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
In the preceding chapters, we discussed our approach to pa-
tients with peripheral neuropathies and reviewed the hereditary
neuropathies. This chapter concerns the acquired forms of neu-
ropathy, which are more common than the hereditary neu-
ropathies. We classify acquired polyneuropathies according to
their presumed pathogenic basis or association with other sys-
temic disorders (see outline above). It is important for the elec-
tromyographer to know how these neuropathies manifest
clinically and to understand their associated laboratory abnor-
malities 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 treat-
ing patients with acquired peripheral neuropathy.
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
IMMUNE-MEDIATED POLYNEUROPATHIES
GUILLAIN-BARRÉ SYNDROME
AND RELATED DISORDERS
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 are-
flexia 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 Guillain-
Barré syndrome (GBS). Haymaker and Kernohan reported the
histopathologic features of 50 fatal cases of GBS in 1949.565
937
938 — PART IV CLINICAL APPLICATIONS
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 ar-
rhythmias, postural hypotension, hypertension, other vasomo-
tor 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.
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 in-
flammation 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 de-
myelination 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
The pathophysiology and neurophysiology of GBS were not
uncovered until one century after the original clinical descrip-
tions 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 neuropa-
thy (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 neu-
ropathy 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 in-
fection. Fifteen to 45% of patients with AIDP have serologic ev-
idence 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 cy-
tomegalovirus (CMV) and Epstein-Barr virus (EBV), other viral
infections have been described in AIDP, including influenza, he-
patitis 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 asso-
ciated with an increased risk of GBS. Other disorders linked to
GBS include other autoimmune disorders, acquired immunode-
ficiency 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 there-
after 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 elec-
trophysiologic signs of motor involvement are typical.297,989a,1331
Progressive weakness usually ensues and is the major com-
plaint of most patients. Muscle weakness may be mild and local-
ized to the distal limbs or progress to such an extent as to render
the patient completely quadriplegic and requiring assisted venti-
lation. 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% simul-
taneously in the arms and legs.1121,1122 Mild facial weakness is ap-
parent in at least half of the patients during the course of the

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 de-
creased stretch reflexes. Autonomic instability is common in
AIDP with hypotension or hypertension and occasionally car-
diac 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 diag-
nosis of chronic inflammatory demyelinating polyneuropathy
(CIDP) (see below). Subacute onset with progression of the dis-
ease 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 impor-
tant 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 sev-
eral months. However, only about 15% of patients are without
residual deficits 1–2 years after disease onset and 5–10% of pa-
tients 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 venti-
lation, 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 accom-
panied by no or only a few mononuclear cells is the characteris-
tic 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 one-
third 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 he-
patitis (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 infec-
tion. 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
Chapter 23 ACQUIRED NEUROPATHIES — 939
The entire peripheral motor and sensory nervous systems, includ-
ing cranial nerves can be involved from the most proximal as-
pects 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. De-
myelination progresses from the loosened paranodal myelin to in-
ternodal demyelination. Monocellular infiltrates may be
appreciated in areas of segmental demyelination. In significant
disease states, polymorphonuclear cells, in addition to mono-
cytes, 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 metal-
loproteinases 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 periph-
eral 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 de-
myelinated. Markers of complement activation (C3d and mem-
brane attack complex) were demonstrated on the outermost
surface of the Schwann cells. Electron microscopy (EM) re-
vealed 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–medi-
ated 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 recep-
tor and interferon-γ, can be found in the serum of patients with
AIDP.554 The humoral arm of the immune system has been impli-
cated 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 comple-
ment-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 re-
lease 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 glyco-
lipids expressed on Campylobacter, Mycoplasma, and other in-
fectious 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
940 — PART IV CLINICAL APPLICATIONS
Table 23-2. Electrodiagnostic Medicine Criteria for
Peripheral Nerve Demyelination*
Conduction velocity reduced in 2 or more nerves
1. If CMAP amplitude is > 80% of lower limit of normal (LLN), the
NCV must be < 80% of LLN.
2. If CMAP amplitude < 80% of LLN, the NCV must be < 70% of LLN.
CMAP conduction block or abnormal temporal dispersion in
1 or more nerves
1. Regions to examine:
• Peroneal nerve between fibular head and ankle
• Median nerve between wrist and elbow
• Ulnar nerve between wrist and below elbow
2. Partial conduction block criteria
• CMAP duration difference between the above noted proximal
and distal sites of stimulation must be < 15%; and
• A > 20% drop in CMAP negative spike duration, or baseline-
to-peak amplitude.
3. Abnormal temporal dispersion and possible conduction block
• CMAP duration difference between the above proximal and
distal sites of stimulation is > 15%; and
• > 20% drop in CMAP negative spike duration or baseline-to-
peak amplitude.
Prolonged distal motor latencies (DML) in 2 or more nerves
1. If CMAP amplitude is > 80% of LLN, the DML must be > 125%
of the upper limit of normal (ULN).
2. If the CMAP is < 80% of LLN, the DML must be > 150% of ULN.
Prolonged minimum F-wave latency or absent F-wave
1. F-waves performed in 2 or more nerves (10–15 trials)
2. If the CMAP amplitude is > 80% of LLN, the F-wave latency
must be > 120% of ULN.
3. If CMAP amplitude is < 80% of LLN, the F-wave latency must be
> 150% of ULN.
* Three
of the four features must be present.46,245
antigens on the Schwann cell because of this molecular mim-
icry. These autoantibodies most likely bind to the Schwann cells
and activate the complement cascade, leading to lysis of myelin
sheaths. Inflammatory cells are subsequently recruited to com-
plete the demyelinating process.
Electrophysiologic Findings. A comprehensive review of
the electrophysiologic literature regarding the various results in
AIDP reveals both a number of consistent as well as contradic-
tory findings.892a There are probably multiple reasons for these
findings, but the most likely explanations include the time
during the course of the illness when the patient is examined,
different recording and stimulating techniques, failure to con-
trol temperature, and examination of insufficient number of
nerves and muscles. AIDP is a dynamic disease with variable
rates of progression in different patients. In addition, different
aspects of the peripheral nervous system are affected with re-
spect to proximal versus distal from one patient to the next, par-
ticularly during the disease’s manifestation within the first
several weeks. The electrophysiologic results are described in
terms of the basic pathophysiology of demyelination with an
occasional and variable secondary axonal loss component.
Electrophysiologic criteria for demyelination have been devel-
oped to aid in the diagnosis of AIDP (Table 23-2).46
Motor Conduction Studies. The most studied aspect of the
peripheral nervous system in AIDP is neural conduction along
the motor nerve fibers. The various parameters examined are the
distal motor latencies, CMAP amplitudes, conduction veloci-
ties, waveform duration and morphology, and F-waves. These
parameters are used for the purposes of diagnosis, prognosis,
and gaining insight into the fundamental pathophysiologic
processes operational in the disease. The electrophysiologic
hallmarks of demyelination include prolonged distal latencies,
slow conduction velocities, temporal dispersion, conduction
block, and prolonged F-wave latencies. In line with the multifo-
cal character of the disease, a hallmark is the asymmetric and
multifocal character of the electrophysiologic abnormalities.
Slowing of nerve conduction may be preferentially localized
to distal nerve segments, proximal nerve segments, or diffusely
throughout the peripheral nervous system.691,692,694,751,901,1395 We
always perform F-wave studies in both upper and lower limbs in
patients suspected of having AIDP because of the early
predilection for the proximal nerve segments and spinal
roots.9,243,245,459,1118 Abnormal F-waves can be expected in as
many as 80–90% of patients during the course of the dis-
ease.9,243,245,996 Several different types of F-wave abnormalities
may be noted. The shortest F-wave latency in a series of 10–15
applied stimuli is commonly used for diagnostic purposes. In
patients with AIDP, this parameter is frequently abnormal (pro-
longed or absent), particularly early in the disease process, but
usually peaks at about 4–5 weeks.9 Unfortunately, when the F-
wave is used in this manner, it is possible for a single motor
fiber to escape pathology and mediate a normal F-wave re-
sponse. An average F-wave latency or the difference between
the minimum and maximum F-wave latencies may be more ap-
propriate; however, these techniques have not been studied in
AIDP. With respect to late responses, H-reflexes also should be
attempted in the lower limb as a method of assessing possible
proximal neural conduction failure. It is also possible to demon-
strate conduction block at the nerve root level by using nerve
root stimulation techniques.89,899
It is possible to observe multiple A waves in patients with
AIDP. An investigation documented that 93% of patients
demonstrated multiple A waves in at least one limb within 7
days of symptom onset.718a In patients with significant axonal
loss and loss of the CMAP, A waves are unlikely to be observed.
Some research criteria for electrophysiologic evidence of de-
myelination have used a 20% reduction in the CMAP amplitude
or negative peak area between proximal and distal sites of stim-
ulation as evidence of conduction block (see Table 23-2, Fig.
23-1).46,245,249 However, other studies have used stricter criteria
(e.g., 30 or 40% reduction in CMAP amplitude or area), and
computer simulation studies suggest a 50% drop in amplitude is
more appropriate for the electrophysiologic evidence of con-
duction block.998a,1098 It seems wise to use different criteria for
arm and leg nerves since the peroneal and tibial nerve normally
display more drop in CMAP amplitude with proximal stimula-
tion than the median and ulnar nerve. A CMAP reduction of at
least 30% for the arm nerves and 40% for the leg nerves seems
appropriate.9 Of importance, there must be less than a 15% in-
crease in the negative peak duration in comparing the proximal
to distal response. This guideline ensures that a reduction in am-
plitude is not a result of excessive temporal dispersion, which
increases the duration of the potential with a concomitant and
compensatory reduction in amplitude, giving the appearance of
conduction block (i.e., pseudoconduction block). If excessive
temporal dispersion is found, it is difficult to state with assur-
ance whether conduction block is present (Fig. 23-2).156 One
method of distinguishing between conduction block and tempo-
ral dispersion is to use small-segment (e.g., stimulate every cen-
timeter) stimulations in the hope of localizing a focal reduction
in amplitude. If there is a gradual reduction in amplitude without
 Chapter 23 ACQUIRED NEUROPATHIES — 941

Figure 23-1. The ulnar nerve is investigated 7 days following the onset of AIDP induced weakness.The peak-to-peak hypothenar
CMAP decreases over 90% when the Erb’s point stimulation site is compared with the wrist.The corresponding waveforms are noted above the
graphic depiction of amplitude reduction.The accompanying graph describes the < 15% alteration in CMAP negative spike duration and peak-to-
peak potential duration, indicating essentially normal degrees of temporal dispersion.The net conclusion of these data is that the reduction in
CMAP amplitude results from conduction block, not temporal dispersion. (From Brown WF, Feasby TE: Conduction block and denervation in
Guillain-Barré polyneuropathy. Brain 1984;107:219–239, with permission.)

an abrupt decline in CMAP area, temporal dispersion is the
likely culprit. However, if a marked reduction in amplitude can
be localized to a short segment (2–4 cm), conduction block is
probably present.248 Excessive reductions in amplitude may be
possible with moderate, but less than abnormal, degrees of tem-
poral dispersion secondary to phase cancellation effects,
whereby the negative and positive aspects of individual CMAP
waveforms cancel each other.789
The concept of conduction block is critical to understanding
the pathophysiologic basis of symptoms in AIDP. Loss of myelin
leads to neural conduction failure. However, conduction block
may occur without demyelination or before demyelination as a
result of antibodies blocking ion channels at the nodes of Ranvier.
Conduction block of nerve impulses leads to acute weakness and
sensory loss. Subsequent reduction in function may be secondary
to an associated axonal loss.156,1301 Some authorities suggest that
conduction block is the earliest electrophysiologic abnormality in
AIDP, being noted in 74% of patients within the first 2 weeks.156
The smaller myelinated nerve fibers may be affected first by con-
duction block with subsequent involvement of the larger
fibers.1270 Conduction block in AIDP can be observed at common
sites of entrapment, such as the carpal tunnel (median nerve), cu-
bital tunnel (ulnar nerve), and fibular head (peroneal nerve).156,158
In patients with rapid recovery, particularly after plasmapheresis
or intravenous immunoglobulin, the improved clinical status
probably results from conduction block resolution rather than re-
myelination or regeneration of the axons.1081
Two important caveats about conduction block should be re-
membered.248 First, within 5–7 days after acute axonal loss, it is
impossible to distinguish between axonal loss and conduction
block because portions of nerve distal to the site of the lesion
are still excitable and generate a corresponding CMAP. Second,
in acute disease presentations, relatively small reductions in
CMAP amplitude may be a result of conduction block; how-
ever, in more chronic disease states or later in the acute disease
process, alterations in conduction velocity may result in pseudo-
conduction block. Therefore, it is somewhat easier to be certain
of conduction block in the acute time frame compared with the
more chronic manifestations of disease.
Examination of the phrenic and facial nerves may be of interest
in patients with AIDP. Profound demyelination can most likely lead
to significant axonal loss with diaphragmatic denervation.484,954,1449
In addition to nerve conduction studies of the phrenic nerve, needle
EMG of the diaphragm may be performed.119 The facial nerve
may be affected as well as the supraorbital nerve; they can be
evaluated with both direct facial nerve stimulation and the blink
reflex, which reveals abnormalities in either or both pathways.690
Within the first week, motor conduction studies can be
normal or show only minor abnormalities. The maximum
degree of motor conduction abnormality occurs within 3–8
weeks; 80–90% of patients with AIDP have abnormalities in at
least one of the motor nerve parameters (distal CMAP latency,
F-wave latency, conduction velocity, conduction block) within 5
weeks of onset.9,10,243,245 Reports of lower percentages of patients
with electrophysiologic abnormalities most likely result from
examining the patients too early or incompletely. Using their
own electrophysiologic criteria for demyelination, Albers and
colleagues found that 70% of patients had demyelination in two
or more nerves and 85% in one nerve.9 Meulstee and colleagues
applied the electrophysiologic criteria for demyelination de-
signed by Albers, Asbury, and Cornblath9,10,73,243,245 to 135 pa-
tients with AIDP sequentially studied during the Dutch-GBS PE
(plasma exchange) and IVIG trials.892 The sensitivity of the cri-
teria for diagnosing demyelination ranged from 3–36% during
942 — PART IV CLINICAL APPLICATIONS
Figure 23-2. Three patients with AIDP are investigated
within 2 weeks of symptom onset, and the corresponding de-
rived CMAPs are displayed. Considerable reductions in CMAP
amplitude are noted when the most proximal response is compared
with that evoked from the wrist. One may easily conclude that con-
duction block is present, based on the CMAP findings. However, nega-
tive spike duration and peak-to-peak CMAP duration exceed the 15%
limit, documenting excessive temporal dispersion and suggesting that if
conduction block is present, it cannot be differentiated from the ex-
cessive differential slowing effects on nerve conduction velocity. (From
Brown WF, Feasby TE: Conduction block and denervation in Guillain-
Barré polyneuropathy. Brain 1984;107:219–239, with permission.)
the first study (performed at a median of 6 days; range of 2–15
days after onset) to 13–46% during the third study (performed
at a median of 34 days; range of 29–49 days after onset).
Unfortunately, it is difficult to state with certainty the most
sensitive motor conduction parameter in confirming a diagnosis
of AIDP, because the specific nerves that were studied, the vari-
ous motor conduction parameters, the timing of the studies in
relationship to disease onset, and the definition of “abnormal”
vary in the published studies. Some suggest that conduction
block is the earliest recognizable electrophysiological abnor-
mality in AIDP.156 However, Albers and colleagues noted that
prolonged and diminished CMAP amplitude was the earliest
abnormality.9 Within 1 week of symptoms, the mean distal
CMAP amplitudes were reduced to approximately 50% of
normal and declined further over the next several weeks. The
North American Guillain-Barré Syndrome Study Group reported
prolonged distal motor latencies and prolonged or absent F-
waves as the earliest abnormal features.243,245 Early abnormalities
of the distal CMAP amplitude and latency and F-waves reflect
the early predilection for involvement of the proximal spinal
roots and distal motor never terminals in AIDP. Subsequently,
the slowing of conduction velocities, temporal dispersion of the
CMAP waveforms, and conduction block become apparent. The
motor conduction abnormalities remain at their nadir for approx-
imately 1 month and then gradually improve over the next sev-
eral weeks to months, but it may take a year or more for
normalization.9 There does not appear to be a correlation be-
tween the nerve conduction velocities or distal motor latencies
and clinical severity of the neuropathy,302,561,806,871,872 although
distal CMAP amplitudes less than 10–20% of normal are associ-
ated with a poorer prognosis.243,245,866,894,895,1059,1312,1333,1423
Sensory Conduction Studies. Multiple sensory nerves
should be examined in both upper and lower limbs. The sural and
superficial peroneal SNAPs can be evaluated in the lower limbs
as well as the median, ulnar, and radial SNAPs in the upper limbs.
Of note, upper limb SNAPs, particularly the median nerve, can be
affected more severely and earlier than the sural SNAPs.9,930 The
exact explanation is multifactorial. It has been suggested that rec-
ognized entrapment sites are more prone to being affected, ac-
counting for slowing of the median SNAP across the carpal
tunnel. The median nerve SNAP is recorded from the thinly
myelinated terminal regions (or stimulated for orthodromic tech-
niques), thus predisposing it to a relatively more early disruption
of function. On the other hand, the sural nerve usually is studied
at a relatively more proximal location in the leg, where it is more
heavily myelinated and does not traverse any potential entrap-
ment sites. The most likely explanation for the observation that
upper limb SNAPs can be more abnormal than lower limb
SNAPs is that the demyelinating process is multifocal rather than
a length-dependent process (as in axonal neuropathies). Thus,
unlike most axonopathies, in which the earliest and most severe
abnormalities involve the distal lower limb nerves (e.g., the sural
SNAP), demyelinating diseases are just as likely to affect the
median and ulnar SNAPs as they are to affect the sural SNAPs.
About 40–60% of patients eventually demonstrate either am-
plitude or conduction abnormalities of various SNAPs; these
findings may not be apparent during the first several weeks of
the disease.989a,996,1120 It can take 4–6 weeks for SNAP abnormal-
ities to peak, at which time significant and easily identifiable
SNAP parameter alterations become obvious.9,1293 The parame-
ter most adversely affected is SNAP amplitude, which is usually
diminished or absent by the third or fourth week. Reduced
SNAP amplitudes can result from secondary axonal degenera-
tion, conduction block, or phase cancellation related to differen-
tial demyelination and slowing of the sensory nerve fibers.
Sensory conduction velocities can be slow and distal latencies
prolonged, but often they do not fall below 80% of the lower
limit of normal.
Rarely, some persons may present with what appears to be
pure sensory symptoms and signs; however, careful investiga-
tion may reveal subtle motor nerve conduction abnormali-
ties.297,989a,1331 With a pure sensory presentation, other disorders
(acute sensory neuronopathy or ganglionopathy) must be ruled
out and detailed neurophysiologic studies performed in an at-
tempt to detect subclinical motor abnormalities.1027,1121

