Histopathology. In children. Patients usually have some abdominal discomfort. the most common finding is an increase in the MUAP amplitude. although a few patients may have attempted suicide or are the victims of attempted homicide. children and adults can present with symptoms and signs of a primarily motor peripheral neuropathy.1420 Electrophysiologic Findings. basophilic stippling of erythrocytes. the peripheral or motor nerve. and number of phases.1420 The severity of the neuropathy is usually related to the amount of metal that enters the patient’s system either acutely or chronically. or paints containing lead products. which can be magnified by the addition of a chelating agent in suspicious cases. Physical examination demonstrates a reduction in pain and temperature with relatively good preservation of proprioception and vibration. distal latency. segmental demyelination. and plantar responses are flexor.1420 Nor is the exact pathogenic mechanism by which lead causes axonal degeneration known. producing a chronic low-level.408. Exposed workers can develop a peripheral neuropathy that is primarily sensory.409.1223.1200. mild cases of neuropathy may be associated with normal CMAPs. and velocity have been reported to be mildly abnormal in studies of relatively large numbers of patients exposed to various forms of lead.123. markedly swollen axons. and sensory examination to all modalities is usually well preserved. from which they are slowly released. In motor and sensory nerve conduction studies. Further studies are required to characterize the peripheral neuropathy in greater detail.183.927 On needle EMG.409. (Epoxy-embedded. an improvement is noted. Laboratory investigation can reveal an elevated serum coproporphyrin level. There is generally a reduction in the number of large myelinated axons with little.1420 It occasionally can be seen in children who consume lead-based paints in older buildings and in industrial workers dealing with metals. HEAVY METAL INTOXICATION A number of metals. toluidine blue stain). However. There are few or no sensory complaints. CMAP amplitudes are decreased in the upper and lower limbs.633. Clinical improvement depends on cessation of exposure and supportive measures. These findings usually are accompanied by fibrillation potentials and positive sharp waves. A 24-hour urine collection demonstrates elevated levels of lead excretion. In some patients. the most common presentation of lead poisoning is encephalopathy. an asymmetric foot drop is likely.1420 A so-called lead line can be seen in some patients.1199.164.1202. and reduced hemoglobin content. However. Deep tendon reflexes are diminished. Most patients are exposed to heavy metals as a result of workrelated activities. especially those with high atomic weights (so-called heavy metals). and only a few patients have been cited in the literature. suggesting a microcytic/hypochromic anemia. Limited electrophysiologic testing demonstrates a mild reduction in motor conduction velocities in the lower limbs. Sural nerve biopsy reveals thinly myelinated. The combination of systemic effects and peripheral nerve dysfunction at times helps to distinguish the type of metal involved. Figure 23-10. It manifests as a bluish-black coloration of gums near the teeth. duration.1223 When these values are compared with values after treatment. a number of the heavy metals can enter various storage zones in the body. When the lower limbs are involved. Usually strength is preserved and patients can ambulate without difficulty aside from pain in the feet.1008 — PART IV CLINICAL APPLICATIONS neuropathies in humans.123.83 Burning paresthesias begin in the feet and progress up the legs. Vinyl Benzene (Styrene) Vinyl benzene or styrene is an industrial liquid used in the manufacture of some plastics and synthetic rubber materials.408. more distally. Nerve conduction velocities are usually reduced to about 70–80% of the lower limit of normal. 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. patients may note the insidious and progressive onset of upper limb weakness. although laboratory determination of serum and urine metal levels is the definitive method of diagnosis. Multiple organ systems can be involved in addition to the peripheral nervous system. continual-dosing phenomenon. Unfortunately. amplitude. It has been speculated that lead may interfere with mitochondrial function.695 Needle EMG examination reveals a reduced number of MUAPs firing at rapid rates in distal muscles. Lead neuropathy is an increasingly rare cause of peripheral nerve disease because of the realization of its harmful effects. Deep tendon reflexes are well preserved. Hexane neuropathy. Some patients also have readily detectable fasciculation potentials. if any. The classic sign is noticeable motor involvement of the radial nerve with a wrist/finger extensor weakness.

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. but the number of treated cases is too small to allow comment on efficacy. Thallium Clinical Features. Distal motor latencies are normal in most patients. Perhaps the most infamous case of organic mercury poisoning resulted from dumping mercuric chloride into Minimata Bay. Pain and temperature sensation is reduced. Mercury vapors exert their toxic effect through their high lipid solubility and thus result in central nervous system effects such as loss of appetite. and odorless salts (sulfate.1420 Prominent degeneration of axons in the sural nerves and lumbar dorsal roots was also observed. Laboratory Features. gastrointestinal symptoms predominate. and dysarthria. Distal muscle atrophy and weakness gradually ensue. Segmental demyelination was absent. It is hypothesized that mercury exerts its toxic effect on neurons by combining with sulfhidryl groups of enzymatic or structural proteins. An initial manifestation of organic mercury poisoning is paresthesias in the distal regions of the limbs.836. With severe intoxication. consist of various mercury salts. the paresthesias progress proximally. Chelating agents such as penicillamine have been used. syphilis. Some degree of peripheral neuropathy may be manifest in particularly sensitive patients. Treatment.5. a number of abnormalities may be found. eventually involving the tongue. patients exposed to mercury present with abnormalities suggestive of motor neuron disease. These solutions are both colorless and highly toxic. Histopathology. and fatigue. Subsequently thallium was used primarily as a rodenticide.1224. Intoxication results from exposure to either organic or inorganic mercurials. The lethal dose of thallium in humans is rather variable but averages about 1 gram or 8–15 mg/kg body weight. Over time. on the other hand. and psychotic behavior may be noted. In patients with long-standing exposure. British anti-Lewisite (BAL). sleep disturbances.1211. proximal weakness and involvement of the cranial nerves can occur. Pathogenesis. although nephrotic syndrome may be a major problem. Treatment. The sural and superficial peroneal nerves may reveal reduced SNAP amplitudes and normal or slightly reduced (> 80% of lower limit of normal) conduction velocities.614.1420 Mercury Clinical Features. Initially thallium salts were used to treat a variety of conditions. the absolute value in individual patients is within normal limits and. these conclusions are of little value because they were performed 7 months or more after cessation of exposure.1205. and carbonate) that are highly soluble in aqueous solutions. Some patients require mechanical ventilation as a result of respiratory muscle involvement.1420 The mainstay of treatment is removing the source of exposure. therefore.1069.342. In acute poisonings with mercury salts. Accidental and intentional poisonings resulted in the banning of thallium for any purpose in the United States in 1965. The population dependent on the fish and crustaceans for food developed mercury poisoning. however.1305 In patients with low blood levels despite clinical symptoms.1069. Occasionally. hence accounting for ataxia and visual complaints. such as tuberculosis. sensory studies may yield low normal values for amplitude and conduction velocity.1367Electrodiagnostic findings in patients exposed to organic mercury and mercury vapors may be abnormal.1420 The burning pain in the feet may be severe enough to limit ambulation. mental confusion.779. where sea life converted the substance into methyl mercury.8. but recruitment is normal. somatosensory evoked potentials of the median nerve demonstrate peripheral potentials but no cortical potentials. acetate. F-wave and H-reflex latencies can be normal or slightly prolonged.1146 Several investigations have noted a distinct lack of electrophysiologic abnormalities in patients with proven mercury exposure. Although this may be statistically significant when patients are compared with a control population. Mercury vapors in poorly ventilated industrial areas also can be a significant health hazard. Fibrillation potentials and positive sharp waves can be seen in the affected muscles. It is. of little diagnostic use. and 24-hour urine collection can reveal an increased concentration.1305 Motor conduction velocities are usually normal or borderline slow with normal CMAP amplitudes. Thallium is a heavy metal that can exist as a monovalent or trivalent species. which are used primarily for industrial purposes. The gastrointestinal system is believed to be the major source of entry into the human body. Chelation therapy with calcium disodium ethylenediamine tetraacetate (EDTA). retrosternal pain. In addition to nausea and abdominal pain. visual and hearing loss. and ringworm. The actual mercury metal or fluid at room temperature is reported to be nonhazardous because it is apparently poorly absorbed from the gastrointestinal tract. Therapeutic use was abolished after full recognition of its toxic effects. Deep tendon reflexes are reduced distally but generally preserved proximally. however.342.1420 The organic form is usually found in methyl or ethyl mercury.1420 Monovalent thallium ions are present in multiple tasteless. The inorganic mercury compounds. Death can result in less than 48 hours after a particularly large dose. . thirst.5 Quantitative motor unit analysis typically demonstrates MUAPs with increased duration and amplitude. reduced mentation.1420 The primary site of pathology appears to be the dorsal root ganglia. but there is usually a lack of abnormal spontaneous activity. still available worldwide as a rodenticide and from time to time may be recognized in victims of homicide attempts. The most important treatment is removing the source of the exposure. Such findings in patients with low-level exposure over years suggests a slow loss of axons with subsequent motor unit remodeling.656. and vibratory perception and proprioception are mildly decreased. Little of the metal may be excreted in the urine because it is highly lipid-soluble and thus remains in the body. When patients with high serum or urine levels are examined. venereal disease. thereby impairing their proper function and leading to degeneration of the neurons. Patients may display ataxia. The needle EMG examination may reveal positive sharp waves and fibrillation potentials in some patients. is readily excreted in the urine. Inorganic mercury. and pencillamine demonstrates variable efficacy. Only a few electrodiagnostic medicine evaluations have been reported in patients with ongoing mercury exposure. Histopathologic evaluation of patients exposed at Minimata Bay demonstrated significant degeneration of the calcarine aspect of the cerebral cortex and cerebellum.Chapter 23 ACQUIRED NEUROPATHIES — 1009 in recruitment usually are not noted until there is moderate loss of axons. Organic mercury intoxication can be extremely difficult to prove. weight loss. Electrophysiologic Findings.

The primary pathologic reaction of the peripheral nervous system to thallium intoxication is axonal loss.342. In particular. Some patients may require mechanical ventilation. in time one can observe multiple Mee’s lines on examination. CNS symptoms may predominate with rapid progression to death due to vascular collapse. these nerves should be examined. also can be demonstrated. Motor conduction studies in the lower limbs can reveal absent CMAPs in the foot intrinsic muscles. or fingernails of affected patients. but the CMAP is markedly reduced. Over the ensuing weeks. thus reducing the number of observed abnormal spontaneous potentials.497a. hence. CSF protein levels also are elevated. Needle EMG examination within the first few days of exposure may reveal only a reduced recruitment of motor units.Because patients usually complain of plantar foot pain.342 Chromatolysis of cranial and spinal motor nuclei and dorsal spinal ganglia has been demonstrated. as seen in AIDP. hair root pigmentation. Serum and urine levels of thallium are increased. Some patients display slow mentation and confusion. It is not known whether the primary insult is to the neuronal cell body or the axons. Mitochondria can appear swollen in experimental cultured neuronal tissue. but it may not be evident until the third or fourth week after exposure and can be rather mild in some patients. progressive loss of muscle strength develops distally. When these responses are present. Pathogenesis. Unfortunately. vomiting..928. A reduction in total numbers of large. but occasional onion-bulb formations are evident.981. and possible hyperreflexia. An electrodiagnostic examination of the patient within the first few days of intoxication reveals no significant abnormalities. Variations in skin coloration create patchy regions with various degrees of increased or decreased pigmentation. The pathogenic basis for the toxicity is also unknown. particularly in the lower limb.981.185. followed within several days by a burning sensation in the feet and hands. Autopsy studies have revealed a loss of anterior horn cells. Clearance from blood is rapid.g.1447 The neuropathy begins 5–10 days after ingestion of arsenic and progresses for several weeks. Within the next 10 days intrinsic foot muscles reveal evidence of denervation by way of positive sharp waves and fibrillation potentials. As in lead intoxication. Maintaining adequate diuresis helps to eliminate thallium from the body without increasing tissue availability from the serum. H-reflexes may be present within the first 10 days after exposure but then disappear and may not return for some time. Treatment.796 By 10 days after thallium exposure. nausea. With acute intoxication. There can be loss of the superficial epidermal layer several weeks after the initial exposure or with chronic low levels of ingestion. They correlate with arsenic exposure. With severe intoxication. It is believed that arsenic reacts with sulfhydryl groups of enzymatic and structural proteins in the neurons. motor nerve conduction studies are .1420 Specifically. Mee’s lines.984. therefore. Electrophysiologic Findings. Arsenic levels are increased in the urine. and diarrhea. By the second and third weeks. Serial studies demonstrate an initial reduction in amplitude in both upper and lower limb CMAPs with a gradual increase over the ensuing years.1010 — PART IV CLINICAL APPLICATIONS Within the first week.631. The upper limb SNAPs are also absent or markedly reduced in amplitude.65. There is a general reduction in nerve fibers of all diameters. the conduction velocity is mildly reduced. Diminished deep tendon reflexes are also noted commensurate with the degree of strength loss.1420 Arsenic Clinical Features.296. Laboratory Features. Soon thereafter.221. especially in the lower limb.410. an acne/malar rash.221. potassium ferric ferrocyanide II may prevent absorption of thallium from the gut. Peripheral nerve biopsies in patients with arsenic poisoning demonstrate an increase in interstitial fibrosis as well as increased endoneurial cells. When obtainable. and mercaptopurine also can result in hair loss. Such symptoms and signs can be suggestive of AIDP. Motor unit remodeling generates MUAPs with elevated amplitudes and durations. chloroprene. With time the denervated muscle fibers are reinnervated. Of note. hair. suggesting central nervous system toxicity. azotemia. Arsenic is another heavy metal that can cause a toxic sensorimotor polyneuropathy.928. sensory studies commonly reveal complete absence of the SNAPs. When present. Of importance. Routine laboratory testing can reveal anemia. pain.497a. This finding is important because the most distal aspects of the peripheral nervous system are preferentially affected first. In patients with both long fingernails and repeated intoxication. basophilic stippling of erythrocytes occasionally is observed as well as an aplastic anemia with pancytopenia. Histopathology. 1420. serum concentration of arsenic is not diagnostically helpful. it is not clear whether the medication is effective once thallium has been absorbed. weakness progresses to the proximal muscles and cranial nerves. Not uncommonly. These abnormalities progress to affect the more proximal muscles in the lower limbs. Segmental demyelination is rare. mild tachycardia and hypertension are noted as well as hyporeflexia about the ankles and the beginning of alopecia. thallium poisoning).and small-diameter myelinated fibers results from axonal degeneration. The hallmark of thallium poisoning is alopecia. alopecia is not pathognomonic for thallium intoxication because exposure to vincristine. arsenic may inhibit the pyruvate dehydrogenase complex. Electrophysiologic Findings.631. The pathogenic basis of arsenic toxicity is not known. the CMAPs may be absent. it is possible to note an absence of the medial and lateral plantar mixed nerve action potentials with preserved sural nerve SNAPs. The traditional electrophysiologic abnormalities are consistent with a primarily axonal sensorimotor polyneuropathy.1420 The resulting impairment of cellular metabolism may lead to neuronal degeneration. with little or no segmental demyelination. such nail abnormalities can be seen in disorders other than arsenic poisoning (e. acute arsenic intoxication should be kept in mind when evaluating patients with an acute onset of sensory and motor loss.1420 However. may become evident by 1 or 2 months. Increased CSF protein levels without pleocytosis. Wallerian degeneration is the prominent feature noted on peripheral nerve biopsy. patients may display continued vomiting. and liver function abnormalities. Limiting the sensory examination to the sural nerve can result in disappointingly normal studies despite profound symptoms. The distal motor latencies are normal or mildly prolonged. Clinical skin changes may be helpful in raising the suspicion of arsenic intoxication. the SNAP is usually reduced in amplitude. If the ingested dosage is large enough. the more proximal lower limb sensory nerves are affected. and the distal sensory latencies or conduction velocities are mildly abnormal. which are transverse lines at the base of the fingernails and toenails.1420 Pathogenesis. Histopathology. Laboratory Features.440. chelating agents are not particularly useful. Most patients with acute arsenic poisoning complain of abrupt onset of abdominal discomfort.