SEP Conduction Studies. We do not routinely perform SEPs
in patients evaluated for AIDP because virtually all of the infor-
mation necessary for diagnosis and prognosis can be readily ob-
tained using routine sensory and motor conduction techniques.996
However, SEPs have a theoretical advantage in that they allow
the opportunity of investigating the proximal aspects of the ner-
vous system not customarily accessible to routine SNAP tech-
niques.446,459,1118,1382 Most studies have substantiated that the
peripheral nervous system is variably affected, with some dis-
ease predisposition toward the proximal or nerve root regions.
Central conduction times are found to be essentially normal.
This may explain why patients demonstrate clinical sensory ab-
normalities and yet little in the way of electrophysiologic periph-
eral SNAP abnormalities.157 Specifically, a lesion in or about the
dorsal root ganglion region may not result in injury to the nearby
cell body but may cause sufficient demyelination to generate an
ectopic focus (paresthesias) and block neural transmission, re-
sulting in variable degrees of numbness. Of interest, brainstem
auditory evoked responses have generally revealed normal re-
sults but a few patients have demonstrated some slowing of con-
duction.946,1118,1180
Needle EMG Examination. The needle EMG examination
in patients with AIDP is primarily adjunctive to explore the pos-
sibility of other disease entities. The earliest motor finding in pa-
tients with AIDP is a reduced recruitment of MUAPs.9,11 A
reduced number of normal-appearing MUAPs firing at rapid
rates may be observed during low levels of force production, par-
ticularly in clinically weak muscles. Spontaneous potentials in
the form of positive sharp waves and fibrillation potentials may
first be seen between weeks 2 and 4, peaking at about the 6–15
weeks; potentials maximize earlier in proximal muscles than in
distal muscles. These abnormal potentials can appear in both
proximal and distal muscles simultaneously. Not unexpectedly,
patients are more likely to have prominent positive sharp waves
and fibrillation potentials when the CMAP is profoundly re-
duced.370,1076 From 15 weeks onward, there is a gradual decline
in the degree of abnormal spontaneous activity. Myokymia can
also be detected in patients with AIDP, especially in facial mus-
cles.289,523,844,1387 These potentials are commonly observed within
the first three weeks of clinical presentation, with a gradual taper
over the ensuing weeks to months. During the first few weeks of
the disease process, the MUAP duration, amplitude, and number
of phases are normal. Over the course of the next 6–16 weeks,
there is an increase in all of these MUAP parameters.9,841 Single-
fiber EMG reveals a mild to moderate increase in fiber density,
substantiating motor unit remodeling in patients with axonal
loss.447 The mean jitter for individual muscles remains normal;
however, occasional individual single muscle fibers may demon-
strate mildly increased jitter, but of an insufficient degree to alter
the value for all potential pairs.
Autonomic Testing. Autonomic instability can be assessed
by measuring the EKG’s R-R interval variation. About 35% of
patients demonstrate an abnormality.967,1048 An alternative
method of assessing the sympathetic nervous system is to inves-
tigate the sympathetic skin response.1203,1249 Although of inter-
est, this parameter does not really contribute to the diagnosis or
prognosis in AIDP and can be rather variable from trial to trial.
Treatment. Plasma exchange (PE)431,514 and intravenous im-
munoglobulin (IVIG)1059,1334 have been demonstrated in pro-
spective controlled trials to be effective in the treatment of
AIDP (Table 23-3). The North American Trial revealed that PE
reduced the time necessary to improve one clinical grade, time
to walk unaided, time on a ventilator, and the percentages of
Chapter 23 ACQUIRED NEUROPATHIES — 943
patients improving after 1 and 6 months compared with the con-
trol group.514 The French Plasmapheresis Group confirmed the
effectiveness of PE.431 PE is believed to remove autoantibodies,
immune complexes, complement, or other humoral factors in-
volved in the pathogenesis of AIDP. The total amount of plasma
exchanged is 200–250 ml/kg of patient body weight over 10–14
days. The removed plasma is generally replaced with albumin.
Thus, a 70 kg patient receives 14,000–17,500 ml (14–17.5 L)
total exchange, which can be accomplished by 4–6 alternate day
exchanges of 2–4 liters each.
IVIG has replaced PE in many centers as the treatment of
choice for AIDP because it is more widely available and easier
to use than PE. The dose of IVIG is 2.0 gm/kg body weight in-
fused over 2–5 days. The mechanism of action of IVIG is not
known. In a prospective controlled trial of IVIG vs. PE, IVIG
was shown to be at least as effective as PE.1334 Subsequent ran-
domized studies confirmed the efficacy of IVIG in AIDP (see
Table 23-3).148,1053 Of importance, one study noted no added
benefit of IVIG after PE.1059
Treatment with IVIG or PE should begin as soon as possible,
preferably within the first 7–10 days of symptoms. However,
improvement with PE and IVIG is often not immediate. The
mean time to improvement of one clinical grade in the various
controlled, randomized PE and IVIG studies ranged from 6 days
to as long as 27 days.431,514,1334 Thus, one may not see dramatic
improvement in strength in patients during PE or IVIG treat-
ments. Clinicians need to be aware of the time frame for im-
provement in AIDP. No evidence indicates that PE beyond 250
ml/kg182,431,612,1119 or IVIG greater than 2 gm/kg is of any added
benefit in patients with AIDP and a stable deficit. Furthermore,
there is no indication for PE followed by IVIG or vice versa.
However, as many as 10% of patients treated with either
PE431,1119 or IVIG182,612 develop a relapse after initial improve-
ment. In patients who suffer such relapses, we give additional
courses of PE or IVIG.
Unlike chronic inflammatory demyelinating polyneuropathy
(see below), corticosteroids do not appear beneficial in the treat-
ment of AIDP; in fact, some patients have done worse.605 A small
study of 25 patients treated with IVIG and intravenous methyl-
prednisolone345 did better than a historical control group treated
with IVIG alone.1334 However, a much larger British study of 142
patients treated with methylprednisolone or placebo (approxi-
mately half the patients in each group also were treated with PE)
failed to demonstrate the efficacy of corticosteroids.515
AIDP in Children. The clinical, laboratory, and electro-
physiologic findings in children with AIDP are similar to those
noted in adults.64,311,143,821,1021a,1086 Almost 75% of children have
an antecedent infection within two months of onset of symp-
toms. The major presenting complaint in children is pain. As in
adults, generalized weakness, sensory loss (including sensory
ataxia), cranial nerve and respiratory muscle weakness, and au-
tonomic dysfunction can occur. Laboratory evaluation is re-
markable for an elevated CSF protein as in adults. Sural nerve
biopsies in children with GBS demonstrate similar histopatho-
logic abnormalities as those described in adults.821
In large series of children with AIDP, electrophysiologic
studies demonstrated prolonged or absent F-waves in 81–88%
within the first few weeks of symptoms.143,1086 During these first
two weeks, 83–100% of the children also had reduced CMAP
amplitudes, and 22–60% had mean CMAP amplitudes less than
20% of the lower limit of normal. In addition, temporal disper-
sion or conduction block of CMAPs was found in 61–74% of
cases. A reduction in nerve conduction velocity was noted in
944 — PART IV CLINICAL APPLICATIONS

Table 23-3. Guillain-Barré Syndrome: Plasmapheresis and IVIG Trials

Plasmapheresis Group Control Group IVIG Group
North American Trial
Number of patients 122 123
Time to improve 1 clinical grade 19 days 40 days
Time to walk unaided (all patients) 53 days 85 days
Time to walk unaided (ventilator patients) 97 days 169 days
Time on ventilator 9 days 23 days
% improved at 1 month 59 39
% improved at 6 months 97 87
French Trial
Number of patients 109 111
% of patients on ventilator after study 21% 43%
Time to wean from ventilator 18 days 31 days
Time to walk unaided 70 days 111 days
Time in hospital 28 days 45 days
Dutch IVIG Trial
Number of patients 73 74
% of patients improving 1 clinical grade after 4 weeks 34 53
Time to improve 1 clinical grade 41 days 27 days
Time to clinical grade 2 69 days 55 days
Ventilator dependent by week 2 42 27%
Number of multiple complications 16 5
PE/Sandoglobulin Trial Group
Number of patients 121 130
Mean change in clinical grade after 4 wk 0.9 0.8
Time to wean from ventilator 29 days 26 days
Time to walk unaided 49 days 51days
Number of patients unable to walk after 48 wk 19 (16.7%) 21 (16.5%)
North American Trial: Guillain-Barré Study Group: Plasmapheresis and acute Guillain-Barré syndrome. Neurology 1985;35:1096–1104; French Trial: French
Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome: Efficiency of plasma exchange in Guillain-Barré syndrome: Role of replacement fluids. Ann
Neurol 1987;22:753–761; Dutch IVIG Trial: van der Meché FGA, Schmidtz PIM, and the Dutch Guillain-Barré Study Group:A randomized trial comparing intravenous
immunoglobulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med 1992;326:1123–1129; Plasma Exchange/Sandoglobulin GBS Trial Group: Plasma
Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group: Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in
Guillain-Barré syndrome. Lancet 1997;349:225–230.This trial also had 128 patients randomized into a treatment group that received plasmapheresis (PE) followed
by IVIG.There was no statistically significant improvement in any outcome measures in this group compared with the groups that received PE or IVIG alone.

two or more nerves in 48% of patients and in at least one nerve
in 70–84%. Prolonged distal motor latencies were evident in at
least one nerve in 57–75% of children. Abnormal SNAPs were
reported in about 70% of patients, with decreased or absent re-
sponses in 52–61% and prolonged distal latencies or slow con-
duction velocities in 9–54%. Needle EMG examination
revealed fibrillation potentials and positive sharp waves in at
least one muscle in 27% of children. Fortunately, most children
with AIDP have a satisfactory recovery, even those with signifi-
cant reductions in CMAP amplitude.143,1021a,1086
Acute Motor-Sensory Axonal Neuropathy
Clinical Features. Feasby and colleagues initially reported
this axonal variant of GBS in 1986.397 Although its existence was
met with early skepticism,1311,1312 recent histologic studies con-
firm that AMSAN is a real disease entity.506,507 Clinically and at
least by initial electrodiagnostic studies, patients with AMSAN
are indistinguishable from those with AIDP.150,159,397,400,424,506,507,
821,841,894,896,1131,1312,1404 As with GBS, sensory abnormalities are
noted initially in the hands or feet and progress later. Patients
with AMSAN develop rapidly progressive and severe general-
ized weakness over only a few days as opposed to a couple of
weeks in most patients with AIDP. Ophthalmoplegia may be noted
as well as difficulty in swallowing. The muscles of facial expres-
sion are also profoundly weak. Most patients require ventilator
support during the course of the disease. Sensation to all modal-
ities is reduced, and complete areflexia is usually evident.
Autonomic disturbances can be observed with respect to blood
pressure instability and cardiac arrhythmias. The prognosis of
AMSAN is much poorer than in AIDP; most patients have a
slow and incomplete recovery.894,896 Only a few children have
been reported with AMSAN; there is some suggestion that the
prognosis, although guarded, is better than in adults.1097
Laboratory Features. As in AIDP, albuminocytologic dis-
sociation of the CSF protein is usually evident during the course
of the neuropathy. In addition, recent infection with C. jejuni
and antibodies directed against antinerve gangliosides, particu-
larly GM1 antibodies, have been demonstrated in many patients
with AMSAN.507,1446 Some authorities suggest that C. jejuni in-
fection and GM1 antibodies are more commonly associated
with axonal forms of GBS (i.e., AMSAN and AMAN) and
poorer prognosis, but this is controversial.741,1446,1447 Some pa-
tients with antecedent C. jejuni infection and GM1 antibodies
have typical AIDP and a good recovery.741,1369
Histopathology. Histologic evaluation performed early in
the course of the disorder is the only way to differentiate axonal
GBS from pseudoaxonal GBS because of their clinical, labora-
tory, and electrophysiologic similarities. In patients biopsied
late in the disease, it can be difficult to distinguish primary ax-
onopathy from secondary axonal degeneration. In several reports

of patients with inexcitable motor and sensory conduction stud-
ies, the histopathology of sensory and motor nerves suggested
severe demyelination rather than primary axonal degenera-
tion.88,109,437,540,842 Nevertheless, some patients with inexcitable
CMAPs and SNAPs clearly have had histologic abnormalities
supportive of a primary axonal insult.397,400,506,507,816 In contrast to
AIDP, demyelination and lymphocytic infiltrates are absent or
only minimally present on nerve biopsy or at autopsy in patients
with AMSAN. Rather, prominent axonal degeneration affecting
the ventral and dorsal roots and the peripheral nerves is evident.
As many as 80% of teased fibers reveal axonal degeneration,
whereas demyelinating features are rare.397,400 Axonal degenera-
tion leads to profound loss of both myelinated and unmyelinated
axons. Griffin and colleagues reported the pathology of three pa-
tients with AMSAN who died early in the course of their ill-
ness.507 They demonstrated that prominent axonal degeneration
of the spinal roots and peripheral nerves without demyelination
or significant inflammation was an early histopathologic feature.
They also noted that numerous macrophages were present in the
periaxonal space of myelinated internode, as were rare intraax-
onal macrophages. Similar histologic abnormalities are seen in
AMAN (see below) but are not typical in AIDP.
Pathogenesis. The pathogenic basis of AMSAN is unknown
and only speculative. AMSAN is most likely due to an immune-
mediated attack directed against epitopes on the axon.507 The
neural epitopes may be gangliosides, such as GM1 or GM1a,
which are present on the nodal axolemma.1446,1447 AMSAN can
follow C. jejuni infection, leading to production of antiganglio-
side antibodies due to molecular mimicry. Early in the course or
with mild disease, binding of the antibodies to neural epitopes
may result in only physiologic conduction block. Complement
activation on nodal and later internodal axolemma and recruit-
ment of macrophages may result in axonal degeneration.
Electrophysiologic Findings. Nerve conduction studies
reveal markedly diminished amplitudes or absent CMAPs
within 7–10 days of onset.159,243,397,400,424,540,841,894,896,1404,1439 The
SNAP amplitudes are also profoundly reduced or absent. As
discussed earlier, low-amplitude CMAPs are one of the earliest
electrophysiologic abnormalities noted in AIDP. Therefore,
hypo- or inexcitability of the motor nerve does not necessarily
imply axonal degeneration. Distal conduction block with or
without demyelination can be responsible for the low-amplitude
distal CMAPs.1311,1312 In fact, it may be impossible, at least ini-
tially, to distinguish AIDP from AMSAN by nerve conduction
studies. Serial nerve conduction studies may be helpful in deter-
mining the underlying pathology and prognosis. Triggs reported
34 patients with “GBS” who had low-amplitude or unobtainable
CMAPs.1311 Of the eight patients with unobtainable CMAPs,
five made good recoveries (suggesting conduction block, not
axonal degeneration), whereas three patients did poorly (pre-
sumably secondary to axonal degeneration). Of 26 patients who
initially had low-amplitude CMAPs, serial conduction studies
revealed decreasing amplitudes in 12 (suggesting worsening of
conduction block or increasing axonal degeneration) and in-
creasing amplitudes in nine (suggesting improvement of con-
duction block). Not unexpectedly, the patients believed to have
electrophysiologic evidence of resolving distal conduction
block had a better prognosis than patients whose distal CMAP
amplitudes progressively declined.
In three patients with AMSAN studied within the first week
of symptoms, Brown recorded CMAP amplitudes as the stimu-
lator was moved from the common distal sites of stimulation
(wrist and ankle) to within 50–100 mm of the motor point by
Chapter 23 ACQUIRED NEUROPATHIES — 945
“inching” technique.159 In each case, the CMAPs after wrists
and ankle stimulation were markedly reduced or absent. As the
sites of stimulation were moved closer to the motor point, the
CMAP potentials progressively increased in size. Nevertheless,
the CMAP amplitudes never exceeded 10% of the lower limit of
normal. These findings were interpreted as most consistent with
axonal degeneration; however, distal demyelination with con-
duction block could not be excluded. These distal-most seg-
ments reportedly had slow conduction velocities, often to less
than 30% of normal, and in one instance to less than 1 m/s.
Ideally, the distal latencies of the CMAPs and the nerve conduc-
tion velocities, when obtainable, should be normal or only mildly
affected. The presence of prolonged distal latencies, slow conduc-
tion velocities, or significantly dispersed distal CMAP waveforms
in patients with low CMAP amplitudes should lead to the consider-
ation of demyelination and conduction block of the distal motor
nerve terminal rather than a primary axonal insult. In the presence
of inexcitable motor nerves, it is impossible to distinguish AIDP
from AMSAN. On the basis of its distinct histopathology, it ap-
pears that AMSAN does exist, although it is a rare condition.
The needle EMG examination demonstrates markedly abnor-
mal reductions in recruitment. Several weeks after the presenta-
tion of major motor weakness, abundant fibrillation potentials
and positive sharp waves can be detected in most muscles, espe-
cially those located in the distal regions of the limbs.88,1446,1447
Treatment. No prospective treatment studies have been per-
formed specifically for AMSAN. Because it is difficult to dis-
tinguish AIDP from AMSAN clinically or electrophysiologically,
at least initially, treatment with either plasma exchange or IVIG
is warranted.
Acute Motor Axonal Neuropathy
Epidemiology. The first detailed descriptions of the AMAN
variant of GBS were by McKhann and colleagues, who reported
the clinical, laboratory, electrophysiologic, and histologic find-
ings in cases of seasonal outbreaks of acute flaccid paralysis in
northern China.867,868 They initially named the disorder Chinese
paralytic syndrome. Because similar cases subsequently were
described throughout the world, the term acute motor neuropa-
thy was believed to be more appropriate.616,1359 In northern
China, AMAN is the most common variant of GBS. AMAN ap-
pears to be less frequent in other areas of the world but is still
quite common. Twenty seven of the 147 (18%) patients enrolled
in the Dutch GBS trial comparing IVIG with PE were later clas-
sified as having AMAN.1334,1359
An antecedent illness has been described in 30–85% of pa-
tients with AMAN in large series.526,821,868,1021a,1359 A preceding
gastrointestinal infection can be elicited in 10–60% of such
cases. In addition, serologic evidence of a recent C. jejuni infec-
tion can be demonstrated in 67–92% of patients.868,1359
Clinical Features. AMAN has been described in children
and adults.585,616,821,867,868,1026,1359 As in AMSAN, there is an abrupt
onset of generalized weakness. The distal muscles often are af-
fected more severely than proximal limb muscles. Cranial nerve
deficits and respiratory failure requiring mechanical ventilation
can be seen in up to one-third of patients.867,868,1026,1359 Unlike
AIDP and AMAN, sensory signs and symptoms are absent.
Autonomic dysfunction in the form of cardiac arrhythmias,
blood pressure fluctuations, and hyperhidrosis may occur. Deep
tendon reflexes may be normal or absent. Of interest, some pa-
tients even develop hyperactive reflexes during the recovery
period.616,868 The median time of recovery is similar to that in
typical AIDP. Patients generally make a good recovery within
946 — PART IV CLINICAL APPLICATIONS
one year, but residual distal limb weakness is common.585 The
mortality rate is less than 5%.868 Second attacks of the illness
have been described in northern Chinese patients, but the actual
recurrence rate is not known.868
Laboratory Features. As with AIDP and AMSAN, albu-
minocytologic dissociation is the rule.616,867,868,1021a,1359 The ab-
sence of prominent CSF pleocytosis helps distinguish AMAN
from poliomyelitis, which it can mimic. Serology evidence of
recent C. jejuni infection can be demonstrated in 67–92% of pa-
tients.868,1359 Anti-GM1 and anti-GD1a antibodies are commonly
detected in patients with AMAN and usually are associated with
recent Campylobacter infection.526,586,868,1359
Histopathology. The earliest histologic abnormalities are
noted at the nodes of Ranvier.530 The nodal gaps can be appre-
ciably lengthened, when the rest of the nerve fiber appears oth-
erwise normal. Immunocytochemistry reveals deposition of IgG
and complement activation products (i.e., C3d and C5b-9) on
the nodal and internodal axolemma of motor fibers and pre-
cedes features of axonal degeneration.530 Deposition of IgG and
complement is also evident on the nodes of Ranvier on teased
fiber analysis and EM.530 These features contrast with the find-
ings in AIDP: early deposition of immunoglobulin and comple-
ment on Schwann cells rather than the axons.530
Macrophages are also evident over the nodes of Ranvier of large
myelinated ventral motor root fibers.530 The macrophages proba-
bly are recruited into the affected nodes and periaxonal space via
complement-derived chemotropic factors.530 These inflammatory
cells insert through the Schwann-cell basal lamina into the nodal
gap. Subsequently, the macrophages can be seen encircling the
nodes and dissecting beneath the myelin sheath into the periaxonal
space. As they enter the perixonal space, the axon retracts from the
adaxonal Schwann cell. In severe cases, the axons then begin to
degenerate, but the innermost myelin sheath (adaxonal lamella)
appears intact. Ho demonstrated active degeneration and severe
loss of large myelinated intramuscular nerve fibers on muscle
biopsies that included the distal motor nerve terminals.585
Pathogenesis. Histopathology and immunologic studies
suggest that AMAN is caused by an immune-mediated attack
against an unknown epitope on the nodal axolemma. As noted
above, serologic evidence of a preceding infection with C.
jejuni and anti-GM1 and anti-GD1a antibodies can be identified
in many patients with AMAN in addition to typical AIDP and
AMSAN. It is speculated that antibodies directed against the
lipopolysaccaride membrane of Campylobacter cross-react with
specific epitopes on the nodal axolemma (e.g., GM1 or GD1a
gangliosides).530 The binding of antibodies to the nodal ax-
olemma with or without subsequent complement activation may
decrease the sodium current or increase the potassium current,
thereby resulting in conduction block.1283 In severe cases,
axonal degeneration occurs via complement-mediated damage
to the axons. The fact that many patients with AMAN syndrome
recover quickly suggests that the low-amplitude or unobtainable
distal CMAPs (see below) are due not necessarily to axonal de-
generation but to distal conduction block. Diminished CMAP
amplitudes and early recovery also may be seen if degeneration
is limited to the distal motor nerve terminal.585
Electrophysiologic Findings. The characteristic electrophysio-
logic feature on nerve conduction studies in AMAN is low-ampli-
tude or unobtainable CMAPs with normal SNAPs.585,616,867,868,1359
When CMAPs are obtained, the distal latencies and conduction
velocities are normal. F-waves are also usually unobtainable but,
when present, show normal latencies. As discussed in the AIDP
and AMSAN sections, the decreased CMAP amplitudes may be
a reflection of distal conduction block or perhaps only degenera-
tion of the distal motor nerve terminal as opposed to widespread
axonal degeneration. Increased spontaneous activity in the form
of fibrillation potentials and positive sharp waves and decreased
recruitment of MUAPs usually can be appreciated.585,616,867,868,1359
Motor unit number estimate (MUNE) performed sequentially
in 7 patients with AMAN demonstrated a marked decrease at the
peak of illness.741a As clinical recovery began, CMAP amplitudes
increased without a significant change in the MUNE. The inves-
tigators suggested that the primary mechanism of early recovery
in AMAN may be collateral reinnervation, with resolution of
conduction block and nerve regeneration occurring later.
Treatment. No treatment trials have been devoted to AMAN,
but it is likely that patients were included in some of the AIDP
trials comparing PE and IVIG. As noted above, 27 of the 147
(18%) of the patients enrolled in the Dutch GBS trial comparing
IVIG with PE were later classified as having AMAN.1334,1359
Subgroup analysis of the AMAN group suggested that IVIG-
treated patients may recover faster than PE-treated patients.
There was no significant difference in outcome, regardless of
treatment (IVIG, PE, or PE followed by IVIG) between AIDP
and AMAN in a subgroup analysis of 369 patients.526 Because of
the ease of administration, we generally treat AMAN patients
with IVIG, 2 gm/kg over 5 days, as in AIDP. PE is an alternative
if IVIG is not available or is contraindicated.
Other Variants of Guillain-Barré Syndrome
Other variants of GBS include Miller-Fisher syndrome
(ataxia, areflexia, and ophthalmoplegia), idiopathic cranial
polyneuropathy, pharyngeal-cervical-brachial weakness with or
without ophthalmoparesis, and paraparetic weakness.645,1118,1124
These disorders may represent an oligosymptomatic form or
forme-fruste of AIDP. Of these possible GBS variants, Miller-
Fisher syndrome is best characterized.
Clinical Features. In 1956, C. Miller-Fisher reported three
patients with ataxia, areflexia, and ophthalmoplegia—a syn-
drome distinct from GBS.420 Since then, over 200 cases of
Miller-Fisher syndrome (MFS) have been described either as
case reports or small series of patients.96,923a,1121 There is a 2:1
male predominance with a mean age of onset in the early 40s.
An antecedent infection occurs in over two-thirds of the cases.
Diplopia is the most common initial complaint (39–78%);
ataxia is evident in 21–34% of patients at onset. Whether the
ataxia is secondary to sensory dysfunction or a cerebellar lesion
is controversial. In our experience, most patients have sensory
ataxia. Ophthalmoparesis can develop asymmetrically but often
progresses to complete ophthalomoplegia. Ptosis usually ac-
companies the ophthalmoparesis, but pupillary involvement is
uncommon. Other cranial nerves also can become involved.
Facial weakness is evident in 32–57%, dysphagia in 26–40%,
and dysarthria in 13–40% of patients. Nearly one-half of pa-
tients describe paresthesias of the face and distal limbs.
Areflexia is evident on examination in over 82%. Mild proximal
limb weakness can be demonstrated in the course of the illness
in approximately one-third of cases. Some patients progress to
more severe generalized weakness similar to typical
GBS.96,105,559,1213 Clinical return of function usually begins
within about 2 weeks after the onset of symptoms, and full re-
covery of function is typically seen within 3–5 months.
Laboratory Features. Most patients with MFS have elevated
CSF protein without significant pleocytosis.96,1121 Serologic evi-
dence of C. jejuni can be demonstrated in some patients as well
as antiganglioside antibodies, in particular anti-GQ1b.213,923a,1448