1420 Electrophysiologic Findings. Treatment. if any. Treatment. It may be related to an immunologic reaction triggered by gold therapy.e. Histopathology. and cardiac conduction blocks may be identified. This section. Patients usually present with complaints of numbness and tingling or burning in the soles of the feet. is not dramatic. with some patients displaying similar sensory findings in the hands. Histopathology. patients with significant neuropathy may show complete absence of SNAPs in the lower limbs with significant reductions in amplitude of upper limb SNAPs.599. indicating both axonal degeneration and segmental demyelination of varying degrees. Both forms are associated with neurologic symptoms.. The few studies that have been performed in humans found a number of peripheral nerve alterations.. weakness may be noted in the distal muscles of the lower limbs. BAL has been tried in a few patients. focuses on patients with a primary thiamine deficiency unrelated to excessive alcohol ingestion.781. Motor studies and needle EMG are normal. 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. Prisoners of war and people consuming milled rice. Maximum abnormalities in motor nerve conduction studies occur approximately 3–5 weeks after exposure. Distal motor latencies are not especially affected. myokymia). Chelation therapy with BAL has yielded inconsistent results in small retrospective studies. . 80–90% of the lower limit of normal). Return to normal requires several years. A mild to moderate reduction in all sensory modalities is noted in a stocking distribution. with depressed upper limb reflexes.g. Electrodiagnostic medicine findings are somewhat variable.320. sodium aurothiomalate) is sometimes used to treat rheumatoid arthritis. The pathogenic basis for the neuropathy is not known.288. On the other hand.463. which always should be examined. associated with progressive conduction block and reductions in the conduction velocities. rash and pruritus) to gold is also noted. Sural nerve biopsies reveal significant axonal loss primarily of large myelinated fibers with little segmental demyelination. Serial studies demonstrate progressive deterioration of the CMAP amplitudes to distal stimulation. accompanied by similar sensory symptoms in the fingertips. with or without accompanying positive sharp waves and fibrillation potentials. Thiamine deficiency is rare except in people who consume alcohol as their major source of nutrition. Patients with connective tissue diseases who do not take gold therapy also can develop peripheral neuropathies.900. Beriberi primarily results from a diet high in processed foods without appropriate vitamin supplements. Calf tenderness may be noted in some patients.e. from which the outer coating is removed. therefore.. needle EMG examination reveals an increase in insertional activity and reduced MUAP recruitment. membrane instability may be noted only in the paraspinal muscles. a systemic reaction (e.1420 Most patients complain first of paresthesias in the distal aspects of the lower and sometimes upper limbs. Myokymia may be noted in both upper and lower limb muscles in some patients.1420 Gold Clinical Features.g. 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. Symptoms due to insufficient dietary intake of thiamine are known as beriberi and may present in two forms: dry and wet. its use is not recommended. The important point about the studies defining the above abnormalities is that they were performed somewhat late in the disease. Pathogenesis. but its efficacy is unclear. but the motor conduction velocity can be mildly reduced in addition to a slight prolongation in the distal motor latency. Nevertheless.659. however. Sinus tachycardia is present. and in some patients normal neural conduction may not be restored. progressing proximally in patients exposed to significant amounts of arsenic. are at risk for developing beriberi. Treatment consists of stopping the gold therapy. a slight prolongation in the SNAPs or mild reduction in amplitudes and conduction velocities may be noted.1411 Such patients customarily are exposed to a single large dose and present clinically with AIDP. Chromatolysis of the anterior horn cells and dorsal root ganglia cells.. along with axonal degeneration and secondary demyelination of the posterior columns. 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. Early in the disease. depending on the degree of peripheral neuropathy at the time of examination. These sensations usually progress over the ensuing weeks with accompanying weakness primarily.1279 Within several days. Not uncommonly. Initially.Chapter 23 ACQUIRED NEUROPATHIES — 1011 mildly to moderately reduced (i. A few patients display spontaneous and vermicular movements of some limb muscles (i. Needle EMG examination reveals positive sharp waves and fibrillation potentials with reduced numbers of motor units in the distal muscles. Motor conduction studies may reveal evidence suggestive of conduction block and prolongation of Fwave latencies. The electrophysiologic studies demonstrate absent or markedly reduced sensory responses. Physical examination may reveal lower limb edema with cardiac enlargement and an apical systolic cardiac murmur (wet beriberi). Gold therapy (e.328. It is wise to stop gold therapy in patients with peripheral nerve symptoms to evaluate the respective roles of gold and connective tissue disease. For example. but by 2–3 weeks marked fibrillation potentials and positive sharp waves are found with reduced number of MUAPs. Some patients treated with gold salts develop a sensorimotor peripheral neuropathy several months after drug initiation. Deep tendon reflexes are absent at the ankles and occasionally at the knees.1379 Mild cases may demonstrate few abnormalities. The CMAPs are well preserved in most patients. has been noted on autopsies. The difference is simply the presence (wet beriberi) or absence (dry beriberi) of congestive heart failure and lower limb edema. Needle EMG examination demonstrates reduced recruitment with occasional positive sharp waves and fibrillation potentials in the distal muscles of the lower limb. the beneficial effect of BAL. but not exclusively in the distal muscles of the lower limbs.1420 NEUROPATHIES RELATED TO NUTRITIONAL DEFICIENCIES THIAMINE (VITAMIN B1) Clinical Features. 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).