Histopathology. Biopsy and autopsy data are limited and
need to be viewed cautiously because some cases that began with
ophthalmoplegia, ataxia, and areflexia later evolved to severe
quadriparesis characteristic of more typical AIDP.1055 These stud-
ies showed normal brainstem findings or only secondary chroma-
tolysis of the oculomotor, trochlear, or abducens nuclei.
Demyelination and mild inflammatory infiltrates were noted
along the course of these cranial nerves. Lymphocytic infiltrates
were also apparent in the sensory ganglia of peripheral nerves.
Pathogenesis. The pathogenic basis of MFS is not known, al-
though it is probably autoimmune. The primary site of the
immune attack (i.e., PNS or CNS) is controversial.96,923a,1121 Most
authorities believe that the clinical, electrophysiologic, and histo-
logic findings point to the PNS, in particular the sensory ganglia
and oculomotor fibers. Similar to other variants of GBS, recent
antecedent infections, including enteritis due to C. jejuni, can be
identified in most patients with MFS. Perhaps through molecular
mimicry, autoantibodies directed against these infectious agents
cross-react with neuronal epitopes. As noted above, anti-GQ1b
antibodies can be detected in most patients with MFS. Of impor-
tance, oculomotor fibers and the sensory ganglion, which are
prominently affected in MFS, are enriched with GQ1b. Anti-
GQ1b antibodies stain sensory neurons in the dorsal root as well
as cerebellar nuclei. In mice infused with serum from patients
with MFS, the GQ1b antibodies were observed to bind to neuro-
muscular junctions.1061 In a complement-dependent process, this
resulted in massive quantal release of acetylcholine from nerve
terminals and eventually blocked neuromuscular transmission.
Electrophysiologic Findings. The most prominent electro-
physiologic abnormality in MFS is reduced amplitudes of
SNAPs out of proportion to prolongation of the distal latencies
or slowing of sensory conduction velocities.304,434,622,11021142,1172,1397
Minimally slowed motor conduction velocities (still within 80%
of normal) and prolonged F-waves have been reported in only a
few patients. CMAPs in the arms and legs are usually normal. In
contrast to limb CMAPs, mild to moderate reduction of facial
CMAPs can be demonstrated in over 50% of patients with
MFS.434 Blink reflex may be abnormal with facial nerve involve-
ment. Reduced facial CMAPs coincide with the loss or mild
delay of R1 and R2 responses on blink reflex testing.299,434,559
Evoked potential studies have given inconsistent results.
Some studies report central conduction abnormalities on so-
matosensory, brainstem, and visual evoked responses.1058,1140
Other studies report normal evoked potentials or slowing local-
ized to the peripheral nervous system.299,622,623,1118
EMG reveals minimal abnormalities.434,622 There is generally
no abnormal spontaneous activity in limb or paraspinal muscles.
However, fibrillation potentials may be detected in facial mus-
cles. Decreased recruitment of MUAPs may be noted in weak
muscles. During recovery, increased MUAP duration, ampli-
tude, and polyphasia can be seen.
Treatment. There are no controlled treatment trials of pa-
tients with MFS. However, it seems prudent to treat patients
with either IVIG or PE, given the presumptive similarity in
pathogenesis with AIDP.
ACQUIRED CHRONIC DEMYELINATING
POLYNEUROPATHIES
Chronic Inflammatory Demyelinating Polyneuropathy
Chronic inflammatory demyelinating polyradiculoneuropa-
thy (CIDP) is an immune-mediated neuropathy characterized by
Chapter 23 ACQUIRED NEUROPATHIES — 947
a relapsing or progressive course. 73,78,147,351,560a,1131a,1168a The re-
lapsing form was recognized as early as 1914 by Hoerstermann
and was described as recurrent polyneuritis.588 The progressive
form of the neuropathy was reported as progressive hyper-
trophic neuritis1133 and chronic Guillain-Barré syndrome
(GBS).303 Austin initially described the steroid-responsive nature
of CIDP in 1958. Dyck retrospectively reported the clinical, labo-
ratory, electrophysiologic, and histologic features of 53 patients
and termed the disorder chronic inflammatory polyradicu-
loneuropathy. 351 Torvik and Lundar proposed the name
chronic inflammatory demyelinating polyradiculoneuropa-
thy to underscore the demyelinating features. Subsequently, other
large series of patients were reported73,130,276,353,477,864,887,1071,1297 and
guidelines for the diagnosis of CIDP were developed.73 In 1991,
the Ad Hoc Subcommittee of the American Academy of
Neurology (AAN) proposed research criteria for the diagnosis of
CIDP (Table 23-4).249 Modifications were recently proposed to
distinguish CIDP from other forms of chronic acquired demyeli-
nating polyneuropathy.1168a With increased recognition, CIDP has
accounted for approximately 10–33% of initially undiagnosed
peripheral neuropathies.73,78,353,864
Clinical Features. Symptoms and signs of the neuropathy
must be progressive for at least two months, which distin-
guishes CIDP from GBS or AIDP.73,249,1168a Some patients have a
subacute onset over 4–8 weeks, a variant that Hughes’ termed
subacute demyelinating.603 The subsequent natural history of
these subacute cases may be that of AIDP (spontaneous remis-
sion) or CIDP (chronic relapses or progression), requiring treat-
ment. Dyck describe four typical clinical courses of progression
in patients with CIDP: (1) chronic monophasic (15%); (2)
chronic relapsing (fluctuations of weakness or improvement
over weeks or months); (34%); (3) stepwise progressive (34%);
and (4) steady progressive (15%).351,363 The pattern of disease
progression in CIDP is analogous to multiple sclerosis, affect-
ing only the peripheral as opposed to central nervous system.
CIDP most commonly presents in adults with a peak inci-
dence at about 40–60 years; there is a slightly increased preva-
lence in men.73,130,276,351,477,560a,864,1071,1297 The relapsing form has
an earlier age of onset, usually in the twenties.73,351 Relapses
have been associated with pregnancy.862 The association of
CIDP with infections has not been studied as extensively as in
AIDP; however, an infection has been reported to precede
20–30% of CIDP relapses or exacerbations.864,1216
Most patients present with relapsing or progressive symmet-
ric proximal and distal weakness of the arms and legs.73,130,
249,363,477,864,1131a,1168a,1297 Weakness of proximal lower limb mus-
cles results in difficulty with ambulating, climbing stairs, and
arising from a low soft chair or commode. Distal lower limb
weakness may cause foot drop, leading to stubbing of toes and
tripping. Distal upper limb weakness impairs fine motor dexter-
ity (buttoning shirts, tying shoes, picking up small objects),
whereas proximal weakness causes difficulties with performing
activities requiring overhead hand use (grooming, putting books
on a high shelf) and lifting or carrying heavy objects (gro-
ceries). Clinical examination usually confirms weakness in
proximal and distal arm and leg muscles. The diagnostic criteria
proposed by Barohn and colleagues require symmetric proxi-
mal and distal weakness.73,1168a However, the AAN criteria are
looser clinically and do not require either proximal or symmet-
ric weakness (see Table 23-4).249 Early in the course of the ill-
ness, only distal weakness may be observed. However, if
weakness remains distal, other diagnoses need to be considered
(e.g., hereditary demyelinating neuropathy, paraprotein-related
948 — PART IV CLINICAL APPLICATIONS

Table 23-4. Research Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Clinical criteria
1. Mandatory
• Progressive or relapsing motor and sensory (rarely only motor or sensory) dysfunction of more than one limb of a peripheral nerve de-
veloping over at least 2 months.
• Hypo- or areflexia.This will usually involve all four limbs.
2. Supportive: Large-fiber sensory loss predominates over small-fiber sensory loss.
3. Exclusionary
• Mutilation of hands or feet, retinitis pigmentosa, ichthyosis, appropriate history of drug or toxic exposure known to cause a similar pe-
ripheral neuropathy, or family history of a genetically based peripheral neuropathy
• Sensory level
• Unequivocal sphincter disturbance
Physiologic studies
1. Mandatory
• Nerve conduction studies, including studies of proximal nerve segments in which the predominant process is demyelination.
• Must have three of four:
(1) Reduction in conduction velocity (CV) in two or more motor nerves:
(a) < 80% of lower limit of normal (LLN) if amplitude > 80% of LLN.
(b) < 70% of LLN if amplitude < 80% of LLN.
(2) Partial conduction block or abnormal temporal dispersion in one or more motor nerves: peroneal nerve between ankle and below
fibular head, median nerve between wrist and elbow, or ulnar nerve between wrist and below elbow.
(a) Criteria suggestive of partial conduction block: < 15% change in duration between proximal and distal sites and > 20% drop in
negative-peak (–p) area or peak-to-peak (p–p) amplitude between proximal and distal sites.
(b) Criteria for abnormal temporal dispersion and possible conduction block: > 15% change in duration between proximal and
distal sites and > 20% drop in –p area or p–p amplitude between proximal and distal sites.These criteria are only suggestive of
partial conduction block because they are derived from studies of normal subjects.Additional studies, such as stimulation
across short segments or recordings of individual motor unit potentials, are required for confirmation.
(3) Prolonged distal latencies in two or more nerves:
(a) > 125% of upper limit of normal (ULN) if amplitude > 80% of LLN.
(b) > 150% of ULN if amplitude < 80% of LLN.
(4) Absent F-waves or prolonged minimum F-wave latencies (10–15 trials) in two or more nerves:
(a) > 120% of ULN if amplitude > 80% of LLN.
(b) > 150% of ULN if amplitude < 80% of LLN.
2. Supportive criteria
• Reduction in sensory CV < 80% of LLN
• Absent H-reflexes.
Pathologic features
1. Mandatory: nerve biopsy showing unequivocal evidence of demyelination and remyelination. Demyelination by either electron microscopy
(> 5 fibers) or teased fiber studies (> 12% of 50 teased fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination).
2. Supportive
• Subperineurial or endoneurial edema.
• Mononuclear cell infiltration.
• “Onion-bulb” formation.
• Prominent variation in the degree of demyelination between fascicles.
3. Exclusionary:Vasculitis, neurofilamentous swollen axons, amyloid deposits, or intracytoplasmic inclusions in Schwann cells or macrophages
indicating adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, or other evidence of specific pathology.
CSF studies
1. Mandatory
• Cell count < 10/mm3 if HIV-seronegative or < 50/mm3 if HIV-seropositive.
• Negative Venereal Disease Research Laboratory Test
2. Supportive: elevated protein.
Diagnostic categories for research purposes. Definite: clinical A and C, physiology A, pathology A and C, and CSF A. Probable: clinical A and
C, physiology A, and CSF A. Possible: clinical A and C and physiology A.
Laboratory studies. Depending on the results of laboratory tests, patients meeting the above criteria are classified into the groups listed
below.The following studies are suggested: CBC, routine chemistries,ANA, serum and urine immunoglobulin studies (including either immunofix-
ation electropheresis or immunoelectropheresis), and HIV and hepatitis serology.The list of laboratory studies is not comprehensive. For in-
stance, in certain clinical circumstances other studies may be indicated, such as thyroid functions, phytanic acid, long-chain fatty acids, porphyrins,
and urine heavy metals.
From Cornblath DR, Asbury AK, Albers JW: Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology
1991;41:617–618.

neuropathy, or distal acquired demyelinating neuropathy).661,1168a
Although most patients (at least 80%) have both motor and sen-
sory involvement, a few patients may have pure motor (10%) or
pure sensory (5–10%) symptoms and signs.73,351,477,560a,1131a
Whether patients with pure motor or sensory involvement, par-
ticularly when it is asymmetric, fall within the spectrum of
CIDP or represent a distinctly different neuropathic disorder
(e.g., multifocal motor neuropathy; see below) is debatable.
As noted above, most patients have sensory involvement.
Sixty-eight to 80% of patients complain of numbness in the
hands or feet.130,351,477,864 Painful paresthesias are less common,
occurring in 15–50% of patients. Sensory examination is abnor-
mal in 68–84% of patients, primarily affecting large-fiber
modalities (vibration and touch).73,130,351,477,864 An associated sen-
sory ataxia, a positive Romberg sign, and a wide-based gait may
be found. Enlarged nerves can be palpated in as many as 11% of
patients.351 The term chronic sensory demyelinating neuropa-
thy has been applied to the few patients who have only sensory
symptoms and signs.264,986,987,1131a However, an electrodiagnostic
medicine evaluation in such patients usually reveals abnormali-
ties affecting the motor nerves.264,986,987 Some patients begin with
only sensory symptoms and signs but later develop motor abnor-
malities.91 In our experience, most patients with a demyelinating
neuropathy who have mainly sensory symptoms and signs with
normal or only mild distal weakness have an IgM monoclonal
gammopathy.661,1168a Whenever a pure sensory neuropathy is pre-
sent, consideration should be given to other diseases as well,
such as Sjögren’s syndrome or paraneoplastic neuronopathy,
both of which are associated with sensory ganglionitis.24
Most patients with CIDP have areflexia or hyporeflexia.
Cranial nerve involvement occasionally occurs but is usually mild
and not the presenting feature. Mild facial weakness is evident in
2–16%, diplopia secondary to ophthalmoplegia in up to 8%,
dysarthria and dysphagia in 9%, and papilledema in 1–7% of pa-
tients.73,130,276,351,864 Vertigo related to vestibular involvement is a
rarely reported complication.433 Some patients can develop
dropped head syndrome secondary to neck extensor weak-
ness.589 Respiratory insufficiency secondary to intercostal muscle
and diaphragm weakness has been reported in 8–15% of pa-
tients.276,351 Autonomic dysfunction (e.g., incontinence and impo-
tence) are less common, occurring in less than 5% of patients.351
Of interest, approximately 3–5% of patients with CIDP also
have evidence of CNS demyelination clinically, electrophysio-
logically (evoked potential studies), or by MRI scans.130,398,570,886,
1005,1012,1131a,1139,1300,1319 The CNS abnormalities can precede or
follow the onset of CIDP. Whether such patients have multiple
sclerosis or if the CNS demyelination in CIDP represents a dis-
tinct immunologic disorder is not known. Patients also may de-
velop a myelopathy due to compression of the spinal cord by
hypertrophied nerve roots.313,340,740,893,902
Other medical conditions may be seen in association with CIDP
or a CIDP-like neuropathy,21,73,247,1131a including HIV infection, he-
patitis, inflammatory bowel disease, systemic lupus erythemato-
sus, diabetes mellitus, monoclonal gammopathy of uncertain
significance (MGUS), POEMS syndrome, lymphoma, and
Castleman disease. Besides the association with the above lym-
phoproliferative disorders, CIDP or a CIDP-like neuropathy has
been described as a paraneoplastic complication of small cell car-
cinoma of the lung, carcinoma of the pancreas and colon, cholan-
giocarcinoma, and melanoma.24,30,31,102,1398 In addition, a CIDP-like
neuropathy may complicate bone marrow and solid organ transplan-
tations, usually in the setting of graft-versus-host disease or trans-
plant rejection.21,22,1289 Furthermore, a toxic-induced neuropathy
Chapter 23 ACQUIRED NEUROPATHIES — 949
resembling CIDP has been associated with certain medications
such as procainamide, cyclosporine, and tacrolimus.22,380 It is not
known whether the pathogenesis, prognosis, and response to treat-
ment of demyelinating neuropathies associated with these medical
disorders are identical to those of idiopathic CIDP. For example,
some patients with diabetes mellitus develop symmetric proximal
and distal weakness, hyporeflexia, and elevated CSF protein and
have demyelinating nerve conduction studies and nerve biopsies
that fulfill research criteria for CIDP (see section on diabetic
neuropathies).24a,241,479,627,729,1033,1261,1322 It is debatable whether such
patients have an unusual form of diabetic neuropathy or superim-
posed CIDP. The demyelinating neuropathies associated with IgG
and IgA monoclonal gammopathies of unknown significance
(MGUS) are usually indistinguishable from CIDP; however, the
neuropathies associated with IgM monoclonal neuropathies may
have somewhat different clinical and electrophysiologic features as
well as a distinct pathogenesis and response to therapy (see below).
Laboratory Features. An elevated CSF protein (> 45 mg/dl) is
found in 80–95% of patients.73,130,351,477,1168a These large studies have
reported CSF protein levels over 1200 mg/dl with a mean of about
135 mg/dl. As with AIDP, the cell count is usually normal, although
up to 10 % of patients have > 5 lymphocytes/mm3.73,276,351,477,1071,1297
Leukocyte count in the CSF should be < 10/mm3 or < 50/mm3 in
HIV-positive patients. Elevated CSF cell counts should lead to the
consideration of HIV infection, Lyme disease, and lymphomatous
or leukemic infiltration of nerve roots. Oligoclonal bands may be
demonstrated in the CSF in approximately 65% of patients.274,1194
As many as 25% of patients with CIDP or a CIDP-like neu-
ropathy have an IgA, IgG, or IgM monoclonal gammopa-
thy.73,477,661,1168a,1217 Paraprotein-related CIDP is addressed in a
separate section. Antibodies directed against myelin proteins
(e.g., GM1 ganglioside, P0 and P2) are present in a small per-
centage of patients.610,680 One study reported a high titer of anti-
tubulin antibodies in patients with CIDP,236 although other
groups have not verified this observation.828,1342
MRI with gadolinium may reveal hypertrophy and enhance-
ment of the nerve roots and peripheral nerves.313,340,740,893,902
Histopathology. The peripheral nerve and nerve root re-
gions are affected, with occasional involvement of the central
nervous system.73,130,363,726,887,1131a When the nerve roots are in-
volved, the ventral rami, posterior rami, or both may be prefer-
entially affected. Segmental demyelination and remyelination
are the most prominent histologic abnormalities (Fig. 23-3) but
are not present in every biopsy because of the multifocality of
the disease process. Chronic demyelination and remyelination
result in proliferation of surrounding Schwann cell processes,
forming so-called onion-bulbs. However, these onion bulbs are
not as prominent as in Charcot-Marie-Tooth disease. A total re-
duction in the number of myelinated fibers is also usually evi-
dent on biopsy. Analysis of teased nerve fibers is the best way to
quantify histologic abnormalities. Large series have demon-
strated segmental demyelination and/or remyelination in
23–68%, axonal degeneration in 5–42%, mixed demyelinating
and axonal features in 12.5–20%, and normal findings in
2–43.5% of teased nerve fibers.73,130,351,560a,1131a,1364a
Endoneurial and perineurial edema also may be appreciated
on biopsy. Schwann cell proliferation and edema can lead to a
hypertrophic appearance of the nerve. The “inflammatory”
component of CIDP is often not evident or is quite subtle on
sural nerve biopsies (see Fig. 23-3). Barohn found small clus-
ters of mononuclear inflammatory cells in only 10.7% of 56
sural nerve biopsies.73 The inflammatory cell infiltrate is evi-
dent in the epineurium, perineurium, or endoneurium and is
950 — PART IV CLINICAL APPLICATIONS
often perivascular. Dyck and colleagues reported perivascular
inflammation, mainly in the epineurium, in 54% of patients and
diffuse endoneurial inflammation in 23%.351 However, these in-
flammatory changes were reported as slight and difficult to dis-
tinguish from normal controls. In the largest series (95 nerve
biopsies), conspicuous perivascular endoneurial inflammatory
infiltrate was noted in only four specimens.130 The percentage of
nerve biopsies demonstrating inflammatory cells is increased
when immunostaining for lymphocytes and macrophages is per-
formed.246,846,1364a The inflammatory component is composed of
macrophages and CD8+ greater than CD4+ lymphocytes.846 Of
note, a similar frequency of inflammatory cell infiltrate within
nerves is seen in various neuropathies, including normal con-
trols, raising concern about their pathogenic role.127,246
Matrix metalloproteinases (MMP) are a family of endopepsi-
dases with overlapping substrate affinities for various extracel-
lular matrix proteins. MMP-2 and MMP-9 (gelatinase A and B)
have been shown to be upregulated in the peripheral nerves in
patients with CIDP.778 T-cells are the predominant source of
MMP-2 and MMP-9, which are capable of degrading compo-
nents of the subendothelial basement membrane, thereby allow-
ing inflammatory cells to disrupt the blood-nerve barrier and
penetrate peripheral nerves.
As evident from the above discussion, nerve biopsy findings
in CIDP are not particularly sensitive or specific. In patients
who fulfill the clinical and electrophysiologic criteria for
CIDP and who have elevated CSF protein concentrations > 1
g/L, nerve biopsies have no additional diagnostic value. 911
However, if the clinical, electrophysiologic, and CSF findings
do not fulfill criteria for CIDP, nerve biopsy is a useful diag-
nostic tool.
Figure 23-3. CIDP. A, Sural nerve biopsy reveals many thinly myeli-
nated nerve fibers with some nerve fibers surrounded by several
layers of Schwann cell proliferation or onion bulbs (epoxy-embedded,
touidine blue stain.). B, A macrophage can be seen engulfing an axon
and digesting the myelin (epoxy-embedded, touidine blue stain.). C,
Paraffins section reveals mononuclear inflammatory cells composed of
lymphocytes and macrophages in the endoneurium (H&E stain.)
Pathogenesis. The pathogenic basis of CIDP is presumably
autoimmune. However, the exact role played by the humoral
and cellular arms of the immune system in the pathogenesis of
CIDP is not fully understood. The exact tissue antigen(s) and
the interaction between the humoral and cellular arms of the
immune response are not known. Several lines of evidence sug-
gest involvement of humoral factors: the similarity between
CIDP and AIDP and experimental allergic neuritis, improve-
ment in patients after plasma exchange, and demonstration of
immunoglobulin and complement on peripheral nerve tis-
sues.276,363 However, large studies have found antimyelin anti-
bodies by direct and indirect immunoflourescent techniques in
only a few patients.363 Furthermore, passive transfer experi-
ments of plasma from patients with CIDP into laboratory ani-
mals has generally produced negative results. Nevertheless,
antibodies directed against axonal elements (e.g., ion channels)
probably are involved early in the pathogenesis of CIDP, pro-
ducing conduction block. The rapid improvement in some pa-
tients after PE or IVIG (see below) can be seen only with
resolution of conduction block because improvement on the
basis of remyelination alone would take longer.
Ultrastructural studies indicate activation of macrophages
with penetration of the basement membrane and displacement
of the Schwann cell cytoplasm.363 The macrophages lyse the su-
perficial myelin lamellae, penetrate along intraperiod lines, and
finally engulf the disrupted myelin by endocytosis. The de-
nuded axons shrink in diameter as much as 50%.363 Sub-
sequently, remyelination occurs by recruitment of normal
Schwann cells. Axons regain much of their original diameter
after remyelination; however, the remyelinated internodes are
shorter and thinner than normal. The laying down of new