Pathogenesis. it is important to assess serum or urine levels of methylmalonic acid and homocysteine. mainly in the distal lower limbs. most electrophysiologic abnormalities. Motor conduction velocities are normal or reduced to not less than 75–80% of the lower limit of normal. altered mentation combined with primarily posterior column and occasionally pyramidal fiber insult (subacute combined degeneration) can result. Vitamin B12-deficient states thus result from dietary deficiency (strict vegetarian diet: lactovegetarian). In patients with B12 levels in the low normal range and symptoms and signs suggestive of cobalamine deficiency. Treatment. Treatment. Motor conduction studies may be normal or demonstrate low-amplitude CMAPs. is important in the production of folate coenzymes. It is found in meat. A complete blood count and smear can reveal megaloblastic anemia. flexor plantar responses. Of importance. fruits.641. The MUAPs display increased durations.733.804.720. malabsorption syndromes (sprue or lower ileum resection). The pathogenic mechanism for the neuropathy associated with cobalamin deficiency is not known.861 The SNAP amplitudes are reduced or absent. Sensory nerve conduction studies document that the distal sensory latencies and conduction velocities are normal or only mildly impaired.664. vegetables. at least in part. The pathogenic basis for neuropathy in patients with thiamine deficiency is not known. Serum cobalamine levels are decreased or in the low range of normal. The cobalamin molecule is a heme-like compound that is water-soluble but lipid-insoluble. gastrointestinal. large amplitudes. a preferential alteration of the peripheral nervous system manifests with complaints of numbness and tingling. Such patients not only have decreased cognitive abilities but also display gait ataxia with primarily lower limb weakness in association with extensor plantar responses. genetic defects in methionine synthetase.534. These metabolites are increased in patients with cobalamine deficiency and can precede abnormalities in serum B12 concentrations. Patients with an autoimmune basis for B12 deficiency may demonstrate autoantibodies directed against gastric parietal cells. Muscle wasting in the foot intrinsic muscles is observed as well as reduced lower limb reflexes. 534. Administration of thiamine improves the symptoms and signs of beriberi.733.571 Needle EMG reveals fibrillation potentials and positive sharp waves in the distal lower limb muscles with significant reductions in motor unit recruitment. Needle EMG demonstrates positive sharp waves and fibrillation potentials.664. In patients with a primarily central nervous system disorder. Cobalamin deficiency is treated with intramuscular injections of vitamin B12.417. 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. Pryridoxine deficiency has been associated with isoniazid and hydralazine treatment. A combination of central and peripheral neural insults is essentially a peripheral neuropathy superimposed on a central nervous system insult. COBALAMIN (VITAMIN B12) Clinical Features. and a number of patients have combined peripheral and central nervous system dysfunction.720. Examination demonstrates decreased or absent deep tendon reflexes in the lower and occasionally upper limbs. whereas axonal degeneration with secondary segmental demyelination is noted in peripheral nerve dysfunction.571 Magnetic stimulation also may demonstrate slow central motor conduction.1021 The molecule is far too large to diffuse readily across the intestinal mucosa.417.571. The electrodiagnostic evaluation reveals abnormalities consistent with a sensory or sensorimotor axonopathy in patients with peripheral neuropathy. and grains do not contain this vitamin. Distal motor latencies are at the upper limits of normal or slightly prolonged. and dairy products. Patients can present with hematologic (megaloblastic anemia). The motor conduction velocities and distal motor latencies are usually normal. However. On the other hand. Cobalamin is necessary for demethylation of methyltetrahydrofolate. Histopathology. abnormal spontaneous activity is noted in the hand intrinsic muscles.571. 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. Tetrahydrofolate. normal deep tendon reflexes or hyperreflexia can be found in addition to upper limb hypertonicity accompanied by lower limb extensor plantar responses. Neurologic symptoms result from both peripheral and central nervous system insult. and neurologic manifestations of vitamin B12 deficiency. therefore. particularly in the dark. followed by 5 mg/day orally. whereas the distal sensory latencies and conduction velocities are essentially normal or only mildly abnormal. the neurologic complications of cobalamine deficiency can be evident before the hematologic abnormalities are appreciated. In the upper limbs.416. 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. Occasionally. and bacteria (blind-loop syndrome) or parasites (Diphyllobothrium latum [fish tapeworm]) that consume the vitamin before it is absorbed. Electrophysiologic Findings. reduced vibration. hyperreflexia. The neuropathy may result from impairment in DNA synthesis or some other biochemical defect. in turn. and there may be an increase in Fwave chronodispersion.599 The CMAP is normal or slightly reduced in the upper limbs and reduced or absent in the lower limbs. and decreased recruitment. Patients complain of the distal limb paresthesias with significant difficulty in ambulating. Thiamine (50 mg) is injected intramuscularly daily for 2 weeks.641. lack of intrinsic factor (pernicious anemia with autoimmune destruction of parietal cells or gastrectomy). Laboratory Features. Impaired energy metabolism due to thiamine deficiency may result in impairment of axonal transport and other high energy-dependent intracellular processes.861 Either the central or peripheral nervous system may be perferentially affected. F-waves and H-reflexes may be prolonged in latency. Thiamine is a coenzyme required for oxidative decarboxylation of ketoacids and transketolation in the pentose phosphate shunt. which is synthesized by the gastric parietal cells. The administration of cobalamin usually reverses. . which are required for DNA synthesis.416. Electrophysiologic Findings. The electrodiagnostic evaluation demonstrates findings consistent with the histopathologic loss of large myelinated axons.804. and a positive Romberg sign. Histopathologic examination reveals degeneration of the posterior columns in patients with central nervous system disorders. A few patients may demonstrate complex repetitive discharges and fasciculation potentials. fish.1012 — PART IV CLINICAL APPLICATIONS Pathogenesis. whereas the SNAP amplitudes are either absent or significantly reduced. it requires a transport molecule known as intrinsic factor.

771. and patients with partial gastrectomies.. Similarly. Folic acid is required in DNA synthesis. Relative sparing of the small-fiber population is noted. (2) deficient fat transport (abetalipoproteinemia.379. VITAMIN E Clinical Features. truncal ataxia is prominent in some patients.1171 The sensory nerve conduction velocities are normal or only borderline reduced. normotriglyeridemic abetalipoproteinemia. Histopathology. 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. short-bowel syndrome.550. as is loss of position and vibration in the lower and upper limbs. Deep tendon reflexes are diminished at the ankles. Pure folic acid deficiencies are extremely rare but may occur in elderly people on poor diets. Preferential proximal muscle weakness in some patients suggests a superimposed myopathic process. Autopsy has demonstrated profound loss of fibers in the dorsal columns and reductions in the cells of the gracile and cuneate nuclei. Needle EMG examinations are normal in most patients. Electrodiagnostic evaluations have been sparse in the few reported patients. It is present in minute amounts in the lipid bilayer constituting the cell membrane. celiac disease. colchicine) also interfere with optimal utilization of folic acid.550. young people consuming only snack foods. Pathogenesis. Some patients note a loss of sensation in the feet. liver has particularly high concentrations. Electrophysiologic Findings. Somatosensory evoked potentials demonstrate normal peripheral nerve potentials. but reduced recruitment associated with fibrillation . Humans absorb folic acid primarily in the proximal jejunum. Manual muscle testing is difficult because of the loss of proprioception makes it difficult for some patients to control their musculature adequately.549. The pathogenic basis for vitamin E deficiency is not known. The sensory and motor nerve conduction velocities are usually normal or mildly reduced. The amplitude may be borderline low. Even with gross movement the upper limbs are described as “not going where the patient desires them to go. Patients with a peripheral neuropathy usually complain of numbness and tingling in the hands and feet with difficulty in ambulating.1153. Histopathology.g. A marked reduction or absence of deep tendon reflexes is a prominent finding. Segmental demyelination is not a feature of vitamin E deficiency. phenobarbitol.1358 Physical examination reveals reduced sensation to touch and vibration with relatively good preservation of pain. Sural nerve biopsy can reveal a reduction in the total number of myelinated fibers and evidence consistent with axonal loss. giving rise to clinical and laboratory features described above with vitamin B12 deficiency.379.Chapter 23 ACQUIRED NEUROPATHIES — 1013 Vitamin B12 Deficiency Secondary to Nitrous Oxide Inhalation Nitrous oxide has been abused because of its ability to cause a euphoric state. temperature. cystic fibrosis. duodenojejunal resections. H-reflexes are typically absent in the lower limbs. and pain and temperature sensation is present in the lower limbs. Progressive loss of speech control also may be noted. Occasional vacuoles in the myelin sheath and break-up of the Schmidt-Lanterman incisures are found. and occasional fasciculation potentials may be observed. Some patients have positive sharp waves and fibrillation potentials. Distal motor and sensory latencies are marginally affected. Patients usually note progressive difficulty in ambulating. Ocular examination reveals ophthalmoplegia and retinopathy in patients with significant disease.549. sulfasalazine.577.404. or both can be present in patients with folic acid deficiency.” Some patients report difficulty in arising from a low chair or placing objects overhead. There is a close relationship between the metabolism of lipids and that of vitamin E. Needle EMG of the distal muscles may be normal or reveal a reduced number of MUAPs. touch. Administration of folic acid usually results in good clinical recovery. chronic cholestasis. and marked slowing and attenuation of central responses FOLIC ACID Clinical Features. but only after the deconjugated form is bound to a specific carrier molecule.511.1229 Dietary sources of folic acid contain primarily the conjugated compound. Treatment.616a. Marked upper and lower limb ataxia is noted. but optimal absorption requires deconjugation through specific enzymes at a pH of 5.149.616a Any of the preceding disorders can result in vitamin E deficiency with neurologic consequences. Three major conditions are associated with vitamin E deficiency: (1) deficient fat absorption (e. whereas SNAP and CMAP amplitudes may be slightly diminished. The first signs of deficiency are megaloblastic erythrocyte alterations. but are normal in other body regions.511. and chylomicron retention disease).1229 Subacute combined degeneration. F-waves are usually prolonged in the upper limb and absent in the lower limbs.404. potentials. as is the absence or significant reduction in deep tendon reflexes. or disorders of the jejunal mucosa. No histopathologic analysis has been done in the limited number of patients reported with folic acid deficiency. secondary to lack of control of the legs and trouble with “sensing” there position in space. Folic acid is found in fruit and vegetables. and intestinal lymphangiectasia).1229 A number of drugs (phenytoin. and (3) a genetically based abnormality of vitamin E metabolism.0. Electrodiagnostic studies demonstrate occasional low-amplitude SNAP responses with normal latencies and conduction velocities.129. hypobetalipoproteinemia. Nitrous oxide can inactivate methylcobalamine. Peripheral nerve biopsy reveals loss of the large-diameter myelinated fibers. positive sharp waves. the CMAPs for both upper and lower limb nerves are well preserved for distal motor latency with a minor reduction in conduction velocity. Neurologic disorders are similar to those encountered with vitamin B12 deficiency (see above). Electrophysiologic Findings. demonstrating that the dorsal root ganglion cell bodies are a major focus of neural loss. and proprioception throughout. Ability to perform fine-motor activities with the hands may be markedly reduced . a sensorimotor peripheral neuropathy. Vitamin E or alpha-tocopherol is a lipidsoluble antioxidant vitamin considered essential for humans. alcoholics. Physical examination reveals an unsteady gait with an inability to walk in tandem as well as a positive Romberg test. Vitamin E has antioxidant properties and may serve to modulate glutamate excitotoxicity. Several patients have developed neuropathy and subacute combined degeneration related to nitrous oxide inhalation. The most consistent finding in vitamin E deficiencies is reduced amplitudes or absent SNAPs. A reduction to vibration. Pathogenesis.129. especially in the dark. It is necessary to measure both serum folic acid and vitamin B12 levels to define a pure folic acid deficiency. Distal muscle atrophy usually is observed on physical examination.