Schwann cell processes and basement membrane, particularly
after several recurrences of demyelination and remyelination,
leads to the typical onion-bulb appearance on biopsy.
Physiologically, paranodal and internodal demyelination impairs
the propagation of the action potential down the nerve.
Demyelination of a nerve segment produces an increased trans-
verse capacitance and reduced resistance in the area, which in turn
cause a leakage of current and increase the time required for the
longitudinal current to reach the next node of Ranvier. If the current
leakage is excessive, there may not be enough current to depolarize
the next node of Ranvier, which is necessary to continue propagat-
ing the action potential. Block of conduction, not slowing of veloc-
ity, is responsible for motor weakness. A recent study demonstrated
that median CMAP amplitudes in patients with CIDP diminished
by 40% after 60 seconds of isometric exercise suggesting that ac-
tivity-dependent hyperpolarization results in worsening of conduc-
tion block.172a Conduction block along the nerve may be present in
lieu of demyelination by the postulated binding and blocking of ion
channels by antibodies. Conduction block may resolve prior to re-
myelination by removal of these antibodies.
Electrophysiologic Findings. In performing nerve conduction
studies in patients with suspected CIDP, we routinely evaluate
median and ulnar CMAPs, SNAPs, and F-waves in the arms.
Peroneal and posterior tibial CMAPs and F-waves and sural
SNAPs are studied in the lower limbs. We study multiple nerves
because of the multifocal nature of the disease process; some
nerves can have normal conduction studies, whereas others nerves
are abnormal. The probability of finding abnormalities in motor
conduction increases in individual patients if multiple nerves are
examined. Because there may be a preferential involvement of the
nerve roots, it is important to assess the proximal segments of the
nerves. Traditionally, F-waves have been used to assess proximal
conduction. Recent studies demonstrate the utility of nerve root
stimulation in diagnosing patients with CIDP.888 One must ensure
a supramaximal stimulus, because submaximal stimulation can
produce falsely slower conduction velocities, prolonged distal la-
tencies, absent F-waves, and pseudoconduction block. Finally, de-
myelination can elevate the peripheral nerve excitation thresholds,
thus requiring a greater current to stimulate the nerves.
Motor Conduction Studies. Electrophysiologic evidence of
demyelination affecting multiple CMAP parameters is the most
useful diagnostic test.10,73,130,276,864,1005,1071,1168a,1227 It is mandatory
to assess CMAP amplitude, temporal dispersion, conduction
block, and F-wave studies for each of the above-noted nerves.
The best-studied motor parameter is nerve conduction velocity.
Characteristically, there is a significant reduction in motor nerve
conduction velocity, usually to less than 70% of the lower limit
of normal.10,73,152,249,1168a In addition, distal motor latencies are
typically prolonged to 125–150% of the upper limit of
normal.10,152,249,1168a F-waves are often unobtainable or have pro-
longed latencies (> 125–150% of the upper limit of normal) in
patients suspected of CIDP.49a,152,442,986,1168a,1319 Subtle abnormali-
ties, such as reduction in the total number of F-waves (not every
stimulus producing an F-wave) or the difference between the
shortest and longest measured F-wave latencies, also may be im-
portant but have not been addressed in a scientific fashion.
A reduction in CMAP amplitude also can be seen at proximal
and/or distal sites of stimulation. A significant drop in CMAP
amplitude or negative peak area in the response obtained from
proximal stimulation compared with distal stimulation is seen
with conduction block. The pathophysiologic basis for true con-
duction block was described above. However, the multifocal
nature of the demyelination can differentially affect the conduction
Chapter 23 ACQUIRED NEUROPATHIES — 951
of individual motor nerve fibers, causing temporal dispersion of
the CMAP. Pseudoconduction block can result from interphase
shifting and cancellation of the negative and positive waveform
subcomponents of individual motor unit potentials with other po-
tentials. Therefore, percentage drop in amplitude or area used in
defining conduction block by nerve conduction studies is contro-
versial. The AAN criteria require a drop in amplitude or area of
only 20% when there is no temporal dispersion (< 15% change in
the duration of the negative peak between proximal and distal
sites of stimulation).249 When temporal dispersion is greater than
15%, only possible conduction block can be assumed. Albers and
Kelly used a 30% drop in amplitude to define conduction block
but did not take into account temporal dispersion.10 Other author-
ities use different degress of amplitude drop depending on the
specific nerve investigated998a Computer simulation studies sug-
gest that temporal dispersion can result in up to a 50% drop in
CMAP amplitude/area.1098 For this reason, we use a 50% drop in
amplitude or area to define conduction block.660,1168 Furthermore,
conduction block should be localizable by inching techniques to
sites not commonly predisposed to compression.
Diminished CMAP amplitudes at distal sites of stimulation
may be secondary to either axonal loss or distal conduction
block (conduction block between the distal site of stimulation
[e.g., the wrist] and the motor nerve terminal). It is difficult to
distinguish between conduction block and axonal loss when the
terminal aspects of the nerve are involved several centimeters or
even millimeters proximal to the muscle’s end-plate region by
motor studies alone. A prolonged distal latency or dispersed
waveform favors demyelination with conduction block or
pseudoconduction block. Investigations have substantiated sig-
nificant conduction block within a short distance of the end-
plate region, documenting the preferential distal involvement.
Increased CMAP amplitudes, decreased conduction block, and
slightly increased conduction velocity may be seen in association
with improvement in strength.49,267,276,354,364,487,535,536,887a,1332 Clinical
improvement is primarily the result of resolving conduction
block. Some contribution to improvement may be related to some
degree of collateral sprouting and regeneration of axons, but this
process occurs at a comparatively much slower pace.
Sensory Nerve Conduction Studies. None of the electrophys-
iologic criteria proposed for the diagnosis of CIDP mention sen-
sory nerve conduction abnormalities. Most patients (> 80%)
with CIDP have low-amplitude or unobtainable SNAPs in both
upper and lower limbs.73,152,153,276,864,986,1071,1332,1372 When sensory
responses are obtainable, the distal latencies are often prolonged
and conduction velocities slow. The slowing is usually not as
severe as that demonstrated in motor nerves. In a study of 18 pa-
tients using the near-nerve technique, sensory conduction slow-
ing was only moderate in proportion to the degree of amplitude
loss.723 In addition, conduction velocity was similar in proximal
and distal segments, and conduction block was evident in a mi-
nority of sensory nerves. These findings suggest that some com-
ponent of the reduced SNAP conduction velocities may be
related to the loss of large myelinated sensory nerve fibers.
A characteristic finding is abnormal median or ulnar SNAPs
(e.g., reduced amplitude, prolonged latency, or slow conduction
velocity) when the sural SNAPs are normal. This pattern sug-
gests that the pathologic process is not length-dependent (as is
typical of axonal neuropathies) and implies a primarily de-
myelinating disease. A similar discrepancy between the upper
and lower limb SNAPs can be seen in a sensory ganglionopathy,
but the electrophysiologic abnormalities in such cases are
axonal, not demyelinating.
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. During the recovery phase, a moderate
degree of improvement in SNAP parameters to the low normal
ranges may be observed. However, continued demyelination/re-
myelination and even mild axonal loss often result in the com-
plete absence of the SNAP.
Evoked Potential Studies. Multimodality evoked potential
studies have been performed in numerous patients diagnosed
with CIDP. Visual evoked, brainstem auditory evoked, and so-
matosensory evoked potentials have revealed that central con-
duction along the pathways examined by the respective tests is
unquestionably slowed in some patients.1012,1319 Anatomic le-
sions noted in corresponding white matter tracts on MRI scans
substantiate these neurophysiologic abnormalities in central
conduction pathways.398,562,886,1005,1372
Needle EMG Examination. Extensive documentation of
needle EMG findings in patients with CIDP is lacking.
Widespread fibrillation potentials and positive sharp waves are
commonly detected in the intrinsic foot muscles and more prox-
imal muscles, such as the tibialis anterior, peroneus longus, and
occasionally gastrocnemius.10,73,267,351,979,986,1227 In patients with
significant proximal weakness, occasional abnormalities can be
observed in the quadriceps and hip girdle muscles. Paraspinal
muscles reveal membrane instability in some patients. The
upper limb has the same pattern of membrane instability (e.g.,
more commonly found in the hand intrinsic than the more prox-
imal muscles). The degree of positive sharp waves and fibrilla-
tion potentials is relatively high during an exacerbation of the
disease, with a reduction, (but not necessarily complete disap-
pearance) during clinical remission. Single-fiber EMG demon-
strates an increase in fiber density and jitter.447
Motor unit action potential amplitudes can be normal or in-
creased in patients with CIDP, depending on the duration and
severity of the disease. A reduced recruitment pattern is ob-
served, with few motor units firing at high rates, especially in
the distal limb muscles. In patients with chronic denervation
and reinnervation, increased MUAP duration, amplitude, and
phases can be seen.
Electrophysiologic Criteria for Diagnosis. Various electro-
physiologic criteria have been proposed for the diagnosis of
CIDP.10,73,249,1168a The criteria developed by Barohn et al. require
slowing of motor conduction velocity in at least two nerves to less
than 70% of the lower limit of normal.73 However, they make no
mention of distal latencies, conduction block, temporal dispersion
or F-wave latencies abnormalities. Albers and Kelly proposed that
three of the four following CMAP parameters must be abnormal:
(1) slowing of conduction velocity in two or more nerves to < 75%
of the lower limit of normal; (2) partial conduction block of 70%
or temporal dispersion in one or more nerves; (3) prolonged distal
latency of greater than 130% in two or more nerves; and (4) pro-
longed F-wave latency of at least 130% in one or more nerves.10
The AAN criteria for CIDP (see Table 23-4) modified the clinical
and laboratory criteria proposed by Barohn and the electrophysio-
logic criteria of Albers and Kelly.249 The electrophysiologic crite-
ria for CIDP adapted by the AAN also take into account the distal
latencies, conduction block, temporal dispersion, and F-wave la-
tencies in addition to conduction velocity slowing, but the degree
of slowing is slightly different from the other proposed criteria and
dependent also on the distal CMAP amplitudes.249
Bromberg compared the electrophysiologic criteria proposed
by Albers and Kelly,10 Barohn,73 and the AAN and found no sta-
tistically significant difference in the sensitivity (range: 48–64%)
in 70 patients who fulfilled clinical criteria for CIDP.150 Thus,
many patients with CIDP do not fulfill electrophysiologic crite-
ria for the diagnosis; this should not dissuade the clinician from
treatment if the clinical features (progressive, symmetric proxi-
mal and distal numbness and weakness) and laboratory features
(e.g., increased CSF protein) are compatible with the diagnosis.
Treatment. Randomized control trials have demonstrated
efficacy of corticosteroids, plasma exchange (PE), and intra-
venous immunoglobulin (IVIG) in the treatment of CIDP.
Patients may respond to one mode of treatment when other
forms of treatment have failed or become refractory. In a
prospective, controlled trial, Dyck found no significant differ-
ence in efficacy between IVIG and PE.364 The treatment of
choice may depend on the patient’s other medical problems
(e.g., avoid IVIG in patients with renal insufficiency) and acces-
sibility (e.g., unavailability of PE, expense of IVIG and PE,
shortage of available IVIG).
Corticosteroids. Austin was the first to demonstrate that
steroids were beneficial in “recurrent polyneuropathy,”54 and
several later series showed similar improvement with
steroids.73,276,477,979,1071,1227 Dyck and colleagues confirmed the ef-
ficacy of prednisone in a randomized control trial.354 We treat
patients with prednisone, 1.5 mg/kg (up to 100 mg) per day for
2–4 weeks, then switch to alternate-day treatment (e.g., 100 mg
every other day).73,887 Patients are maintained on this dose of
prednisone until their strength is normalized or there is a clear
plateau in clinical improvement (usually around 6 months).
Subsequently, the dose of prednisone is slowly decreased by 5
mg every 2–3 weeks to 20 mg every other day. At this point, we
taper the prednisone no faster than 2.5 mg every 2–3 weeks.
Using this mode of treatment, Barohn noted that the time of ini-
tial improvement ranged from several days to five months
(mean: 1.9 months) and the time to maximal improvement aver-
aged 6.6 months.73 Functional muscle recovery is first noted in
the proximal limb muscles. Significant improvement in strength
was noted in 95% of patients after one year of treatment.
Intermittent high-dose intravenous corticosteroids may also be a
useful therapy for CIDP and perhaps associated with fewer side
effects.910
The significant side effects related to long-term corticosteroid
treatment include osteoporosis, glucose intolerance, hyperten-
sion, cataract formation, aseptic necrosis of the hip, weight
gain, hypokalemia, and type 2 muscle fiber atrophy. We pre-
scribe calcium (1000–1500 mg/day) and vitamin D (400–800
IU/day) for osteoporosis prophylaxis. In addition, in post-
menopausal women, we recommend estrogen replacement, if
not contraindicated, and also start alendronate (5 mg/day). We
obtain baseline bone density studies and repeat the study every
6 months while patients are taking prednisone. If a patient has
or develops osteoporosis, we start alendronate (10 mg/day).
Alendronate also can be started to help prevent osteoporosis in
patients who may be particularly susceptible (e.g., post-
menopausal women, patients with borderline low DEXA
scores) We obtain baseline and periodic fasting blood glucose
and serum electrolyte levels. Patients need to be instructed
about a low-sodium, low-carbohydrate diet to avoid excessive
weight gain, hypertension, and diabetes mellitus. We recom-
mend physical therapy and an exercise program to reduce these
side effects.
Plasma Exchange. PE was found to be effective in patients
with CIDP in several retrospective, uncontrolled case reports or
small series.238,396,423,510,788,1201,1310 Two prospective, randomized,
double-blinded, placebo-controlled trials using sham PE

demonstrated the efficacy of PE.354,535 Unfortunately response to
treatment is transient, usually lasting only a few weeks. Thus,
chronic intermittent PE or the addition of immunosuppressive
agents is required. No specific guidelines have been established
for treating CIDP with PE; treatment needs to be individualized.
We have used PE, usually in combination with prednisone, in
patients with severe generalized weakness because the response
may be quicker to PE than to prednisone alone. We exchange
approximately 200–250 ml/kg body weight in 5 or 6 exchanges
over a 2-week period. Some patients require more exchanges
for maximal improvement. Thereafter, exchanges can be sched-
uled every 1–2 weeks and the duration between exchanges grad-
ually increased. PE alone can be used but requires indefinite
repeated treatments, which are costly, associated with adverse
side effects, and technically difficult in some patients. We use
PE alone in patients in whom we wish to avoid long-term pred-
nisone (e.g., patients with poorly controlled diabetes mellitus or
HIV infection) or in whom IVIG is contraindicated (e.g., pa-
tients with renal insufficiency). We also have used a trial course
of PE in patients who do not fulfill all of the criteria for CIDP or
those that have an underlying condition making the diagnosis
difficult (e.g., diabetes and superimposed CIDP-like neuropa-
thy).24a Because the response to PE is generally faster than the
response to prednisone, one often can determine earlier whether
such patients may have an immune-responsive neuropathy.
Intravenous Immunoglobulin. Several uncontrolled studies
have been reported showing improvement in CIDP patients with
IVIG.55,247,332,386,477,1338,1353,1354 In 1990, Van Door report benefit of
IVIG in a small double-blind, placebo-controlled trial.1337
However, another small trial study found no improvement with
IVIG therapy.1354 Subsequently, larger double-blind, placebo-
controlled, cross-over studies convincingly demonstrated that
IVIG is efficacious in CIDP.536,1338 Dyck and colleagues com-
pared PE with IVIG in an observer-blinded, randomized trial
and found no clear difference in efficacy.364
For many authorities, IVIG has become the treatment of
choice in CIDP. As with PE, patients require repeated courses of
IVIG because improvement is only transient. The time frame
and dose of IVIG treatments need to be individualized. Initially,
we begin IVIG treatment with a dose of 2 gm/kg body weight
over 2–5 days. Subsequent dosing depends on clinical response.
One method of dosing is to repeat IVIG courses after subse-
quent relapses. However, we have found that after several re-
lapses some patients do not improve to baseline and are left with
a deficit even after treatment. Therefore, after the initial course
of IVIG, we administer IVIG (2 gm/kg) every 4 weeks and
gradually try to increase the interval between courses as toler-
ated. In this way, we try to avoid exacerbations of weakness.
Some patients become refractory to IVIG, in which case PE
may restore responsiveness to IVIG.92
IVIG is well tolerated by most patients. Of importance, a
serum IgA level should be assayed in patients before adminis-
tering IVIG. Patients who are IgA-deficient due to IgE anti-IgA
antibodies or a congenital deficiency may develop anaphylactic
reactions to IVIG, which may contain some IgA.341 In addition,
IVIG should be used cautiously in patients with diabetes and
avoided in those with renal insufficiency because it has been as-
sociated with renal failure secondary to acute tubular necro-
sis.1284 Some patients develop headaches, diffuse myalgias, and
flu-like symptoms. A few patients have aseptic meningitis.144
Rare thrombotic complications (e.g. stroke, myocardial infarc-
tion) perhaps are related to hyperviscosity. In addition, neu-
tropenia is common but rarely clinically significant.
Chapter 23 ACQUIRED NEUROPATHIES — 953
Azathioprine. 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.186,1016,1043,1377 A prospective, randomized, but nonblinded, 9-
month study of 27 patients with CIDP noted no significant bene-
fit when azathioprine (2 mg/kg/day) was added to prednisone.355
However, the dose of azathioprine was small (we go up to 3
mg/kg/day) and the duration of this study was too short. It can
sometimes take longer than 9 months before any benefit is noted
from azathioprine in other immunologic disorders. Whether aza-
thioprine has a prednisone-sparing effect (i.e., allows a lower
dose of prednisone) has not been adequately addressed.
We usually do not treat CIDP with azathioprine alone, but it
is an option in patients who cannot be given prednisone, PE, or
IVIG. We have used azathioprine in combination with pred-
nisone in patients resistant to prednisone taper. We begin aza-
thioprine at a dose of 50 mg/day and gradually increase over a
few months to a total dose of 3 mg/kg/day. Approximately 12%
of patients receiving azathioprine develop fever, abdominal
pain, nausea, and vomiting, requiring discontinuation of the
drug.698 Other side effects include bone marrow suppression, he-
patotoxicity, risk of infection, and future malignancy. We moni-
tor CBC and LFTs every 2 weeks while adjusting the dose of
azathioprine and once a month when the dose is stable.
Cyclophosphamide. Only a few retrospective studies evalu-
ated the use of cyclophosphamide in the treatment of CIDP.
Both oral (50–150 mg/day) and monthly pulses of intravenous
cyclophosphamide (1 gm/m2) have been reported to be benefi-
cial in some patients, either in combination with prednisone or
in steroid-refractory cases.721,864,1071,1398 The major side effects of
hemorrhagic cystitis, bone marrow suppression, increased risk
of infection and future malignancy, teratogenicity, alopecia,
nausea, and vomiting have limited its use. Monthly pulsed intra-
venous cyclophosphamide is associated with less risk of hemor-
rhagic cystitis. CBCs and urinalysis must be monitored
frequently in patients treated with cyclophosphamide.
Cyclosporine. Several retrospective reports suggest that cy-
closporine can be effective in some patients with CIDP, even in
those refractory to other modes of therapy, including prednisone,
PE, IVIG, and cyclophosphamide.72,510,587,709,824 Cyclosporine has
been associated with a decreased relapse rate in patients with the
relapsing form of CIDP and improved strength and function in
those with the chronic progressive form. The major side effects
of cyclosporine include nephrotoxicity, hypertension, tremor,
gingival hyperplasia, hirsuitism, and increased risk of infection
and future malignancies (mainly skin cancer and lymphoma).
We initially administer cyclosporine at a dose of 4–6 mg/kg/day
orally, aiming for a trough level of 150–200 mg/dl. Electrolytes
and renal function need to be monitored closely.
Interferons. There are a few reports of CIDP patients bene-
fiting from α-interferon.476,547,1147 Harada and colleagues re-
ported a beneficial response to α-interferon as a first-line
treatment in one patient.547 Significant improvement with α-in-
terferon was reported in two patients, one a young child, who
was unresponsive to prednisone, azathioprine, and cyclo-
sporine.1147 Gorson et al. performed a prospective, unblinded
study of α-interferon in 16 patients with CIDP refractory to
conventional therapies and found that 56% improved with α-in-
terferon.476 Recently, IVIG proved beneficial as a first-line ther-
apy in previously untreated CIDP patients.887a A beneficial
response to interferon β-1a was reported in a child with relaps-
ing CIDP.218 Subsequently, the same authors conducted a
double-blind, placebo-controlled, cross-over study of interferon
954 — PART IV CLINICAL APPLICATIONS
β-1a in 10 patients with CIDP and found no benefit.527 In addi-
tion, 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.736
Total Lymphoid Irradiation. Total lymphoid irradiation was
reported to be effective in 3 of 4 patients unresponsive to pred-
nisone or cyclophosphamide.1125
Prognosis. In our experience, more than 90% of patients im-
prove with therapy; however, at least 50% demonstrate a subse-
quent relapse within the next 4 years and less than 30% achieve
remission off medication.73,1168,1168a Other studies have reported
that only 66% of patients respond to one of the three main ther-
apies for CIDP (prednisone, PE, or IVIG).130,477 The differences
in response rates among studies may relate to how the authors
defined “CIDP.” We require symmetric, proximal, and distal
arm and leg weakness to diagnose CIDP.1168a Patients with
mainly sensory symptoms, mild distal weakness, or asymmetric
motor involvement may fulfill AAN criteria249 and could have
been included in other series of CIDP patients. These patients
are much less responsive to specific forms of therapy and skew
the prognosis in these series.1168a We have found that patients
treated early are more likely to respond, underscoring the need
for early diagnosis and treatment.1168,1168a Progressive course,
CNS involvement, and particularly axonal loss have been asso-
ciated with a poorer long-term prognosis.130
CIDP in Children. Monophasic, relapsing, and chronic pro-
gressive forms of CIDP can begin in childhood.167,218,232,389,442,560a,
816,1036,1146a,1147,1220,1227,1287,1318,1346 The clinical, laboratory, and elec-
trophysiologic features are similar to those in adulthood.
Children commonly present with difficulty in ambulating.
Children respond to the standard forms of treatment, although
prospective control trials have not been performed.
With childhood onset, CIDP may be confused with a heredi-
tary neuropathy (i.e., Charcot-Marie-Tooth disease [CMT]).
Obviously, the family history is an important starting point. An
electrodiagnostic medicine evaluation can be of considerable
help in determining the correct diagnosis. CMT is associated
with symmetric and diffuse involvement of the peripheral
nerves. Thus, temporal dispersion and conduction block are not
seen on electrophysiological studies.789 Furthermore, there is
usually uniform slowing of conduction velocities of all the
motor nerves in the arms and legs as well asymmetric involve-
ment of proximal and distal segments. In contrast, the multifo-
cal nature of CIDP results in nonuniform slowing of conduction
velocities, temporal dispersion, and conduction block.
Paraprotein-related Neuropathies and CIDP. Whether pa-
tients with paraproteins (i.e., monoclonal gammopathy) who have
clinical, laboratory, and electrophysiologic criteria of demyelinat-
ing sensorimotor neuropathy should be classified as having CIDP
is a matter of debate.661,1168a Dyck and colleagues suggest that para-
protein-related neuropathies should be separated from idiopathic
CIDP.363 Criteria for CIDP developed by Barohn73 and the AAN249
allow for CIDP with concurrent illnesses, including monoclonal
gammopathies of uncertain significance (MGUS). Lines of evi-
dence suggest that paraproteins, particularly IgM monoclonal
proteins, are involved in the pathogenesis of at least some types
of idiopathic polyneuropathy. The incidence of paraproteins in
patients with peripheral neuropathy is higher than in the general
population.668 Furthermore, there is an increased incidence of pe-
ripheral neuropathy in patients with MGUS.748 Although IgG is
the most common paraprotein in the general population, IgM is
by far the most common monoclonal protein in patients with pe-
ripheral neuropathy.476,480,699,768,1064,1216,1217,1218,1437
The clinical and electrophysiologic features of polyneuropathy
associated with monoclonal gammopathies are heterogeneous and
imply a multifactorial pathogenesis. Most studies indicate that
IgM-MGUS neuropathies are distinct from IgG and IgA-MGUS
neuropathies.360,480,969 IgM-MGUS neuropathies are typically de-
myelinating but can be axonal. Demyelinating and axonal neu-
ropathies seem to occur at relatively similar frequencies in IgG- and
IgA-MGUS. The IgM-MGUS neuropathy seems to be less respon-
sive to various immunotherapies than IgG- and IgA-MGUS neu-
ropathies.360,423,661,969,972 At least 50% of the IgM-MGUS group have
antibodies directed against myelin-associated glycoprotein (MAG).
There does not appear to be any significant clinical, electrophysio-
logic, histologic, or prognostic (including response to treatment)
differences between IgM-MGUS neuropathy with or without anti-
MAG antibodies. It is not clear whether MGUS-related demyeli-
nating neuropathies are distinct from CIDP. Confusion has arisen
because many papers about MGUS neuropathy do not distinguish
between patients with electrophysiologic features consistent with
demyelination and patients whose nerve conduction studies are
consistent with an axonal or mixed axonal-demyelinating
process.360,480 Most series have not taken into account the distribu-
tion of muscle weakness in patients with MGUS-neuropathies
(e.g., whether they had distal weakness only or both proximal and
distal weakness).661 Some series of patients with CIDP have chosen
to exclude351,535,536 or include73,476 patients with MGUS. Recently,
more attention has been devoted to subcategorizing the clinical and
electrophysiologic features of the different types of MGUS-neu-
ropathy (e.g., IgM vs. IgG/IgA and axonal vs. demyelinating neu-
ropathy) and directly comparing the demyelinating subgroups of
MGUS neuropathy with idiopathic CIDP.
Yeung reported 62 patients with MGUS neuropathy (IgM 46,
IgG 11, IgA 5).1437 Most patients presented with a late-onset distal
and symmetric sensorimotor neuropathy. Sensory ataxia and
tremor were common. There was no significant difference be-
tween the various subgroups, except that patients with IgM neu-
ropathy had more significant tremor. Nerve conduction studies
apparently were not significantly different from patients with id-
iopathic CIDP, but data and statistical analysis were not provided.
However, nerve biopsies were significantly different in the IgM
group compared with the IgG and IgA groups. Most IgM patients
had features of demyelination on nerve biopsy along with widely
spaced myelin sheaths and deposition of immunoglobulin on the
nerves. In contrast, demyelinating features were uncommon, and
widely spaced myelin sheaths and immunoglobulin deposition
were not seen in patients with IgG and IgA neuropathy.
Gosselin480 described the clinical, laboratory, and electrophys-
iologic features of 65 patients with MGUS neuropathy (IgM 31,
IgG 24, IgA 10), and Suarez and Kelly1265 reported the features
of 39 patients with MGUS neuropathy (23 IgM, 13 IgG, and 3
IgA). Slightly more than half of the IgM patients were anti-MAG
positive. Clinical symptoms reflected mainly a sensory distur-
bance; patients in the IgM-MGUS group experienced more dis-
ability related to the sensory loss. Weakness was only a minor
feature. In the series of Suarez and Kelly, nerve conduction stud-
ies revealed demyelination in only 2 patients in the IgG group
and 8 patients in the IgM group; 10 patients in the IgM group
had mixed axonal-demyelinating studies.1265 In both series, the
nerve conduction studies revealed more slowing of conduction
velocities and prolongation of the distal latencies in the IgM
group compared with the IgG and IgA patients.480,1265 There were
no significant clinical or electrophysiologic differences between
IgM MAG-positive and IgM MAG-negative patients. Sub-
sequently, the Mayo group performed a double-blinded trial of

PE vs. sham pheresis in 21 patients with IgM and 19 IgG/IgA-
MGUS neuropathy.360 There was a trend toward improvement in
the IgG/IgA group but not in the IgM group.
Simmons and colleagues compared the clinical, laboratory,
and electrophysiologic features of 77 patients with idiopathic
CIDP but without MGUS with those of 26 patients with MGUS
who fulfilled criteria for CIDP (13 IgM and 13 IgG/IgA).1216–1218
Patients with MGUS-CIDP had a more indolent course, more
frequent sensory disturbance with ataxia, and less severe weak-
ness than patients with idiopathic CIDP. There was no signifi-
cant difference in the elevation of CSF protein levels in the two
groups. They found no difference in various motor parameters
between the MGUS-CIDP and the idiopathic CIDP groups;
however, the MGUS-CIDP group had more severe sensory con-
duction abnormalities. Subgroup analysis of patients with IgM-
CIDP revealed a smaller terminal latencies index (TLI). The
TLI can be calculated as follows: TLI = terminal distance
(mm)/conduction velocity (m/s) × distal latency (ms). A small
TLI is indicative of distal accentuated demyelination.
Although analyzing the response to treatment is limited by
the retrospective nature of the study and varying therapeutic
regimens, the idiopathic CIDP group had a significant greater
improvement rate (88%) than the MGUS-CIDP group
(50%).1216 In a long-term follow-up study, four patients with id-
iopathic CIDP were reclassified.1218 Two developed MGUS, one
POEMS syndrome, and another Castleman’s disease. Three
MGUS-CIDP patients were also reclassified. One patient, who
was unresponsive to treatment, was later found to have a plas-
macytoma. Another unresponsive patient developed acute myel-
ogenous leukemia. The third patient, who was initially
responsive but then became resistant to therapy, developed mul-
tiple myeloma. The study illustrates that MGUS is not necessar-
ily benign; as many as 25% of patients later develop an
underlying malignancy.746,748,768 Furthermore, patients with
CIDP who are or become refractory to therapy should be reeval-
uated for monoclonal gammopathy and underlying malignancy.
Some series have focused only on IgM-MGUS neuropa-
thy.203,649,672,1235 These studies have confirmed the observation of
the above series of mixed MGUS neuropathies in that most pa-
tients with IgM-MGUS neuropathy have predominantly distal
sensory signs and symptoms and demyelination on nerve con-
duction studies. Kaku and Sumner also noted that patients with
anti-MAG IgM-MGUS had disproportionately prolonged distal
latencies in comparison with the slowing of conduction veloci-
ties, which results in a short TLI (< 0.25).649 The TLI in the anti-
MAG positive patients was significantly shorter than in normal
volunteers, patients with CMT type 1, and patients with idio-
pathic CIDP without MGUS. Other authors have commented on
the shortened TLI in IgM-MGUS.969
Treatment is another controversial issue in regard to MGUS
neuropathy, particularly in IgM-MGUS with or without anti-
MAG antibodies. Several retrospective studies and unblinded or
uncontrolled prospective series have reported benefit with corti-
costeroids, PE, cytotoxic agents, immunoabsorption, and IVIG,
even in IgM-MGUS neuropathy.107,237,672,964,971,1007,1064,1400 A major
obstacle in designing and interpreting these studies, particularly
in regard to IgM-MGUS, is that the disability of many patients
is related predominately to sensory impairment, which is diffi-
cult to measure objectively. Katz and colleagues treated 10 pa-
tients with IgM-MGUS and distal acquired demyelinating
symmetric neuropathy with a variety of immunomodulating
therapies.661 Three patients reported symptomatic improvement
in sensory symptoms, but none had objective improvement in
Chapter 23 ACQUIRED NEUROPATHIES — 955
the motor examinations. There are only a few prospective, con-
trolled treatment trials of IgM-MGUS neuropathy. A double-
blind, placebo-control study (PE vs. sham pheresis) was
performed in patients with MGUS neuropathy, as previously
mentioned.360 Improvement was noted in only IgG and IgA
MGUS neuropathy, but it did not reach statistical significance.
Dalakas performed a double-blind, placebo-controlled, cross-
over study of IVIG in 11 patients with demyelinating IgM-
MGUS neuropathy.282 Only modest benefit from IVIG was
noted: two patients had improvement in strength, and one had
less sensory impairment. An open-label, randomized, prospec-
tive trial comparing IVIG (10 patients) with interferon-α (10
patients) in IgM-MGUS neuropathy also found modest benefit
from IVIG.830 There was improvement in sensory deficits as
measured by the Clinical Neuropathy Disability Score with in-
terferon-α; however, there was no improvement in clinical
motor function or motor nerve conduction studies.830 The same
investigators subsequently performed a prospective, double-
blind placebo-controlled trial of interferon-α in IgM-MGUS
neuropathy and found no beneficial response.831
Axonal Variant of CIDP. A few reports in the literature sug-
gest that there is an axonal variant of CIDP,219,334,644,657,924,1321 al-
though its existence is controversial.401 The basis for the
suggestion of an axonal variant of CIDP is that some patients did
not fulfill electrophysiologic criteria for demyelination on nerve
conduction studies or nerve histopathology was more suggestive
of an axonopathy or normal. However, one-third of patients with
CIDP do not fulfill the strict research criteria for the diagnosis, as
discussed above.150 Furthermore, nerve histopathology is neither
sensitive nor specific and can be normal or show features more
suggestive of an axonopathy rather than a demyelinating polyneu-
ropathy.73 In fact, if one carefully reads the reports suggesting an
“axonal CIDP,” many were associated with slow conduction ve-
locities and prolonged distal latencies and F-waves, although not
in the “demyelinating” range. Surprisingly, one report classified
patients as having chronic relapsing axonal polyneuropathy (based
on histopathology) despite nerve conduction velocities between
25 and 30 m/s in the median, ulnar, and tibial motor nerves.644
Conduction block greater than 50% in multiple nerves was evident
from nerve conduction data in another report.657 One series of five
patients commented on normal sural nerve conduction studies.1321
Normal sural SNAPs in combination with abnormal upper limb
SNAPs are more suggestive of a demyelinating process or perhaps
a ganglionopathy than an axonopathy. Of note, most patients re-
ported with “axonal CIDP” had elevated CSF protein, similar to
typical CIDP. In addition, most patients with “axonal CIDP” im-
proved within weeks to a few months of starting some form of im-
munotherapy. This time frame is too short for improvement based
on regeneration of axons and is more consistent with remyelina-
tion or reversal of conduction block. Perhaps, as in GBS (e.g.,
acute motor axonal neuropathy, acute motor and sensory axonal
neuropathy), futures studies will prove the existence of an axonal
CIDP. For now, however, we agree with Feasby that the concept of
an axonal form of CIDP is premature.401
Distal Acquired Demyelinating Symmetric Neuropathy
It may be more helpful to classify patients with acquired de-
myelinating polyneuropathies, particularly patients with MGUS,
by pattern of weakness (i.e., whether the patients have no weak-
ness/only mild distal weakness or if they demonstrate both prox-
imal and distal weakness). Recently, Katz and colleagues
described the clinical and electrophysiologic features of 53 con-
secutive patients with an acquired symmetric demyelinating
956 — PART IV CLINICAL APPLICATIONS

Table 23-5. Comparison of the Chronic Acquired Immune-Mediated Demyelinating Polyneuropathies

CIDP DADS MADSAM MMN
Clinical features
Weakness Symmetric proximal and None or only mild Asymmetric distal > Asymmetric, distal >
distal weakness symmetric distal proximal, arms > legs proximal, arms > legs
weakness
Sensory loss Yes; symmetric Yes; distal and symmetric Yes; asymmetric No
Reflexes Symmetrically reduced Symmetrically reduced Asymmetrically reduced Asymmetrically reduced
or absent or absent or absent or absent
Electrophysiology
CMAPs Demyelinating features Demyelinating features, Demyelinating features, Demyelinating features,
including CB excluding CB including CB including CB
SNAPs Abnormal Abnormal Abnormal Normal
Laboratory findings
CSF protein Usually elevated Usually elevated Usually elevated Usually normal
Monoclonal protein Occasionally present, IgM usually present Rarely present Rarely present
usually IgG or IgA (most anti-MAG–
positive)
GM1 antibodies Rarely present Rarely present Rarely present Frequently present
Sensory nerve biopsies Demyelinating/remyelinat- Demyelinating/remyelinat- Demyelinating/remyelinat- Demyelinating/remyelinat-
ing features are common ing features are com- ing features are ing features are scant,
mon with Ig deposition common if present at all
evident in paranodal
regions
Treatment response
Prednisone Yes Poor Yes No
Plasmal exchange Yes Poor Not adequately studied No
IVIG Yes Poor Yes Yes
Cyclophosphamide Yes Poor Not adequately studied Yes
CIDP = chronic inflammatory demyelinating polyneuropathy, DADS = distal acquired demyelinating symmetrical, MADSAM = multifocal acquired demyelinating sen-
sory and motor, MMN = multifocal motor neuropathy, CMAPs = compound motor action potentials, SNAPs = sensory nerve action potentials; CB = Conduction
block, CSF = cerebrospinal fluid, MAG = myelin-associated glycoprotein, IVIG = intravenous immunoglobulin. (From Amato AA, Barohn RJ: Clinical spectrum of
chronic inflammatory demyelinating polyneuropathies. Muscle Nerve 2001;24:311–324, with permission.)

neuropathy.661 Of the 53 patients, 23 had proximal and distal
arm and leg weakness, defined by the authors as necessary for
the diagnosis of CIDP. Only 5 patients with CIDP (22%) had a
monoclonal gammopathy (4 IgG kappa and 1 IgM lambda). In
contrast, 30 patients had only distal symptoms (8 pure sensory
loss, 12 distal sensory loss plus ankle dorsiflexor and foot in-
trinsic weakness). The term distal acquired demyelinating
symmetric (DADS) neuropathy was applied to these patients
(Table 23-5).661,1168a Monoclonal proteins were detected in 20 of
30 cases of DADS neuropathy (18 IgM kappa, 2 IgG kappa).
Anti-MAG antibodies were found in 67% of patients with IgM-
DADS neuropathy. The patients with IgM-DADS neuropathy
were older (mean age: 62 years) than patients with idiopathic-
DADS neuropathy (mean age: 47 years) who had no associated
monoclonal protein or patients with CIDP (mean age: 51 years).
The authors found no significant electrophysiologic differences
between IgM-DADS, idiopathic DADS, or CIDP, including
for classifying patients by clinical phenotype is evident in the
following discussions of multifocal motor neuropathy (MMN)
and multifocal acquired demyelinating sensory and motor
polyneuropathy (MADSAM) (see Table 23-5).
Multifocal Motor Neuropathy
Multifocal demyelinating neuropathy with conduction block
was first described by Lewis and colleagues in 1982.790 They de-
scribed five patients with asymmetric motor and sensory loss who
had persistent conduction block on conduction studies of motor
nerves. The patients also had objective sensory abnormalities on
nerve conduction studies and sensory nerve biopsies. Most of the
following reports described patients with pure or predominantly
motor multifocal neuropathies with conduction block or other
electrophysiologic features of demyelination. This entity became
known as multifocal motor neuropathy (MMN).50,189,406,407,660,
647,722,1025,1027,1029,1049,1050,1131 Nevertheless, many articles about

analysis of the terminal latency index. Most importantly, pa-
tients with IgM-DADS neuropathy demonstrated a poor re-
sponse to immunotherapy, whereas patients with idiopathic
DADS and CIDP (with or without an associated monoclonal
protein) usually improved with therapy. In contrast, patients
with idiopathic DADS or CIDP usually demonstrated objective
improvement with immunotherapy. Distinguishing the acquired
forms of chronic demyelinating polyneuropathies by clinical
phenotype (i.e., pattern and distribution of involvement) is
useful in predicting the presence of IgM monoclonal proteins
and, more importantly, response to treatment.1168a Further support
MMN credit Lewis790 and colleagues with the initial description.
We consider patients with objective sensory loss in addition to
motor dysfunction to have a different neuropathy, termed multifo-
cal acquired demyelinating motor and sensory (MADSAM) neu-
ropathy. Some patients with objective sensory abnormalities and
probable MADSAM neuropathy have been included in some
series of MMN. The contamination of MADSAM neuropathy in
some series of patients with MMN creates some difficulty in in-
terpreting laboratory data and therapeutic response rates because
of the distinct differences between MMN and MADSAM neu-
ropathy (see Table 23-5).