or CMAP amplitude in either upper or lower limbs. A rare patient may demonstrate an abundance of short-duration. distal motor latency.1396. 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. especially to the exclusion of adequate nutritional intake. Correction of the hypophosphatemia results in clinical and electrophysiologic improvement.853. requiring assisted ventilation. Needle EMG may only reveal reduced recruitment. areflexia. and urinary incontinence usually are noted. examination demonstrates reduction to all sensory modalities in a glove-and-stocking distribution. and reduced perception of all sensory modalities are noted on physical examination. but autonomic dysfunction is common.71 The upper and lower limb SNAP responses were reduced in amplitude with mild prolongation of the distal sensory latencies. The lower limb CMAPs are reduced in amplitude and temporally dispersed. The distal motor latencies and conduction velocities demonstrated no significant abnormalities. Jamaican neuropathy occurs in two forms: (1) ataxic neuropathy or tropical ataxic neuropathy and (2) spastic or tropical spastic paraparesis. Early recognition is imperative because treatment can arrest and sometimes reverse the neurologic symptoms. The exact cause is unknown but may be associated with some form of toxin or malnutrition.1204. Electrodiagnostic evaluation reveals an absence of SNAPs.1113. ataxia. Sural nerve biopsies reveal axonal loss of both myelinated and unmyelinated fibers. and a few patients may have electrical myotonia. Slow progression of leg weakness. In acute and chronic forms of alcohol-related polyneuropathy. Unlike GBS. JAMAICAN NEUROPATHY Clinical Features. if evident. findings are worse in the lower than in the upper limbs.100 Electrophysiologic Findings. Examination reveals spastic paraparesis with hyperreflexia in the lower limbs and extensor plantar responses. Patients complain of paresthesias that begin in the feet and progress to the upper limbs and remainder of the body. paresthesia.1008. F-waves can be difficult to elicit or completely absent.405. implying the presence of a superimposed myopathic process. People who have consumed alcohol for many years. numbness. There is only one electrodiagnostic medicine report of a patient with the ataxic form of Jamaican neuropathy. as a distal sensorimotor peripheral neuropathy.95. Distal lower limb weakness is common. Lower limb absence of deep tendon reflexes is the rule. whereas those at the knee and upper limbs are diminished.. is mild. The disorder is usually a result of vitamin B12 malabsorption. Histopathology. Motor conduction studies are normal with no alterations in conduction velocity. with both peripheral and central degeneration of sensory nerve fibers. but distal upper limb weakness and occasionally proximal lower limb weakness can be demonstrated.71. 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. depressed deep tendon reflexes.1426 Cranial nerves are spared. Pathogenesis. can develop a generalized sensorimotor primarily axonal peripheral neuropathy. impotence. Needle EMG is also typically normal. In Jamaica. Motor conduction studies reveal slowed lower limb conduction velocities. Treatment. Weakness. Upper and lower limb Fwave minimal latencies were normal. An occasional patient presents with symptoms and signs suggestive of myopathy as opposed to neuropathy. retrobulbar neuritis and deafness are rather common. Much more common in alcoholics is insidious onset of a slowly progressive sensorimotor polyneuropathy. Clinical Features.180. but strength is well preserved.63. Needle EMG examination shows reduced MUAP recruitment with fibrillation potentials and positive sharp waves in the distal limb muscles. A few patients may demonstrate rare fibrillation potentials in distal muscles with some MUAP parameter alterations. CSF protein in alcohol-related acute axonal polyneuropathy is usually normal or only slightly elevated. whereas those in the upper limb were preserved. The sensory ganglia also are involved.6.1276. The ataxic form of the disease is characterized by the onset of burning feet.1208. lowamplitude. and burning pain.1413 Some patients present with acute or subacute onset of paresthesias.178. Patients present mainly with numbness. Lower limb CMAP amplitudes were reduced.1014 — PART IV CLINICAL APPLICATIONS document slowing of central conduction with loss of posterior column fibers. ALCOHOLIC NEUROPATHY HYPOPHOSPHATEMIA Patients undergoing hyperalimentation can develop hypophosphatemia if insufficient phosphate is included. with profound loss of posterior column modalities and fewer alterations in pain and temperature sensation. back pain. polyphasic MUAPs with early recruitment. Needle EMG was consistent with chronic axonal loss in that reduced numbers of MUAPs had prolonged durations and increased amplitudes.1114 The spastic form of the disease may be more common and involves primarily the pyramidal tracts at or about the lumbosacral region. see above). Weakness also may involve the respiratory muscles. suggesting a neurogenic type of motor unit remodeling. hence the neurogenic disorder is understandable. resembling AIDP.104. Nutritional deficiency with prominent weight loss 2–3 months before onset of the acute neuropathy is common. as opposed to other parts of the world. Patients ambulate with a scissors gait. . numbness. or. 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.1416 The peripheral nerve manifestations may present in an acute fashion.1035. Some cases of tropical spastic paraparesis probably are caused by human Tcell lymphotropic virus type I (HTLV-1.1.1433 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. and weakness.84. Abnormal membrane instability in the form of fibrillation potentials and positive sharp waves is apparently not particularly common. Deep tendon reflexes at the ankles are usually absent. 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. dysesthesias. which can resemble GBS. more commonly.