Clinical Features. Multifocal motor neuropathy (MMN) is
an immune-mediated demyelinating neuropathy characterized
clinically by asymmetric weakness and atrophy, typically in the
distribution of individual peripheral nerves.50,189,209,406,647,660,722,
1027,1028,1049,1131,1168a,1289a MMN is commonly misdiagnosed as
amyotrophic lateral sclerosis (ALS); however, as noted above,
the muscle involvement is in the distribution of individual pe-
ripheral nerves, not spinal roots. The incidence of MMN is
much less than that of ALS; some large neuromuscular centers
diagnose one case of MMN for every 50 patients with ALS.209
The male-to-female ratio is approximately 3:1. The age at onset
of symptoms is usually early in the fifth decade of life, ranging
from the second to eighth decade of life. Typically, diagnosis is
delayed by several years because of the slow, insidious progres-
sion and misdiagnosis of the disorder. In a selective series of 16
patients with MMN (no patients with even mild sensory abnor-
malities were included), the average age of onset was 40.5 years
(range: 20–64 years) with an average duration of illness of 7.6
years (range: 2–20 years) at the time of diagnosis.660
Patients develop focal muscle weakness accompanied by
cramps and fasciculations, usually beginning in the distal upper
limbs. Onset in the lower limbs also can occur. Patients gener-
ally present with intrinsic hand weakness, wrist drop, or foot
drop. In a series of patients with MMN, initial involvement was
in the arms in 12 (75%) and in the legs in four patients (25%).660
Weakness typically progresses over several years to involve
other limbs. Mild sensory symptoms have been described, but if
there is objective sensory loss, one should consider MADSAM
neuropathy. Rare patients may develop respiratory weakness
due to involvement of the phrenic nerves.122a
Physical examination reveals weakness in a multifocal pattern
in the upper and lower limbs, paralleling a peripheral nerve(s) as
opposed to the spinal segmental/root distribution seen in motor
neuron disease. A helpful feature is the lack of atrophy in weak
muscle groups early in the course of the illness; however, de-
creased muscle bulk can result in time from secondary axonal
degeneration. Fasciculations may be observed in affected limb
muscles. Sensory examination should be normal, as previously
discussed. Deep tendon reflexes are highly variable in that unaf-
fected regions can be normal, whereas weak and atrophic mus-
cles are usually associated with depressed or absent reflexes.
Occasionally, normal or even mildly hyperactive reflexes can be
elicited, but corticospinal tract signs (i.e., clonus, spasticity, ex-
tensor plantar responses) are not seen. Cranial nerve abnormali-
ties in MMN have been described646,1072 but are uncommon.
The above symptoms and signs can appear quite similar to a
lower motor neuron variant of ALS.647,1025,1027,1029 The observation
of fasciculations, weakness, and essentially preserved sensation
is certainly suspicious for an anterior horn cell disorder.
However, the multifocal peripheral nerve involvement, as op-
posed to spinal root level of dysfunction, combined with sparing
of muscle bulk points to the diagnosis of MMN. For example, a
patient may have reduced strength in the ulnar-innervated hand
intrinsic muscles, yet the median-innervated thenar muscles are
completely normal, obviating a C8/T1 spinal level disorder.
Laboratory Features. In contrast to CIDP and MADSAM,
CSF protein is usually normal in patients with MMN. Twenty to
84% of patients with MMN have detectable IgM antibodies di-
rected against gangliosides, mainly GM1 but also GM2.648,660,718,765,
1031,1050,1150 The importance of these antibodies in terms of patho-
genesis is unknown and continues to be vigorously debated. We
have not found these antibodies useful for diagnosis of MMN. In
high titers the antibodies appear to be rather specific for MMN,
Chapter 23 ACQUIRED NEUROPATHIES — 957
but the sensitivity of the test is too low. The most sensitive and
specific test is the nerve conduction study (see below). The pres-
ence or absence of antiganglioside antibodies in a patient who has
electrophysiologic abnormalities consistent with MMN adds little
to the diagnosis.
Pathogenesis. MMN is believed to be immune-mediated.
Early descriptions of MMN led to debate as to whether MMN is
a distinct entity or simply a variant of CIDP.101,133,140,204,207,
763,1027,1028,1168a,1303 Although opinions still vary, MMN is gener-
ally regarded as a distinct entity because it represents a rela-
tively uniform group of patients who differ significantly from
patients with CIDP in terms of laboratory features, histopathol-
ogy, and response to treatment.
The disparity between motor and sensory nerve involvement
suggests that the autoimmune attack may be directed against an
antigen specific for the motor nerve. The pathogenic role for anti-
ganglioside antibodies is not known. According to some reports,
reduction of antibody titer correlates with clinical improvement
after immunotherapy1049,1050; however, other studies have demon-
strated no such correlation.205,965 Furthermore, there has been no
correlation between the presence or absence of antiganglioside an-
tibodies and response to immunotherapy in some series.133,660,832,1285
Sera from patients with MMN injected into rat sciatic or tibial
nerves in-vivo and in vitro was shown to induce conduction block
in some studies37,1107,1169,1320 but not in others.557 Anti-GM1 sera
raised from immunized rabbits produced abnormalities in sodium
and potassium channels in isolated rat myelinated motor nerve
fibers.1283 An immune attack directed against an ion channel may
account for conduction block of neural impulses, and a secondary
inflammatory attack may result in demyelination. However, this
hypothesis is only speculative. As noted above, not all patients with
MMN have detectable antiganglioside antibodies; at best, these an-
tibodies can be considered only a marker of the disease.209
Electrophysiologic Findings. In MMN, there is often evi-
dence of conduction block in multiple upper and lower limb
nerves (Fig. 23-4).50,133,189,406,648,722,774a,1025,1027,1028,1049,1050,1131,1285,1289a
Conduction block is not located at the expected common nerve
entrapment sites, but in the mid-forearm or leg, upper arm,
across the brachial plexus, or nerve root region. The region of
blockade can be localized to relatively small regions of nerve be-
tween 30–100 mm when short-segment (1-cm intervals) stimula-
tion is used. Conduction block may be present not only in
multiple different nerves but also at several locations along the
course of the same nerve. Across the focal segment displaying
conduction block, conduction velocity is markedly reduced, sug-
gesting demyelination. A reduction in the distal CMAP ampli-
tude can be seen in chronic lesions due to secondary axonal loss.
There are no universally accepted criteria for defining defini-
tive conduction block.248,998a,1098,1168a,1271,1289a A completely absent
response to proximal stimulation with a persevered response to
distal stimulation is considered sound evidence of conduction
block, provided this finding persists for more than 5–8 days.
When there is a greater than 50% amplitude reduction from prox-
imal to distal stimulation sites, temporal dispersion is not present,
and a focal region of nerve (e.g., 30–50 mm) can be identified
with the drop in amplitude, it is reasonable to conclude that con-
duction block is present, although not without some doubt, partic-
ularly in chronic lesions. In chronic disorders with severe axonal
loss, remodeling of motor units can create MUAPs with long du-
rations that may phase-cancel with other motor units. The result
is a reduction of the CMAP amplitude with proximal stimulation
secondary to the normal dispersion of motor nerve conduction ve-
locities, hence producing pseudoconduction block. This finding
958 — PART IV CLINICAL APPLICATIONS

Figure 23-4. Motor and sensory nerve conduction studies of the left median nerve in a patient with multifocal motor neuropa-
thy with conduction block. A, Stimulation of the median nerve in a control subject demonstrating normal temporal dispersion and reduction
in both CMAP and SNAP amplitude.The marked reduction in SNAP amplitude is a normal phenomenon secondary to significant temporal disper-
sion and phase cancellation. B,The patient demonstrates a significant reduction in CMAP amplitude between 30 mm and 57 mm proximal to the
wrist with an associated increase in CMAP temporal dispersion and fragmentation of the CMAP. Note that sensory conduction across the same
nerve is essentially unaffected and quite similar to the control nerve. (From Krarup C. Stewart JD, Sumner AJ: A syndrome of asymmetric limb
weakness with motor conduction block. Neurology 1990;40:118–127, with permission.)

may be observed in motor neuron disease, giving the false im-
pression of conduction block, but careful analysis reveals an ab-
sence of focal reduction in amplitude. Instead, a gradual
reduction in MUAP size is seen with increasing separation of
stimulation sites. The previously defined criteria of conduction
block with respect to AIDP and CIDP may be valid, but debate
continues. Further investigations are required to resolve the issue.
Although motor conduction block has been considered the
electrodiagnostic hallmark of MMN,50,133,189,406,646,722,1025,1027,1029,
1030,1049,1050,1131,1289a other features of demyelination (i.e., pro-
longed distal latencies, temporal dispersion, slow conduction
velocities, and prolonged or absent F-waves) are typically pre-
sent on motor nerve conduction studies.205,235,660,1013,1094 Diagno-
sis does not require conduction block if other features of
demyelination are present.660,1013 The electrophysiologic fea-
tures of demyelination have been noted to improve with treat-
ment in some but not all cases.774a
The sensory nerves characteristically demonstrate normal
SNAP parameters using surface or near-nerve recording tech-
niques.189,648,660,763,1131 Of importance, there are no sensory con-
duction abnormalities in the mixed peripheral nerve in the
region where conduction block can be demonstrated in motor
fibers. For example, if a blockade of neural conduction is found
in the median nerve CMAP at the mid-arm level, median nerve
SNAPs should be documented with stimulation at the wrist and
mid-forearm segments. There should be no significant reduction
of SNAP amplitude above that normally anticipated or slowing
of SNAP conduction velocity across the same segment of
blocked motor fibers. A marked reduction in SNAP amplitude
normally found in sensory nerves (phase cancellation) can con-
found this attempt. Near-nerve needle recording techniques for
SNAPs can be used to maximize the amplitude and help distin-
guish the presence or absence of conduction block over a focal
neural segment in the sensory nerve fibers, particularly with se-
quential stimulation sites every centimeter.
Needle EMG findings depend on several factors.189,646,660,763,1131
Unaffected muscles should demonstrate no abnormalities. When
a clinically weak muscle is investigated, the numbers of motor
units with rapid firing rates are reduced. This finding is docu-
mented with or without axonal loss because conduction block
and denervation appear essentially the same with respect to
MUAP recruitment. When secondary loss of axons has occurred,
positive sharp waves and fibrillation potentials are commonly
detected in degrees commensurate with the amount of nerve

injury and clinical wasting. A muscle with clinical weakness but
preserved bulk is likely to reveal few if any fibrillation potentials
and positive sharp waves. Fasciculation potentials and, rarely,
myokymic discharges may be noted. Single-fiber EMG reveals
increased fiber density and jitter in clinically weak and unaf-
fected muscles.757 These abnormalities improve after treatment.
Histopathology. Most reports of sensory nerve biopsies in
MMN describe normal findings, mild loss of myelinated fibers, or
minimal axonal degeneration.965,1025,1027,1030,1049 Some groups have
noted scant findings of demyelination and remyelination on sural
nerve biopsies.133,251 Corse et al. reported that sensory nerve biop-
sies of 11 patients with MMN showed a slightly increased number
of thinly myelinated large caliber axons, with small onion bulb for-
mations; these demyelinating features were “never extensive.”251
They described no evidence of subperineurial or endoneurial
edema or mononuclear inflammatory cell infiltrate in the
epineurium or endoneurium.251 The histologic features on sensory
nerve biopsy in MMN are in sharp contrast to those seen in CIDP.
A few reports of motor nerve and mixed motor and sensory nerve
biopsies have demonstrated features of demyelination and remyeli-
nation, small onion bulb formation, and mild perivascular inflam-
mation.50,647 Of note, the demyelination appeared asymmetric
between and within nerve fascicles in at least one reported case.647
Treatment. In contrast to CIDP and MADSAM neuropathy,
few patients (<3%) with MMN improve with high doses of cor-
ticosteroids or PE.50,200,324,406,647,722,965,1025,1049 Azathioprine has
been administered in a few patients without noticeable improve-
ment.205,722,1025 Anecdotally, we have found a similar lack of effi-
cacy with azathioprine.
Intravenous cyclophosphamide was the first immunosuppressive
agent demonstrated to be effective in MMN; over 70% of reported
patients improved clinically after treatment.406,722,763,1025,1049,1285,1289a
No double-blinded, placebo-controlled trials have been per-
formed with cyclophosphamide; however, a similar degree of
improvement has not been seen with prednisone, PE, or azathio-
prine, suggesting that the improvement is not just a placebo re-
sponse. The initial dose of intravenous cyclophosphamide in
large series of patients has been 3 gm/m2 given over an 8-day
period. Subsequently, monthly courses of intravenous cy-
clophosphamide (0.5–1.0 gm/m2) or oral cyclophosphamide (2
mg/kg) can be instituted after 1 month. However, this high dose
of intravenous cyclophosphamide (3 gm/m2) is associated with
alopecia, nausea and vomiting, hemorrhagic cystitis, and signif-
icant bone marrow suppression. We have rarely used cyclophos-
phamide, given its short-term and long-term side effects, since
the reported efficacy of IVIG in MMN. In patients who cannot
tolerate IVIG, we recommend lowering the initial intravenous
pulse of cyclophosphamide to 0.5 or 1.0 gm/m2 to avoid severe
side effects. The subsequent doses can be titrated upward or
downward as tolerated. Patients should be treated with mesna
and well hydrated to avoid hemorrhagic cystitis. Nausea can be
managed with ondansetron or gransetron.
IVIG is now the treatment of choice in MMN. Efficacy has
been demonstrated in numerous studies,57,205,268,646,660,832,1289a in-
cluding one double-blinded placebo-controlled trial.56,774a IVIG
is given initially in a dose of 2 gm/kg over 2–5 days with subse-
quent maintenance courses as necessary, similar to the manage-
ment of CIDP. Oral cyclophosphamide in combination with
IVIG may prolong the interval between IVIG infusions.891
Improvement usually is noted within a few days or first few
weeks of treatment. Unfortunately, not all patients with MMN
respond to IVIG. Some series have noted that later age of
onset832 and patients who have significant muscle atrophy133 do
Chapter 23 ACQUIRED NEUROPATHIES — 959
not respond as well to treatment. We give three courses of monthly
IVIG before concluding that a patient has failed treatment.
Multifocal Acquired Demyelinating Sensory
and Motor Neuropathy
As discussed above, patients with MMN should have no objec-
tive sensory abnormalities clinically or on NCS. Several series,
however, have included patients with mild objective sensory
deficits or abnormal sensory NCS.133,251,722,832,965 Whether such pa-
tients constitute a separate nosological entity, represent a focal
variant of CIDP, or simply have MMN with mild sensory involve-
ment is the subject of some debate. Recently, there have been sev-
eral series of patients who resemble MMN but have objective
sensory abnormalities clinically, electrophysiologically, and his-
tologically. The term multifocal acquired demyelinating sen-
sory and motor (MADSAM) neuropathy was coined to
describe this suspected variant of CIDP (see Table 23-5).1168,1168a
Although we believe that MADSAM neuropathy probably
represents an asymmetric form of CIDP, the concept is useful
because it emphasizes that the disorder is not merely a variant
of MMN with associated sensory findings. Therefore, we favor
using theterm MADSAM neuropathy to underscore the distinc-
tion between these patients and patients with MMN. However,
as an alternative to MADSAM neuropathy, the eponym Lewis-
Sumner syndrome also has been used in recognition of the
clinicians who first described this neuropathy.790
Clinical features. There are now over 50 well-described patients
with MADSAM neuropathy.23,456,478,790,973,989,1131a,1168,1168a,1303,1329,1330
The signs and symptoms of MADSAM neuropathy are essen-
tially those of mononeuropathy multiplex. There is a 2:1 male
predominance. The average age of onset is in the early 50s
(range: 14–77 years). Onset is usually insidious and slowly pro-
gressive with initial involvement usually in the arms; however,
the legs also can be be initially involved and often become af-
fected over time. There is usually a 2–3 year lag from the onset
of symptoms to diagnosis. Motor and sensory losses conform to
a discrete peripheral nerve distribution rather than a generalized
stocking or glove pattern. Some patients describe pain and
paresthesias. Cranial neuropathies have been reported, includ-
ing optic neuritis, oculomotor, trigeminal, and facial nerve
palsies. Most patients have decreased or absent muscle stretch
reflexes in a multifocal, asymmetric distribution; however, some
have complete areflexia.
Laboratory Test Results. There are differences in CSF protein
and GM1 antibodies between patients with rigorously defined
MADSAM neuropathy and MMN (see Table 23-5).989,1168,1168a CSF
protein is elevated in 60–82% of patients with MADSAM neuropa-
thy (mean level of around 70 mg/dl).23,456,478,790,973,989,1168,1303,1329,1330
The frequency of CSF protein abnormalities and concentration is
less than that normally seen in patients with typical generalized
CIDP but clearly different from MMN, in which CSF protein con-
centration is usually normal. In MMN in which patients with sen-
sory signs were excluded, only 1 of 11 patients with MMN had an
elevated CSF protein.660,1168 As noted previously, most patients with
MMN (range: 56–90%) have antibodies to GM1. In contrast, only
1 of 45 tested patients with MADSAM neuropathy have had de-
tectable GM1 antibodies.456,478,989,1168,1303,1329,1330 In patients with de-
myelination localized to the cervical roots or brachial plexus, MRI
scans have demonstrated enlarged nerves, which enhance in some,
but not all, cases.23,1303,1329,1330
Histopathology. Sensory nerve biopsies demonstrate many
thinly myelinated, large-diameter fibers and scattered demyelinated
fibers in most reported cases (Fig. 23-5).456,478,790,973,989,1168,1303,1329
960 — PART IV CLINICAL APPLICATIONS
Figure 23-5. Mutlifocal acquired demyelinating sensory and
motor (MADSAM) neuropathy or Lewis-Sumner syndrome.
Sural nerve biopsy demonstrates a mild loss of myelinated nerve fibers
and many thinly myelinated fibers, some surrounded by early onion-
bulb formations (epoxy-embedded, touidine blue stain).
Subperineurial and endoneurial edema and mild onion bulb forma-
tions also may be appreciated as in CIDP. Teased fiber preparations
reveal demyelinated or remyelinated internodes in 3–88% of the
fibers. A smaller percentage of teased fibers show features of
axonal degeneration (range: 0–6%). Prominent, asymmetric loss of
large myelinated nerve fibers between and within fascicles may be
seen on nerve biopsies.1168 Similar asymmetric abnormalities had
been reported in three other patients with MADSAM neuropa-
thy.456,973 Asymmetric involvement was apparent on motor nerve
biopsy in one patient with MMN at the site of conduction block.647
Asymmetric fiber loss with demyelination may represent the
pathologic correlate of the clinical neurologic findings of asymmet-
ric demyelinating mononeuropathy multiplex. Although this fea-
ture can suggest an ischemic process, axonal loss secondary to
severe multifocal demyelination may cause a similar clinical pic-
ture. There has been no evidence of necrotizing vasculitis on any
reported biopsies, although some have noted nonspecific, mild
perivascular inflammation.790,989,1303 A biopsy specimen from the
brachial plexus in one patient demonstrated prominent infiltrates
consisting of mainly T-cells and, to a lesser extent, B-cells.1329
Pathogenesis. The pathogenic basis for MADSAM neu-
ropathy is not known. We believe that MADSAM falls into the
spectrum of CIDP and probably has a similar pathogene-
sis.23,1168,1168a MADSAM neuropathy and CIDP are similar with
respect to CSF and sensory nerve biopsy findings as well as re-
sponse to corticosteroids. MADSAM neuropathy meets the
CIDP criteria formulated by the Ad Hoc Subcommittee of the
American Academy of Neurology (AAN) AIDS Task Force.249
In contrast to the CIDP classifications established by Dyck351
and Barohn,73 the AAN criteria do not require symmetric
deficits. The pathogenic basis for the asymmetric involvement
is unclear. We believe that MADSAM and CIDP are distinct
from MMN, as demonstrated by objective sensory abnormali-
ties and differences in laboratory results, histopathology, and re-
sponse to steroids.1168a
Electrophysiologic Findings. As with CIDP and MMN,
nerve conduction studies in MADSAM neuropathy demon-
strate conduction blocks, temporal dispersion, prolonged distal
latencies, prolonged F-waves, and slow conduction velocities
in one or more motor nerves.23,456,478,790,973,989,1168,1168a In contrast
to MMN, the sensory studies are also abnormal. SNAPs are
usually absent or small in amplitude, similar to those in pa-
tients with generalized CIDP. EMG may reveal fibrillation po-
tentials and positive sharp waves as well as polyphasic,
long-duration MUAPs that recruit early. The electrophysio-
logic abnormalities improve with treatment.
Treatment. Although prospective, controlled trials have not
been performed, retrospective series have demonstrated that most
patients with MADSAM neuropathy improve with IVIG treat-
ment.23,456,478,790,973,989,1168,1303,1329,1330 A similar response to IVIG is
noted with CIDP and MMN. In contrast to MMN but similar to
CIDP, most patients with MADSAM neuropathy also demon-
strate improvement with steroid treatment.23,456,790,973,989,1168,1303
This difference illustrates the importance of distinguishing
MADSAM from MMN, in which cyclophosphamide is the only
other medication reported to be beneficial besides IVIG.
SENSORY NEURONOPATHIES AND
AUTONOMIC NEUROPATHIES
Idiopathic Sensory Neuronopathy/Ganglionopathy
This disorder is believed to be caused by an autoimmune
attack directed against the dorsal root ganglia; hence the terms
sensory neuronopathy and ganglionopathy are more appro-
priate than sensory neuropathy. The differential diagnosis of
sensory neuronopathy includes paraneoplastic syndrome, which
is typically associated with anti-Hu antibodies, and sensory gan-
glionitis related to Sjögren’s syndrome. Certain medications or
toxins, infectious agents, and other systemic disorders also are
associated with a sensory neuronopathy. These causes of sen-
sory neuronopathy are discussed in their relevant sections.
Despite extensive evaluation, many cases of sensory neuronopa-
thy have no clear etiology; so-called idiopathic sensory neu-
ronopathy is discussed below.
Clinical Features. Idiopathic sensory neuronopathy has
been reported in over 100 patients.44,277,411,537,705,1232,1257,1419,1445
There is a slight female predominance, and the mean age of
onset is 49 years (range: 18–81 years).1232 The neuronopathy
can present acutely with an abrupt onset over a few hours or de-
velop more insidiously over several months or years. The course
can be monophasic with a stable or remitting deficit, chronic
progressive, or chronic relapsing. A few patients experience a
flu-like illness with or without diarrhea shortly before the onset
of symptoms. The most common presenting complaint is numb-
ness, often described as a “dead” or “novocaine-like” feel-
ing.1419 Hyperesthesia with prickly, lancinating pain can also
develop during the course but is usually not the presenting or
most prominent symptom. Numbness can begin in the face,
trunk, or limbs. Symptoms begin asymmetrically and in the
upper limbs in nearly one-half of patients. Usually, the sensory
symptoms are generalized, but they can remain asymmetric.
Because of the prominent large-fiber sensory loss, patients de-
scribe clumsiness of the hands and gait instability.
Marked reduction in vibration and position sense is evident
on examination. The deficit can be more impaired in the arms
than legs, unlike length-dependent axonal neuropathies. Pain
and temperature sensations are less affected. Manual muscle
testing is usually normal. Some muscle groups may appear
weak because of impaired modulation of motor activity due to
the proprioceptive defect. Patients often complain of “weak-
ness” when referring to difficulty with gait or clumsiness.
However, these symptoms are related to the severe sensory