1429 Less than 20% of patients have hand intrinsic weakness..199 Motor conduction studies in the lower and upper limbs follow a pattern similar to that of the sensory nerves. 180. Symptoms restricted to the upper limbs. A dose-dependent toxic effect of alcohol on sensorimotor and autonomic nerves was noted in a case-controlled study.968.Chapter 23 ACQUIRED NEUROPATHIES — 1015 Histopathology.746 Therefore.1429 Such patients have normal sensory nerve conduction studies.1292 All of these findings are consistent with a primarily axonal neuropathy accompanied by motor unit remodeling.. facial flushing. Brainstem and visual evoked potentials may be abnormal in alcoholic patients. upper limb nerves may be markedly abnormal.1378. Classified in the category of idiopathic sensory or sensorimotor polyneuropathies are patients who appear to have pure small-fiber sensory neuropathies. Although patients have normal fasting blood glucose and hemaglobin A1C levels. Motor examination is normal in patients with small-fiber sensory neuropathies.968 Physical examination reveals a stocking-glove pattern of sensory loss. or paresthesias occur in 40–60% of patients. sharp stabbing paresthesias. Sharp. Most patients present with sensory symptoms between the ages of 45 and 70 years.387. discomfort or pain is quite common (65–80% of patients). As the condition progresses.g. or deep aching sensation) in the feet. the presenting symptoms were numbness and tingling with pain in 63%.1045.84. thyroid.970 The overall incidence of monoclonal proteins in older populations is approximately 5%.969.. cranial nerve involvement. lancinating pain. Pinprick is reduced in 75–85% of patients.1378. and renal functions should be normal. Patients may complain of numbness. Laboratory tests for fasting blood glucose. and nerve biopsies demonstrate a relatively normal density of large myelinated nerve fibers.1426 Wallerian degeneration is the primary abnormality. B vitamin group. significant degrees of axonal degeneration can be observed. numbness or tingling without pain in 24%. Symptoms and signs of autonomic impairment (e.1429 The average time to involvement of the upper limbs is about 5 years. Motor conduction studies in the upper limb usually are less affected early in the disease.968. The F-waves are only mildly prolonged in latency but become harder to obtain as the corresponding CMAP amplitudes decline.445. vitamin B12. and vibratory perception is reduced in over 50% of patients. In about 50% of patients.594 Reduced pinprick or temperature sensation is noted in almost all patients. the sural nerve conduction velocity is mildly to moderately reduced. Fewer than 14% of patients have a reduction in proprioception.474. However. liver. the conduction velocity worsens mildly.178. diarrhea) are seen in the majority of patients with painful sensory neuropathies. With marked reduction in the lower limb sensory responses. Vibratory perception is the sensory modality most commonly impaired (80–100% of patients). Deep tendon reflexes are usually absent at the ankle and diminished at the knees and upper limbs. Mild distal weakness and atrophy involving foot intrinsic muscles and the ankle dorsiflexors and evertors are evident in as many as 40–75% of cases.g. constipation. Of importance is the progressive reduction in CMAP amplitudes. but it may be related in part to nutritional deficiency (e. the cause of 10–35% of all polyneuropathies cannot be determined.1045. The hands often become affected over time. numbness.1429 The diagnosis of chronic idiopathic polyneuropathy is one of exclusion.851. Abstaining from alcohol and consuming an optimal diet can improve the peripheral neuropathy. reduced or increased sweating. Singlefiber EMG shows an increase in fiber density accompanied by increased jitter and blocking. 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. fewer than 10% of patients have reduced reflexes at the ankles.1429 These sensory symptoms begin in the toes. ANA. the relationship between monoclonal proteins and pathogenesis of the neuropathies is unclear.594.972a Laboratory Features. Approximately 80% of patients complain of burning pain in the feet. and fewer than 25% have a positive Romberg sign. Electrodiagnostic evaluation reveals a sensory or sensorimotor polyneuropathy. The relative refractory period can be used to detect early abnormalities in patients without clinical evidence of peripheral neuropathy.873.1070. oral glucose tolerance tests are abnormal in approximately one-third of patients.486.918 Electrophysiologic Findings.970. SPEP. Despite extensive evaluation.6.968.1204. slowly progress up the legs. whereas light touch is impaired in 54–92%.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. burning.853.970. Such cases are categorized as chronic idiopathic polyneuropathy. Chronic acquired sensory or sensory motor polyneuropathies occur in approximately 3% of middleaged to older adults.84.474. suggesting that the central portions of the cranial nerves also are affected.1413. whereas the more slowly progressive form results in only a few degenerated axons despite documentation of an overall loss of fibers. ESR. but the SNAP amplitude eventually may become unobtainable.g.968.1426 CHRONIC IDIOPATHIC SENSORY OR SENSORIMOTOR POLYNEUROPATHY Clinical Features. For example.970 In a large series of 93 patients with idiopathic sensory polyneuropathy. as is the SNAP amplitude.582.474. Similar findings are noted in time when the upper limb muscles are investigated.594. Treatment. dry eyes or mouth.272. the mild weakness is not clinically significant and is not the primary symptom or sign of the neuropathy in which sensory abnormalities predominate.1045.198. impotence.1429 Approximately 15–25% of patients have generalized areflexia. and pain alone in 10%.1429 Proprioception is impaired in only 20–30% of patients.104. the H-reflex latencies can become prolonged until they also disappear.968.723.1271a About 5–10% of patients with chronic idiopathic sensory or sensorimotor polyneuropathy have a monoclonal protein. Reductions in the total number of largeand small-caliber myelinated fibers maintain the bimodal fiber distribution. and eventually reach the distal upper limbs. incontinence. and superimposed autonomic neuropathy are exceptional. with small degrees of secondary segmental demyelination. A reduced number of MUAPs is detected with increased durations and numbers of polyphasic MUAPs.16 Needle EMG of the distal lower limb muscles characteristically reveals positive sharp waves and fibrillation potentials.1428. but in chronic alcoholics. The exact cause of peripheral nerve insult in alcoholism is unknown.970. In fact. sensory symptoms are confined to the lower limbs.970. or pain (e.1224a. folate) or a direct toxic effect of alcohol on peripheral nerves. Over time. Pathogenesis. In the acute form of peripheral neuropathy. A strong pathogenic relationship . the upper limb sensory responses begin to demonstrate a reduction in velocity (no greater than 70–80% of the lower limit of normal) as well as a reduction in SNAP amplitude. tingling. Deep tendon reflexes are usually normal.

1016 — PART IV CLINICAL APPLICATIONS has been demonstrated only in patients with demyelinating sensorimotor polyneuropathies and IgM monoclonal proteins.596. normal.1428. Electrophysiologic Findings. desipramine) are most commonly used. He also had difficulty in climbing stairs. The needle EMG examination is consistent with an axonal neuropathy. HIV infection. motor and sensory nerve conduction studies as well as needle EMG are. MUAP changes of long-duration and increased-amplitude potentials also can be detected. carbamazepine. other large studies.5) can be used to measure density of small intraepidermal fibers. Antiepileptic medications (e. even with quantitative analysis. The disturbing neuropathic pain often can be eased with various medications. Sensory nerve conduction studies demonstrate either absent or reduced amplitudes.. As expected. Positive sharp waves.g. In more than one-third of patients with painful sensory neuropathies. protein gene product 9. In patients with pure small fiber neuropathies. Acute onset of weakness and sensory complaints..574. calf. No treatment slows the progression or reverses the “numbness” or lack of sensation. but the weakness in the proximal limb muscles was slightly greater than in the distal ones. 60% had motor conduction abnormalities.1045 However.1045 Pathogenesis.1045. even by the original group of investigators.387.1045. substance P. QSART) is abnormal in some patients. and calcitonin gene-related proteins can be used to measure the density of sudomotor axons innervating sweat glands. Most patients with chronic idiopathic sensory or sensorimotor polyneuropathy have axonal neuropathies histologically and electrophysiologically (see below). A 40-year-old male physician is seen in the hospital with a 4-week complaint of diminished sensation and mild weakness.1429 Furthermore.593. In the large series of patients with idiopathic sensory polyneuropathy reported by Wolfe and colleagues. Demyelination is not a prominent feature. connective tissue disorders... Thus. The nonnarcotic analgesic. phenytoin) and antidepressant medications (e. autonomic testing (e. piloerector nerves to hair follicles.1260 Treatment.1429 Panels screening for various antiganglioside and other antinerve antibodies (e. motor nerve conduction studies are often abnormal.g. and reduced recruitment usually are detected in the foot intrinsic and distal lower limb muscles. autonomic testing demonstrates abnormalities in some patients.594.1429 In addition.1051 However. causing axonal loss with compensatory motor unit remodeling through collateral sprouting. and nerves to small arterioles. Axonal degeneration and regeneration with secondary demyelination are often evident on biopsy. or thigh). ILLUSTRATIVE CASES CASE 1:ACUTE ONSET OF LIMB WEAKNESS Reason for Referral. QST may reveal abnormal thermal and vibratory perception. others may have a degenerative or immunologic basis. progression of reduction in muscle strength was noted throughout. During this same period. Recent studies suggest that glucose intolerance alone without frank diabetes may be the cause of neuropathy in as many as one-third of patients. anti-GM1. fibrillation potentials. followed in 2 days by prominent numbness and tingling in the hands. QST. In profound disease.5 or PGP 9. 