ataxia resulting from the loss of proprioception. Most patients
have difficulty in knowing the position of their feet and hands in
space. This problem can be readily demonstrated by having the
patient perform the finger-nose-finger test with eyes open and
then closed. Patients may have only mild dysmetria with eyes
open. However, when the eyes are closed, patients consistently
miss their nose and the examiner’s stationed finger. When the
eyes are closed, the upper limbs also may begin to move in
space, so-called pseudoathetoid movements. Patients exhibit a
positive Romberg sign and, not surprisingly describe more gait
instability in the dark. Deep tendon reflexes are decreased or
absent, whereas plantar reflexes are flexor.
Idiopathic sensory neuronopathy is a diagnosis of exclusion.
A detailed history and examination are essential to exclude
toxin-induced neuronopathy, paraneoplastic syndrome, or dis-
order related to connective tissue disease (e.g., Sjögren’s syn-
drome).24,504 Of importance, the sensory neuronopathy can
precede the onset of malignancy or sicca symptoms (i.e., dry
eyes and mouth); therefore, these disorder should always be
kept in mind. Pertinent laboratory and malignancy work-up
should be ordered. One also should inquire about sicca symp-
toms. We refer patients to ophthalmology for Rose-Bengal stain
and Schirmer’s test. A lip or parotid gland biopsy is obtained in
all suspected patients. Subacute sensory neuronopathy also has
been associated with recent Epstein-Barr virus infection.1138
Laboratory Features. The CSF protein is normal or only
slightly elevated in most patients.1413 However, the CSF protein
can be markedly elevated (reportedly as high as 300 mg/dl)
when examined within a few days in cases with hyperacute
onset. Only rare patients exhibit CSF pleocytosis.1419 MRI scan
can reveal gadolinium enhancement of the posterior spinal
roots.1371 Increased signal abnormalities on T2-weighted
images may be seen in the posterior columns of the spinal
cord.770 Some patients have a monoclonal gammopathy (IgM,
IgG, or IgA).277,1419 Antiganglioside antibodies, particularly
anti-GD1b antibodies, have been demonstrated in some cases
of idiopathic sensory neuronopathy associated with IgM mono-
clonal gammopathy.281
Antineuronal nuclear antibodies (anti-Hu and anti-Purkinje
cell antibodies) should be assayed in all patients with sensory
neuronopathy to evaluate for paraneoplastic syndrome. Like-
wise, antinuclear, SS-A, and SS-B antibodies should be ordered
to look for evidence of Sjögren’s syndrome, which also can pre-
sent with a sensory neuronopathy.
Histopathology. Sensory nerve biopsies demonstrate a re-
duction in the total number of myelinated nerve fibers. Some
studies have shown a preferential loss of large myelinated fibers
compared with small myelinated fibers.347 However, in a study of
22 sural nerve biopsies, Windebank et al. found no difference in
the median myelinated fiber diameter from control biopsies.1419
They noted significant loss of both large and small myelinated
nerve fibers as well as axonal atrophy. Usually there is a lack of
inflammation in peripheral nerve specimens, although a mild,
nonspecific perivascular infiltrate occasionally is seen.1419
Segmental demyelination is also absent on nerve biopsies.
An autopsy performed 5 weeks after onset of idiopathic sen-
sory neuronopathy in one man revealed widespread inflamma-
tion involving sensory and autonomic ganglia.537 These ganglia
were severely depleted of neurons, and Wallerian degeneration
of the posterior nerve roots and dorsal columns was evident.
However, the motor neurons and roots were spared. Immuno-
histochemical analysis suggested a CD8+ T-cell–mediated cyto-
toxic attack against the ganglion neurons.
Chapter 23 ACQUIRED NEUROPATHIES — 961
Pathogenesis. The disorder is believed to be caused by an
autoimmune attack directed against the dorsal root ganglia.
Serum from patients with idiopathic sensory neuronopathy im-
munostains dorsal root ganglia cells in culture and inhibits neu-
rites.1335 The neuronal epitope to which the autoantibodies are
directed is still unknown, but the ganglioside GD1b has been
hypothesized to be the target antigen.281 GD1b is localized to
neurons in the dorsal root ganglia, and antibodies directed
against this ganglioside have been detected in some patients
with idiopathic sensory neuronopathy. Rabbits immunized with
purified GD1b develop ataxic sensory neuropathy. Pathologic
examination of the affected rabbits revealed loss of the cell
bodies in the dorsal root ganglia and axonal degeneration of the
dorsal column of the spinal cord and of the sciatic nerve. No ev-
idence 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.537 Of note, antiganglioside antibodies, including
anti-GD1b, were detected in this patient’s serum.
Electrophysiologic Findings. The most prominent electro-
physiologic abnormality is absent or low-amplitude SNAPs.6,271,
411,663,705,1232,1257,1371,1419,1445 When SNAPs are obtainable, the distal
sensory latencies and nerve conduction velocities are normal or
only mildly abnormal. Motor nerve conduction studies either
are normal or reveal only mild abnormalities. The CMAP am-
plitudes are reduced in less than 20% of patients.1419 Motor
nerve conduction velocities are normal or only slightly de-
creased. Likewise, distal motor latencies and F-waves are usu-
ally normal.
In addition, H-reflexes and blink reflexes typically are unob-
tainable.51,1419 An abnormal blink reflex favors a nonparaneo-
plastic etiology for sensory neuronopathy but does not exclude
an underlying malignancy.52 However, the masseter reflex or
jaw jerk, which is abnormal in patients with sensory neuropa-
thy, is usually normal in patients with sensory neuronopathy,51
because the masseter reflex is unique among the stretch reflexes
in that the cell bodies of the afferent limb lie in the mesen-
cephalic nucleus within the CNS. The sensory cell bodies inner-
vating the limbs, in contrast, reside in the dorsal root ganglia of
the PNS. In regard to facial sensation and the blink reflex, the
afferent cell bodies lie in the gasserian ganglia outside the CNS.
Needle EMG is usually normal, although a few patients may
have positive sharp waves and fibrillation potentials in the distal
upper and lower limb limb muscles.1419 Myokymic discharges
were recorded in one patient with chronic progressive sensory
neuronopathy.1445 Some degree of MUAP alterations, suggest-
ing chronic motor unit remodeling, is described in a few pa-
tients. Decreased recruitment is not a prominent feature.
Treatment. Various modes of immunotherapy have been
tried, including corticosteroids, PE, and IVIG.277,537,1371,1419,1445
However, it is difficult to assess efficacy of any specific treat-
ment regimen because none has been studied in a prospective,
double-blinded, controlled fashion. Furthermore, a few patients
may improve spontaneously, and many stabilize even without
treatment. Once the cell body of the sensory neuron is de-
stroyed, it will not regenerate. Thus, there is no indication to
treat a patient with a stable deficit. In the acute setting or in pa-
tients with a chronic progressive deficit, a trial of immunother-
apy may be warranted.
Idiopathic Autonomic Neuropathy
Clinical Features. Young et al. were the first to report a de-
tailed clinical, laboratory, and histologic description of acute
962 — PART IV CLINICAL APPLICATIONS
pandysautonomia.1441,1442 Subsequently, there have been several
small reports, most limited to one or two patients with idio-
pathic autonomic neuropathy.35,86,231,388,407,553,566,818,874,889,950,1041,1077,
1230,1262,1266,1288,1348,1434 There appears to be heterogeneity in onset,
type of autonomic deficits, presence or absence of somatic in-
volvement, and degree of recovery. Recently, the Mayo Clinic
reported the largest series in a detailed study of 27 patients with
idiopathic autonomic neuropathy who were followed for a mean
of 32 months.1266 Approximately 20% of patients had selective
cholinergic dysfunction, and 80% of patients had various de-
grees of widespread sympathetic and parasympathetic dysfunc-
tion. The most common symptom was orthostatic dizziness or
lightheadedness (about 80% of patients). Gastrointestinal in-
volvement, as indicated by complaints of nausea, vomiting, di-
arrhea, constipation, ileus, or postprandial bloating is the
second most common symptom (over 70% of patients).
Thermoregulatory impairment with heat intolerance and poor
sweating was also present in most patients. Blurred vision, dry
eyes and mouth, urinary retention or incontinence, and impo-
tence are often present. As many as 30% of patients also de-
scribed numbness, tingling, and dysesthesia of the hands and
feet. Muscle strength was normal. Most patients had a mono-
pathic course with progression followed by plateau and slow re-
covery or stable deficit.1266 Although some patients exhibit
complete recovery,1348,1442 recovery tends to be incomplete in
most.1266
Laboratory Features. The CSF often reveals slightly ele-
vated protein without pleocytosis.1266 There are no serologic or
immunologic abnormalities in the blood. Supine plasma norepi-
nephrine levels are not different, but standing levels are signifi-
cantly reduced compared with normal controls.1266
Specialized tests to look for abnormalities of the autonomic
nervous system are required for diagnosis.865,875,1088 Cardio-
vascular studies reveal orthostatic hypotension and reduced
variability of the heart rate to deep breathing in over 60% of pa-
tients.1077,1266 An abnormal response to Valsalva maneuver (i.e.,
exaggerated fall in blood pressure during early phase II of the
response, absent recovery of systolic and diastolic blood pres-
sure during late phase II, or reduced or absent overshoot of sys-
tolic and diastolic pressures during phase IV) can be
demonstrated in over 40% of patients.
Summated quantitative sudomotor axon reflex test (QSART)
scores are abnormal in 85% of patients.1266 Most patients have
abnormal thermoregulatory sweat tests with areas of anhidrosis
Table 23-6. Vasculitides Associated with Peripheral
Neuropathy
Primary vasculitis
Large vessel vasculitis; 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
in 12–97% of the body. Gastrointestinal studies can demonstrate
hypomotility anywhere from the esophagus to the rectum.
Histopathology. Nerve biopsies have been performed on only
a few patients.35,407,950,1262,1266,1440,1442 Reduced density of mainly
small diameter myelinated nerve fibers has been described.
Stacks of empty Schwann cell profiles and collagen pockets can
be seen. Scant epineurial perivascular inflammation may be seen.
Pathogenesis. The disorder is thought to result from an au-
toimmune attack directed against peripheral autonomic fibers or
the ganglia. A subset of patients may have antibodies directed
against calcium channels, which are present on presynaptic au-
tonomic nerve terminals.
Electrophysiologic Findings. Routine nerve conduction
studies and EMG are usually unremarkable.1266 Motor conduc-
tion studies are normal. Most patients have normal sensory con-
duction studies, although a few have diminished amplitudes and
slightly prolonged distal latencies. Quantitative sensory testing
may reveal abnormalities in thermal thresholds.818 Sympathetic
skin response may be absent.388,406,1440 Needle EMG is generally
normal, but in one report stimulated single-fiber studies demon-
strated increased jitter.1077 With increased rate of stimulation the
amount of jitter decreased. The authors speculated that the mech-
anism was autoantibodies directed against calcium channels on
presynaptic autonomic nerve terminals and, to a lesser extent,
the neuromuscular junction. However, whether autoantibodies to
calcium channels were present in this patient was not reported.
Treatment. Conclusions about the efficacy of immunother-
apy are limited by the retrospective and uncontrolled nature of
most reports. PE, prednisone, IVIG, and other immunosuppres-
sive agents have been tried with variable success.566,1077,1230,1266
The most important aspect of management is supportive therapy
for orthostatic hypotension and bowel and bladder symp-
toms.865,875 Fluodrocortisone is effective for increasing plasma
volume. Fluodrocortisone is administered only in the morning
or in the morning and at lunch to avoid nocturnal hypertension.
We begin treatment at 0.1 mg/day and increase by 0.1 mg every
3–4 days until blood pressure is controlled. Midodrine, a pe-
ripheral α1-adrenergic agonist, is also effective and can be used
in combination with fluodrocortisone. Midodrine is started at
2.5 mg/day and can be gradually increased to 40 mg/day in di-
vided doses (every 2–4 hours) as necessary. Gastrointestinal hy-
pomotility can be treated with metaclopramide, cisapride, or
erythromycin. Bulking agents, laxatives, and enemas may be
needed in patients with constipation. Urology should be con-
sulted in patients with neurogenic bladders. Patient may require
cholinergic agonists (e.g., bethanechol), intermittent self-
catheterization, or other modes of therapy.
VASCULITIC NEUROPATHIES
Definition/Classification. Vasculitis is a histologic diagno-
sis requiring transmural inflammation and necrosis of the blood
vessel walls. Mere perivascular inflammation is a nonspecific
finding and does not necessarily indicate vasculitis (necrotizing
vasculitis). Necrotizing vasculitis results in ischemia in tissue
supplied by the injured vessels. Vasculitic disorders can be clas-
sified based on the caliber of involved vessel (i.e., small,
medium, or large vessel), whether the vasculitis is primary (e.g.,
polyarteritis nodosa, Churg-Strauss disease, Wegener’s granulo-
matosis) or secondary to other systemic disorders (connective
tissue diseases, infection, drug reactions, malignancy), or
whether the vasculitis is systemic or isolated to the peripheral
nervous system (PNS) (Table 23-6).519,701,1125a
 Chapter 23 ACQUIRED NEUROPATHIES — 963

Figure 23-6. Diagrammatic representation of the three patterns of peripheral nerve involvement commonly encountered in
vasculitic neuropathies. In true mononeuritis or mononeuropathy multiplex, individual nerves create an asymmetric pattern of clinical involve-
ment. In this example, the patients demonstrate a combination of right peroneal, right superficial radial, and left ulnar nerves affected. In overlap-
ping mononeuritis multiplex, multiple neighboring nerves are involved on both sides of the body.There is a certain degree of asymmetry when the
same nerve on the left vs. the right is considered, thus distinguishing this form of dysfunction from distal symmetric polyneuropathy.The distal
symmetric polyneuropathy is what its name implies: symmetric with respect to the nerves and degree of involvement when the two sides are
compared. (From Kissel JT, Mendell JR:Vasculitic neuropathy. Neurol Clin 1992;10:761–781, with permission.)

Clinical Features. All of the vasculitic disorders have cer-
tain clinical features in common, with variations on a central
theme of vascular compromise.519,563,697,700,701,1125a,1159 Each spe-
cific disease has unique characteristics of its primary systemic
manifestations, but there is significant overlap of clinical mani-
festations, particularly in terms of peripheral nerve involvement.
Three patterns of peripheral nerve involvement can be appre-
ciated (Fig. 23-6).701 The first is a mononeuropathy multiplex
or multiple mononeuropathies. Several individual nerves may
be affected, creating a distinctly asymmetric pattern of involve-
ment. A second pattern, so-called overlapping mononeuropa-
thy multiplex, is formed when the same nerves on both sides of
the body are affected but to differing degrees and in differing
distributions. The result is a generalized, yet asymmetric pattern
of involvement. Finally, over time fairly uniform and general-
ized involvement of peripheral nerves can develop, producing
the classic glove-and-stocking deficit similar to most distal
symmetric polyneuropathies. The mononeuropathy multiplex
patterns (simple and overlap forms) are the most common,
found in 60–70% of cases at the time of diagnosis, whereas a
distal symmetric polyneuropathy is evident in approximately
30–40% of patients.697 The differential diagnosis of patients with a
mononeuropathy multiplex pattern is quite broad (Table 23-
7).997,1022 We prefer the terms multiple mononeuropathies or
mononeuropathy multiplex to mononeuritis multiplex because
the latter term implies a histologically defined rather than a clin-
ically defined syndrome.1022
The most common symptom in patients with vasculitis is a
burning dysesthetic type of pain confined to the anatomic distri-
bution of the affected nerve(s). Usually, both motor and sensory
fibers are affected, resulting in numbness and weakness con-
forming to specific nerve distributions. In patients with the
distal symmetric pattern, sensory loss and weakness are located
in the typical glove-and-stocking distribution.
Histopathology. In patients with suspected vasculitic neu-
ropathies, the sural, superficial sensory peroneal, and superficial
radial sensory nerves are the most appropriate to consider for
biopsy.701 We prefer the superficial peroneal nerve, if it is clini-
cally involved, because the peroneus brevis muscle can be biop-
sied at the same time. The diagnostic yield is increased when
both nerve and muscle are biopsied.234,697,700,701,1159
The definitive histologic diagnosis of vasculitis requires
transmural inflammatory cell infiltration and necrosis of the
vessel wall (Fig. 23-7).697,700,701,997,1020,1393 Immunocytochemistry
often reveals deposition of immunoglobulin (IgM and/or IgG),
complement, and membrane attack complement on blood ves-
sels. Another important observation is the asymmetric nerve
fiber loss between and within individual nerve fascicles. Active
Wallerian degeneration is evident on plastic/epoxy resin sec-
tions and teased fiber preparations.
964 — PART IV CLINICAL APPLICATIONS