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..574. patients with small-fiber neuropathies display a selective loss of small myelinated nerves and unmyelinated nerve fibers.1070. Abnormalities of median and ulnar CMAPs are much less common. amitriptyline.g. Scattered T-cells may be seen on nerve biopsy although neither significant inflammation of the nerves nor vasculitis is present. immunologic staining (e. when obtainable.g.948.970..703.968.474. particularly of the sural SNAPs. some cases probably will be determined to be genetic. Distal latencies and conduction velocities of the peroneal and posterior tibial CMAPs are normal or only slightly impaired. Antibodies directed against vasoactive intestinal polypeptide.594.1045.1427–1429 CSF examination is usually normal and thus unwarranted.574. and routine nerve biopsies are often normal. anti-Hu antibodies) have no role in screening patients with chronic idiopathic sensory neuropathy. Intraepidermal nerve fibers arise entirely from the dorsal root ganglia and are believed to represent the terminals of C and Aδ nociceptors.1428. by definition.594. Approximately 3 weeks before this examination he noted the onset of numbness and tingling in the left and right toes. Occasionally both tibial and peroneal nerve responses to the foot intrinsic muscles are absent.g. in which nerve conduction studies.. if present.455 Some authors have reported that as many as 30% of patients with chronic idiopathic sensory neuropathy demonstrate antisulfatide antibodies.1427. painful sensory neuropathies related to diabetes mellitus. is mild. similar but less severe findings are noted in the upper limbs.1045.972a. .g. Despite the fact that sensory symptoms are much more prominent and weakness. hepatitis B or C).968.851.407a. have failed to show increased titers of antisulfatide antibodies. also may be tried. PCR amplification of the variable T-cell receptor γ-chain gene reveals the frequent occurrence of dominant T-cell clones of unknown significance. 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.1045.873. nortriptyline. These findings are consistent with a long-standing peripheral neuropathy. QST demonstrates abnormal thermal and vibratory perception in as many as 85% of patients.970.1045 After a punch biopsy of the skin in the distal lower limb (foot.972a.1271a. or quantitative sensory testing (QST). nerve biopsies are normal.and small-diameter myelinated fibers and small unmyelinated fibers can be seen on quantitative morphometry. herpes zoster infection) (Table 23-9). These sensations slowly progressed proximally along both upper and lower limbs over the next 2 weeks to involve all 4 limbs and the trunk. History.1429 Loss of large. nerve conduction studies.1224a. Histopathology. regardless of its cause (e. intraepidermal nerve fiber density on skin biopsies represent the only objective abnormality even after extensive evaluation. With advances in molecular genetics. gabapentin.1429 Our approach to treating the painful paresthesias and burning sensation is similar to the treatment of neuropathic pain. The density of these nerve fibers is reduced in patients with small-fiber neuropathies.1045 However.1045. most of whom have anti-MAG antibodies.1429 The most common motor findings are reduced peroneal and posterior tibial CMAP amplitudes.445.968.1429 Sensory nerve conduction velocities.811.g. whereas distal sensory latencies are normal or slightly prolonged. The pathogenesis probably is multifactorial.474.859.1045. are normal or only mildly slow. Sural nerve biopsies confirm the axonal nature of chronic idiopathic sensory polyneuropathies. tramadol. we do not routinely perform nerve biopsies on patients with chronic idiopathic sensory polyneuropathies. The findings on nerve biopsy are rather nonspecific and not helpful in finding the cause of the neuropathy.

His blood pressure. No evidence suggests conduction block in any of the motor nerves studies in comparing CMAP duration and proximal vs.2 R median 1. is 160/90 mmHg and is verified at the elevated level by the patient in the resting state. Approximately 5 days before hospital admission.1 8. but secondary to coordination of the legs. The patient denies any history of illness over the past 3 months. or retain fluids in the mouth.7 R sural 4. The patient demonstrates electrophysiologic evidence of a mild degree. purse the lips.0 59.8 55.1 Note.1 R facial 5. 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. DML.9 39. The patient cannot tandem walk and ambulates with a mildly wide-based gait. The proximal upper and lower limb muscles are approximately 4/5 and the distal muscles are 4+/5. Motor and sensory amplitudes are measured baseline to peak. Needle Electromyography. distal amplitudes. His resting heart rate is approximately 90 beats/minute compared with a previous level of 60 beats/minute.5°C posterior to the right lateral malleolus. suggesting a widespread demyelinating neural process. Physical Examination.4 10. 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. Extraocular muscle movements are intact. The F-wave latencies are reported as the shortest in a series of 15.0 cm) R ulnar 3. 3. Supramaximal stimulation alone produced approximately one-half as many responses as stimuli delivered.9 57. He also noted that he could no longer walk with a narrow base gait or perform a heel-to-toe gait. 2.5 (7. Distal motor latencies are prolonged for lower limb nerves and the median nerve. A needle EMG investigation is performed on the right upper and lower limb. During physical examination 3 weeks after the onset of abnormal sensations and weakness. ms.9 25.0 38. worse on the right than on the left. nerve conduction velocity. Nerve conduction studies are performed in the right upper and lower limbs. sensory amplitude. 5.2 R tibial 11. DSL S Amp DML M Amp NCV Nerve (ms) (µV) (ms) (mV) (m/s) F-wave R median 4. The mid-palm temperature is 32. Cerebrospinal fluid analysis revealed an elevated protein level and no cells. but approximately 6 weeks before the onset of symptoms.4 4. Sensory latencies are measured to peak and motor latencies to initial negative onset. Deep tendon reflexes are absent throughout.Chapter 23 ACQUIRED NEUROPATHIES — 1017 not because of weakness. S Amp. All F-waves are abnormally prolonged and reduced in number compared with the number of stimuli delivered. using a disposable monopolar needle.6 7. 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. milliseconds.5°C on the right and 31. A reduction in position and vibration sensation is noted in the toes only. the patient is alert and oriented. The nerve conduction velocities in the lower limb are mildly slowed.5 5.4 3. he noted loss of the nasolabial fold bilaterally. Mildly abnormal distal motor latencies.2 R peroneal 4. distal motor latency. The morphology of motor unit action potentials appeared normal. and the patient states that previously they were easy to obtain and symmetric. Pinprick and temperature are reduced in the distal regions of the upper and lower limbs bilaterally. By the time of the examination the patient has received two doses of intravenous immunoglobulin (IVIG). The distinct lack of mentation difficulties excludes an overt central nervous system disorder.8 5.1 15. In general. DSL. 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 C4–T1 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.0 58. Needle EMG examination reveals no abnormalities in any of the muscles tested. Shoulder shrugging is approximately 4/5 bilaterally. Sensory and motor evoked response amplitudes are at the lower spectrum of normal for this patient. Over the course of the next several days it became increasingly difficult to close his eyes.7 4. the history and physical findings suggest a mild to moderate degree of peripheral nervous system dysfunction. millivolts. Running was rather difficult. mV. Summary of Findings 1. meter/second. Nerve Conduction Studies. An obvious bilateral facial palsy is noted with an inability to bury the eyelids or hold air in the mouth on compressing the cheeks.8 10. again not because of overt weakness.1 37.0 34. The markedly abnormal F-waves suggest that a significant degree of the pathology is located proximally and not amenable to routine nerve conduction testing. m/s. Manual muscle testing demonstrates a reduction in neck flexor and extensor strength. but because of a decreased ability to sense where his limbs were. Electrodiagnostic Medicine Impression 1. normal nerve conduction velocities in the . he had received the second dose of a hepatitis immunization. microvolts.1 3. motor amplitude. Comment The patient has comparatively less pronounced motor weakness than objective sensory loss. distal sensory latency. NCV. µV.9 10. the patient states that the reduction in strength is significant since he participated noncompetitively in weight-lifting activities. M Amp. 4. normally 108/70 mmHg. Of note. Reduced numbers and prolongation of F-waves with essentially normal limb conduction velocities are somewhat confirmatory of a preferentially proximal peripheral nerve disorder.

nerve conduction velocity. . The mid-palm temperature is 33. Sensory latencies are measured to peak and motor latencies to initial negative onset. particularly during the early stage of the disease. however. Nerve conduction studies are performed in the right upper and lower limbs. given the lack of muscle wasting. There is some suggestion of at least a 25-pound weight loss over the past year.4 4. Over the same period the patient noted an extension of the numbness and tingling to the lower limb just distal to the knee region. DSL S Amp DML M Amp NCV Nerve (ms) (µV) (ms) (mV) (m/s) F-wave R median 4. 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. motor amplitude. although not impossible.2 R peroneal Absent Absent R tibial 6.9 0.2 R median 2. and the skin demonstrate numerous spider angiomata. Previous medical records indicate a weight of 140 pounds 18 months ago. making ambulation increasingly difficult.2 3. as are the hip flexors and extensors.6 0. Manual muscle testing demonstrates 3+/5 for the toe extensors/flexors and ankle dorsiflexors/plantarflexors. Over the past 8 months the burning has intensified.6 35. Needle EMG abnormalities are absent and support the lack of significant axonal loss or conduction block.0 34. 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 C4–T1 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 L1–S1 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. In the upper limb.6 2. In some patients with profound disease. Needle Electromyography.8 44. 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. it is important to document its presence by careful recording the CMAP amplitude subsequent to multiple stimulation sites along the course of different nerves. Progressive lower limb numbness and weakness. The preservation of CMAP amplitudes. Cranial nerves are intact. S Amp. presently weighing 100 pounds. Although conduction block was not demonstrated by this patient. Sensation is decreased to all modalities in a typical glove-andstocking distribution. Motor and sensory amplitudes are measured baseline to peak. minimal strength reduction. 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.0 DSL. the patient recovered relatively close to his previous level of functioning over the ensuing 8 months.5 (7. microvolts. and absent abnormal spontaneous activity suggest a good clinical prognosis with eventual motor return. ms. the axilla-to-elbow and forearm-to-wrist segments can be readily assessed for conduction block. 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. and borderline abnormalities in the lower limbs document a mild slowing of nerve conduction in both upper and lower limbs. the absence of membrane instability is certainly expected. m/s. Plantar responses are neutral. Mild hepatomegaly is noted on abdominal examination.9 5. The electrophysiologic findings are rather nonspecific but certainly compatible with the clinical impression of AIDP.0 5. 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. sensory amplitude.1018 — PART IV CLINICAL APPLICATIONS upper limbs. Indeed. distal sensory latency.5°C posterior to the right lateral malleolus.2 3. In examining the lower limb. About 1 month ago similar symptoms began in the fingertips and now involves both hands. milliseconds. The patient admits to smoking approximately 2–3 packs of cigarettes per day for the past 15–20 years. millivolts. Needle EMG is of minimal help in formulating a diagnosis in the above patient. which define the presence of axonal loss. Knee flexors and extensors are 4–/5. mV. distal motor latency. it is possible to detect positive sharp waves and fibrillation potentials. The patient also states that walking is becoming difficult because of more frequent tripping on pavement. cachectic-appearing woman is referred for an electrodiagnostic medicine evaluation of progressive lower limb numbness and weakness. CASE 2: PROGRESSIVE LOWER LIMB NUMBNESS AND WEAKNESS Reason for Referral. and good preservation of CMAP amplitudes to distal stimulation.0 35. DML. A needle EMG investigation is performed on the right upper and lower limb. meter/second.9 47. NCV. A 45-year-old. She is alert and cooperative with a definite odor of alcohol about her. The jaw jerk is present but diminished. lack of significant conduction block distal to the forearm.5 36.0 cm) R ulnar 4. Physical Examination. History. A dramatic reduction in amplitude not accompanied by an abnormal increase in CMAP duration certainly suggests neural blockade. it is rather difficult.1 4. Deep tendon reflexes are absent at the ankle and knee with diminished reflexes for the biceps and triceps. µV.5°C on the right and 32. The patient appears older than her stated age and is quite thin. Nerve Conduction Studies.0 R sural Absent L sural Absent L peroneal Absent L tibial 6. using a disposable monopolar needle. M Amp. 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.

Muscle Nerve 1991.22:222–226. The needle EMG examination reveals a reduced number of motor units with denervation in the distal upper and lower limb musculature. eliminating the costly and inefficient “shotgun” approach to evaluating patients with neuropathy. Jackson CE.19:140–146. 7. Worley KL: Chronic relapsing brachial plexus neuropathy with persistent conduction block. Brown MB. 2.62: 487–491. 9. the authors emphasize that electrodiagnostic medicine specialists must be knowledgeable about the underlying pathophysiology and treatment of the different types of acquired peripheral neuropathy. Shahani BT. A complaint of progressive numbness. Ziegler DK. Ackil AA. accompanied by weakness. 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. Alderson K. 6.43:1513–1518. These findings suggest profound axonal loss. Kelly JJ: Acquired inflammatory demyelinating polyneuropathies: Clinical and electrodiagnostic features. 17. the appropriate laboratory work-up should be ordered. Billmaier DJ. Albin RL. S Med J 1980. Muscle Nerve 1989. Neurology 1990. Kim JY. 19. Again. are compatible with the impression of a distal axonal generalized polyneuropathy affecting both motor and sensory fibers. Comment The patient provides a history compatible with significant alcohol intake for a prolonged period.27(suppl):S7–12. Alter M: The epidemiology of Guillain-Barré syndrome.37:196–200.g.Chapter 23 ACQUIRED NEUROPATHIES — 1019 Summary of Findings 1. Based on clinical and electrodiagnostic studies. 14.10:323–328. but the major abnormality is a reduction in all CMAP amplitudes. Muscle Nerve 1996. Young RR. Amato AA. weight loss. again supporting the impression of preferential axonal loss as the major disease process. Levine SP. Barohn RJ: Neurological complications of transplantation. small-fiber sensory). Altman D. An electrodiagnostic medicine evaluation reveals a number of confirmatory electrophysiologic findings. and smoking history. Shahani T. Despite the obvious clinical history and physical examination as well as the electrodiagnostic findings. given the CMAP amplitude. In the upper limbs. Neurology 1987. Arch Neurol 1975. 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. Albers JW: Long-term follow-up of pyridoxine induced acute sensory neuropathy-neuronopathy. 15. CONCLUSION Because of the vast number of acquired peripheral neuropathies.14:858–862.1:68–73. Ahrens EM. Mendell JR.20: 1303–1307. Young RR: Sural nerve conduction and late responses in children undergoing hemodialysis. motor. et al: Sensorimotor neuropathy in a patient with Marinesco-Sjogren syndrome. 3. JAMA 1983. However. diabetes mellitus) and occult disorders (carcinoma of the lung) should be pursued to some degree. Neurology 1993. Boston. the distal motor latencies are mildly prolonged and the conduction velocities reduced. 16. The clinical history and examination are the most important aspects of evaluating patients with neuropathy. et al: Toxic polyneuropathy due to methyl n-butyl ketone. Ann Neurol 1990. Albers JW. Lin JT: Mercury intoxication simulating amyotrophic lateral sclerosis.32:1168–1174. et al: Acute sensory neuropathy-neuronopathy from pyridoxine overdose.25:314–316. Greenberg HS. Cornblath DR. Int J Derm 1986. with the lower limbs more affected than the upper limbs. 4. Meckler RJ. The nerve conduction studies in the lower limbs are absent. Greene DA: Frequency of median mononeuropathy in patients with mild diabetic neuropathy in the early diabetes intervention trial (EDIT). is certainly suspicious for a generalized sensorimotor peripheral neuropathy. 13. 21. 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1030 — PART IV

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Chapter 23
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1032 — PART IV

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