Table 23-7. Mononeuropathy Multiplex: Differential mononeuropathy multiplex pattern reveals asymmetric SNAP
Diagnosis abnormalities. For example, the left sural and right superficial
Ischemic neuropathies peroneal SNAPs may be absent or reduced in amplitude,
Polyarteritis nodosa whereas the right sural and left superficial peroneal SNAPs are
Wegener’s granulomatosis relatively unaffected. The same comments apply to the upper
Churg-Strauss syndrome limbs.
Connective tissue disorders associated with vasculitic neuropathies Motor conduction studies reveal similar findings to those noted
(e.g., SLE, RA, MCTD) for sensory nerves. The CMAP is commonly absent or signifi-
Nonsystemic vasculitis neuropathy cantly reduced in the affected nerves. Distal latencies are normal
Remote effect of cancer or slightly prolonged, whereas conduction velocities are normal or
Diabetic microangiopathy only mildly reduced compared with the lower limit of normal. F-
Amyloidosis waves may be difficult to obtain in nerves with severe axonal loss.
Atherosclerotic vascular disease When obtainable, F-waves latencies are normal or only slightly
Drug-induced (e.g., amphetamine, sulphonamides) prolonged. With mononeuropathy multiplex, an asymmetric pat-
tern of motor conduction abnormalities between limbs can be
Demyelinating neuropathies
demonstrated. Of interest, it is possible to observe conduction
Multifocal motor neuropathy (MMN)
block in some patients with vasculitic neuropathies.624,800,860,907,1115
Multifocal acquired sensory and motor neuropathy
The cause probably is related to ischemia, which produces con-
(MADSAM)
duction failure, and can be observed in patients either with
Paraproteinemic polyneuropathies (e.g., IgM monoclonal
mononeuropathy multiplex or generalized sensorimotor forms
gammopathies)
of involvement.
Hereditary liability to pressure neuropathy
The needle EMG examination characteristically demon-
HIV-associated demyelinating neuropathy
strates fibrillation potentials and positive sharp waves in mus-
Infectious neuropathies cles innervated by the affected nerve. Reduced recruitment of
Leprosy MUAPs is also evident in the distribution of the affected nerves.
Herpes zoster In long-standing disease, motor unit remodeling results in
Lyme disease MUAPS of long duration and relatively increased amplitude,
HIV-associated with cytomegalovirus which fire in reduced numbers. The distal muscles are more
Hepatitis B and C likely than the proximal muscles to demonstrate such abnormal-
Compression neuropathy ities. Documenting fibrillation potentials in a specific nerve dis-
Primary compression neuropathies (e.g., traumatically induced) tribution can be quite helpful in delineating the pattern of a
Secondary compression neuropathies (e.g. , superimposed on mononeuropathy.
generalized peripheral nerve disease; e.g., diabetes mellitus and
carpal/cubital tunnel syndrome) Primary Systemic Vasculitic Disorders Affecting
Large and Medium-sized Vessels
Neoplastic infiltration
Neurofibromatosis Giant Cell Vasculitis. There are two forms of giant cell
Local infiltration by tumor tissue arteritis (GCA): temporal arteritis and Takayasu arteritis.Only
temporal arteritis has been associated with peripheral neuropa-
Granulomatous infiltration
thy.162,176,193,468,716 GCA affects medium-sized and large vessels,
Sarcoid
particularly the aortic arch and all its branches, including the in-
Sensory perineuritis
ternal and external carotid arteries and vertebral arteries. Patients
Lymphomatoid granulomatosis
usually complain of headaches and diffuse myalgias. Jaw and
Other disorders tongue claudication is not uncommon. Vision loss secondary
Lumbosacral plexus neuropathy to ischemic optic neuropathy occurs in 8–23% of patients.176,716
Brachial plexus neuropathy Stroke is another important complication. Approximately 14%
Modified with permission from references 997 and 1122. of patients with temporal arteritis have peripheral nerve involve-
ment, resulting in multiple mononeuropathies, radiculopathies,
plexopathies, or generalized sensorimotor peripheral neuropa-
Electrophysiologic Findings. The electrodiagnostic medi- thy.176 Corticosteroids are usually highly effective in patients
cine findings noted in this section pertain to all of the specific with GCA.
disorders listed below. Polyarteritis nodosa is used as a template Laboratory evaluation is remarkable for elevated ESR in 97%
disease to illustrate what can be anticipated in vasculitic axonal of patients.176 The temporal artery is often tender, and a cord can
sensorimotor neuropathies. To be sure, there are minor varia- be palpated. Unfortunately, as many as one-third of temporal
tions for each disorder and individual patients, but the descrip- artery biopsies lack definitive features of arteritis.176 The classic
tions noted are generally applicable. The interested reader is histologic feature is an inflammatory infiltrate with giant cell
encouraged to pursue the specific citations noted for each dis- formation in the blood vessels.
ease about particular electrodiagnostic medicine findings. The
description of electrophysiologic findings pertains to individual Primary Systemic Vasculitic Disorders Affecting
nerves in patients with mononeuropathy multiplex as well as to Medium-sized and Small Vessels
all involved nerves in a more generalized sensorimotor periph- Polyarteritis Nodosa. Polyarteritis nodosa (PAN) is the most
eral neuropathy.81,132,563,579,697,982,997,1345,1393 common of the necrotizing vasculitides with an incidence rang-
Sensory nerve conduction studies typically reveal SNAP am- ing from 2–9 per million.162,193,517–519,700,701,1125a The onset is usually
plitude reductions in the distribution of the affected nerves. A between 40 and 60 years of age. PAN is a systemic disorder

Figure 23-7. Vasculitis. A, Sural nerve biopsy demonstrates necrotizing vasculitis with obliteration of the vessel lumen. B, Immunoperoxidase
stain demonstrates deposition of complement (C3) in the walls of affected blood vessels.
involving small- and medium-caliber arteries in multiple
organs. Fifty to 70% of patients with PAN have evidence of pe-
ripheral neuropathy. Mononeuropathy multiplex is the most
common pattern of involvement, and the sciatic nerve or its per-
oneal or tibial branch is the most frequently affected nerve.
Cranial neuropathies and CNS involvement are uncommon
(< 2% of patients).519 Besides the peripheral neuropathy, multi-
system dysfunction is also present, consisting of varying de-
grees of hepatic, renal, muscular, skin, and gastrointestinal
involvement. However, the lungs are generally spared. Myalgias
and arthralgias are frequent (30–70% of patients). Skin lesions,
including petechiae, papules, livido reticularis, subcutaneous
nodules, and distal gangrene, may be evident in 25–60% of pa-
tients.519 Vasculitis of the gastrointestinal tract can manifest as
abdominal pain or bleeding. Ischemia of the kidneys can lead to
renal failure. Orchitis is also a classic symptom of PAN. Con-
stitutional symptoms of weight loss, fever, and loss of appetite
are usually noted.
Laboratory evaluation is remarkable for elevated ESR greater
than 60 mm/hr in 78–89% of patients.519 Rheumatoid factor, C-
reactive protein, and alpha-2 globulins also are elevated.
Leukocytosis with normochromic anemia usually is seen. As
many as one-third of cases are associated with hepatitis B anti-
genemia.517,519 In addition, hepatitis C and HIV infection have
been reported with PAN.519 Abdominal angiograms may reveal
a vasculitic aneurysm, which may be helpful in patients with
nondiagnostic biopsies.
PAN primarily affects medium-sized arteries; however,
smaller vessels may be involved.519,701 The infiltrate is composed
mainly of CD8+ T-cells and macrophages. Polymorphonuclear
cells may be evident in the area of fibrinoid necrosis.
Immunocytochemistry can demonstrate deposition of IgM, IgG,
complement, and membrane-attack complement on blood ves-
sels. Granuloma formation and eosinophilic infiltration are not
present on nerve biopsies; their absence can be useful in distin-
guishing PAN from Churg-Strauss syndrome.
The pathogenic mechanism of PAN is unknown. Kissel and
Mendell suggest a T-cell–dependent, endothelial cell-mediated
process; complement-mediated vascular damage plays a sec-
ondary role.701
Churg-Strauss Syndrome (Allergic Angiitis/Granuloma-
tosis). Churg-Strauss syndrome (CSS) is a rare disorder that
manifests much like PAN.162,193,222,240,519,560,983,1125a The incidence is
Chapter 23 ACQUIRED NEUROPATHIES — 965
roughly one-third that of PAN, but the frequency of PNS and
CNS involvement is similar. In contrast to PAN, patients with
CSS usually present with respiratory involvement. They typi-
cally develop allergic rhinitis, nasal polyposis, and sinusitis fol-
lowed by asthma. In CSS, asthma begins later in life, whereas
common asthma usually develops before the age of 35 years.
Pulmonary infiltrates are present in nearly one-half of patients,
usually in association with asthma and hypereosinophilia.
Symptoms and signs of systemic vasculitis occur an average of
3 years after onset of asthma. Rather than an ischemic
nephropathy, as in PAN, 16–49% of patients with CSS develop
necrotizing glomerulonephritis. Besides the differences in res-
piratory and renal system involvement, the other systemic man-
ifestations of CSS are similar to those in PAN. In particular,
multiple mononeuropathies are found in 64–75% of patients.519
Laboratory evaluation is remarkable for eosinophilia, often
> 109/L, leukocytosis, and elevated ESR, C-reactive protein,
rheumatoid factor, and serum IgG and IgE levels. The associa-
tion of eosinophilia with asthma is highly suggestive of the di-
agnosis. CSS also is associated strongly with antineutrophil
antibodies (ANCA), primarily myeloperoxidase or p-ANCA,
because of its perinuclear staining pattern. These p-ANCA anti-
bodies are present in as many as two-thirds of patients.519
Histopathology reveals necrotizing vasculitis involving
medium-sized and small arteries and veins. The inflammatory
infiltrates consist mainly of CD8+ cytotoxic T-lymphocytes and
CD4+ helper T-lymphocytes. Eosinophils are also present in the
infiltrate but not as extensively as the T-lymphocytes. Less com-
monly, intravascular and extravascular granulomas are evident
in and around these blood vessels.519,560,794
Wegener’s Granulomatosis. Wegener’s granulomatosis is a
rare disorder consisting of necrotizing granulomatous involve-
ment of the upper and lower respiratory tract and glomeru-
lonephritis.162,335,393,590,621,634,701,963,1125a,1259 The early symptoms of
respiratory disease (nasal discharge, cough, hemoptysis, and
dyspnea) and facial pain help to distinguish this from other vas-
culitic disorders. About 30–50% of patients may have some
form of neurologic dysfunction, although only 15–20% have
peripheral neuropathy. Either a mononeuropathy multiplex or
generalized symmetric pattern of involvement can be found. The
presence of peripheral neuropathy correlates with the severity of
renal involvement.621 Cranial neuropathies, particularly the
second, sixth, and seventh nerves, are involved in approximately
966 — PART IV CLINICAL APPLICATIONS
10% of cases as a result of extension of the nasal or paranasal
granulomas rather than vasculitis.963
Laboratory evaluation is remarkable for the presence of anti-
neutrophil antibodies directed against proteinase-3.621 The im-
munofluorescent staining pattern is diffuse within the
cytoplasm; thus the name c-ANCA. The specificity of c-ANCA
for Wegener’s granulomatosis is 98% and the sensitivity is 95%.
The vasculitis is similar to PAN, affecting medium-sized and
small blood vessels. Granulomatous infiltration of the respira-
tory tract and necrotizing glomerulonephritis also are seen. The
lack of peripheral eosinophilia and eosinophilic infiltrates on
biopsy and the absence of asthma help to distinguish Wegener’s
granulomatosis from CSS.
Microscopic Polyangiitis. The clinical symptoms of micro-
scopic polyangiitis (MPA) are similar to those of PAN, except
that the lungs are often involved.519,701,1173 Inflammation of pul-
monary capillaries leads to diffuse alveolar damage and intersti-
tial fibrosis. MPA is about one-third as common as PAN; the
average age at onset is 50 years. Polyneuropathy complicates
14–36% of cases.519,701,1173
Impaired renal function, as illustrated by increased BUN and
creatinine as well as hematuria, is evident in most patients.
Kidney biopsy reveals the presence of focal segmental thrombo-
sis and necrotizing glomerulonephritis. Extracapillary prolifera-
tion forms crescents in the majority of glomeruli. Hepatitis
serology is negative. Laboratory evaluation usually demon-
strates the presence of p-ANCA antibodies, although c-ANCA
antibodies occasionally can be detected. As the name implies,
microscopic polyangiitis affects small arterioles, venules, and
capillaries.519,701 Unlike PAN, there are few or no immune de-
posits on the blood vessels.
Behçet’s Syndrome. Behçet’s syndrome is characterized by
recurrent oral and genital ulcerations associated with inflamma-
tion of the eye.428,935,1280,1375 Additional manifestations include
arthritis, thrombophlebitis, skin lesions, and vasculitic lesions
involving the small to medium-sized arteries. The cause is un-
known. Men are believed to be affected more commonly than
women. The central nervous system is affected (brainstem
strokes, meningoencephalitis, psychosis) more frequently than
the peripheral nervous system. Either a mononeuropathy multi-
plex or generalized sensorimotor peripheral neuropathy may be
present.
Secondary Systemic Vasculitides
Vasculitis Associated with Connective Tissue Disease.
Peripheral neuropathy is a frequent complication in patients
with underlying connective tissue diseases; however, true vas-
culitis as the basis of the neuropathy is much less common.606,997
Secondary vasculitis associated with connective tissue disease
is most common in rheumatoid arthritis, followed by systemic
lupus erythematosus, Sjögren’s syndrome, and, less frequently,
systemic sclerosis. The clinical, histologic, and electrophysio-
logic features are similar to those of PAN. The different forms
of peripheral neuropathy associated with connective tissue dis-
orders are discussed in more detail in a subsequent section.
Infection-related Vasculitis. Vasculitis with peripheral ner-
vous systemic complications can result from a number of infec-
tious agents.452 The most common agents associated with
vasculitis of the PNS are viruses, including herpes varicella
zoster, cytomegalovirus (CMV), human immunodeficiency
virus (HIV), and hepatitis B and C. Mononeuropathy multiplex
related to HIV or CMV infection occurs in up to 3% of patients with
AIDS.145,1158 Hepatitis B and C can cause PAN, a medium-sized
systemic vasculitis, but also are associated with small-vessel
vasculitis related to cryoglobulinemia (discussed below). Lyme
disease caused by the spirochete, Borrelia burgdorferi, also is
associated with a variety of peripheral neuropathies, which can
caused by vasculitis. These disorders are discussed more fully
in the section, “Neuropathies Related to Infection.”
Malignancy-related Vasculitis. Various malignancies have
been associated with “vasculitis” of the peripheral nervous system.
The most common are small cell carcinoma of the lung (SCCL)
and lymphoma, but carcinoma of the kidneys, bile duct, prostate,
and stomach also have been described.639,809,845,985,990,1165,1307,1357,1443
However, most of the reported cases are not associated with
necrotizing vasculitis. Rather, transmural and perivascular in-
flammation of small blood vessels without necrosis is the most
common histopathologic feature.990 As noted previously, this is
a nonspecific abnormality. Of note, several cases of SCCL were
associated with anti-Hu antibodies. Patients with the paraneo-
plastic anti-Hu syndrome can present with symmetric or asym-
metric sensory loss, dysesthesias as well as motor weakness and
clinically and electrophysiologically may resemble patients
with true peripheral nervous system vasculitis.24 Lymphomas
can be complicated by nonvasculitic paraneoplastic neu-
ropathies.24 Furthermore, lymphomatous infiltration of the
nerves can cause multiple mononeuropathies or generalized
neuropathy. Nevertheless, rare cases of vasculitic neuropathy
have been reported in patients with cancer.
Drug-induced Hypersensitivity Vasculitis. In contrast to
systemic necrotizing vasculitis, hypersensitivity vasculitis sec-
ondary to drug reactions is a self-limited process.701 Never-
theless, short-term treatment with corticosteroids is often
necessary and useful. Cutaneous manifestations predominate
the clinical picture. Vasculitis of the CNS is much more
common with drugs of abuse (e.g., amphetamine, cocaine,
opioids), but the PNS occasionally is involved.161,1254 The patho-
genesis most likely relates to a complement-mediated leukocy-
toclastic reaction.701
Vasculitis Secondary to Essential Mixed Cryoglobulinemia.
Cryoglobulins are immunoglobulins that precipitate out of solu-
tion when exposed to a cool temperature but dissolve into solution
when warmed. Cryoglobulins are circulating immune complexes,
usually immunoglobulins directed against polyclonal im-
munoglobulins. There are three types of cryoglobulins. Type I cy-
roglobulins are composed of monoclonal immunoglobulins,
usually IgM, directed against polyclonal IgG. Type I cryoglobu-
lins most frequently occur in patients with plasma cell dyscrasias.
Type II cryoglobulins are composed of a combination of mono-
clonal IgM and polyclonal immunoglobulins directed against
polyclonal IgG. Type III cyoglobulins are a mixture of polyclonal
IgM, IgG, and IgA directed against polyclonal IgG. Type II and III
are the most common and are also called mixed cryoglobulinemia.
Mixed cryoglobulinemia can be associated with other diseases,
such as a lymphoproliferative disorders, connective tissue dis-
eases, and hepatitis B and C. Essential mixed cryoglobulinemia
(ECM) refers to situations in which mixed cryoglobulinemia is
found without a systemic disorder other than viral hepatitis.
Recent studies have revealed that most cases of EMC are associ-
ated with hepatitis C antigenemia. The incidence of peripheral
neuropathy in patients with various type of cryoglobulinemias
ranges from 25–90%.184,291,412,450,682,800,945,1125,1295,1327 Most patients
also demonstrate a painful, distal, symmetric polyneuropathy,
but a mononeuropathy multiplex pattern also may occur.
The neuropathy can result from ischemia due to hyperviscos-
ity or vasculitis related to immune-complex deposition in small

epineurial blood vessels. Electrophysiologic studies are simi-
lar to those in PAN. Sensory studies demonstrate an absence
or reduction in the SNAP amplitudes, affecting the lower limb
nerves to a greater degree than the upper limb nerves.184,291,412,
450,682,800,945,1295,1327 When present, conduction velocities are
mildly reduced; however, a few patients demonstrate signifi-
cant reductions in velocity. Motor studies reveal an absence or
significant reduction in the CMAP amplitude of the lower
limb nerves. One patient has been reported with evidence of
conduction block.800 In long-standing disease, the median and
ulnar nerves display similar findings. Nerve conduction stud-
ies show borderline normal or somewhat reduced conduction
velocities, with an occasional nerve having a conduction ve-
locity reduced to less than 70% of the lower limit of normal.
F-wave studies are abnormal in most patients at some time
during the course of the disease. Needle EMG examination
demonstrates fibrillation potentials and positive sharp waves
with a reduced number of voluntary MUAPs in the distal
upper and lower limb muscles.
Nonsystemic Vasculitis
Nonsystemic or Isolated PNS Vasculitis. Vasculitis iso-
lated to peripheral nerves accounts for 30–58% of vasculitic
neuropathy.292,358,563,697,955,1020,1125a,1159,1163 The clinical, electro-
physiologic, and histopathologic features of isolated peripheral
nerve vasculitis are quite similar to those of PAN, except that
other organ systems are not significantly involved. There can be
subclinical involvement of muscle, as apparent on muscle biop-
sies, but the clinical manifestations of the disease suggest pref-
erential involvement of the peripheral nerves. In fact, some have
suggested that vasculitis may be more likely to be evident on
peroneus brevis muscle biopsies than on a superficial peroneal
nerve biopsy,1159 although this has not been our experience.234
Patients can manifest with multiple mononeuropathies or a gen-
eralized symmetric sensorimotor polyneuropathy.
Laboratory testing may demonstrate elevated ESR or low
ANA titers. The vasculitis typically involves small and medium-
sized arteries of the epineurium and perineurium. Immune com-
plex deposition on these blood vessels can be appreciated. The
trigger for this rather selective vasculitis is not known. Matrix
metalloproteinases (MMP) are a family of endopepsidases with
overlapping substrate affinities for various extracellular matrix
proteins. MMP-2 and MMP-9 (gelatinase A and B) are upregu-
lated in the peripheral nerves in patients with nonsystemic vas-
culitis.778 T-cells are the predominant source of MMP-2 and
MMP-9, although stroma cells of the perineurium and en-
doneurium are an additional source. These MMPs are capable
of degrading components of the subendothelial basement mem-
brane, thereby allowing inflammatory cells to disrupt the blood-
nerve barrier and penetrate into peripheral nerves.
Of importance, the prognosis is considerably better than that
for systemic vasculitic disorders. Survival rates are similar to
age-matched controls. Furthermore, the neuropathy may be
more likely to respond to corticosteroids alone or to require a
shorter duration of cyclophosphamide.
Treatment of Vasculitic Neuropathy
Systemic vasculitis is treated intially with a combination of
corticosteroids and cyclophosphamide.169,517,519,560,701 Cortico-
steroids were used to treat systemic vasculitis in the 1950s, and
the 5-year survival rate increased from 10% to 55% by the mid-
to-late 1970s.519 The addition of cyclophosphamide to corticos-
teroids further increased the 5-year survival rate to over 80%.519
Chapter 23 ACQUIRED NEUROPATHIES — 967
Hypersensitivity vasculitis and isolated PNS vasculitis can be
treated with prednisone alone.
We generally initiate corticosteroid treatment with pulsed
methylprednisolone (1 gm intravenously every day for 3 days),
then switch to oral prednisone (1.5 mg/kg/day, up to 100
mg/day) as a single dose in the morning. After 2–4 weeks, we
switch to alternate-day prednisone (100 mg qod). Collateral
treatment includes calcium and vitamin D supplementation as
well as bisphosphonates to prevent and treat steroid-induced os-
teoporosis, as discussed in the section about chronic inflamma-
tory demyelinating polyneuropathy.
Cyclophosphamide is started at the same time as cortico-
steroids and can be given orally or in intravenous pulses. Oral
cyclophosphamide at a dose of 1.0–2.0 mg/kg is a more potent
suppressor of the immune system but is associated with more
adverse side effects (e.g., hemorrhagic cystitis) than intravenous
pulses. We prefer monthly intravenous pulses of cyclophos-
phamide at a dose of 500–1000 mg/m2 of body surface area.
Sodium 2-mercaptoethane sulfonate (mesna) is given to reduce
the incidence of bladder toxicity, and ondansetron is used to
diminish nausea. Patients should be vigorously hydrated to min-
imize bladder toxicity. After intravenous pulses of cyclophos-
phamide, the leukocyte count drops with a nadir after 7–18
days, during which time the risk of infection is greatest. We
check complete blood counts and urinalysis before each treat-
ment. Urinalysis is obtained every 3–6 months after treatment
because of the risk of future bladder cancer.
We continue with high-dose corticosteroids and cyclophos-
phamide treatment until the patient begins to improve or the
deficit at least stabilizes, usually within 4–6 months.
Subsequently, prednisone is gradually tapered by 5 mg every
2–3 weeks. Pulsed cyclophosphamide is generally continued for
at least 1 year. If patients do not respond to pulsed cyclophos-
phamide, oral dosing should be tried before concluding that the
patient failed cyclophosphamide treatment. Patients with CSS
often require continued low-doses of prednisone secondary to
associated asthma. Relapses are uncommon in PAN, MPA, and
isolated PNS vasculitis but occur in as many as 50% of cases of
Wegener’s granulomatosis.519,621 Such patients may require life-
long immunosuppressive therapy.
There is less experience with other immunosuppressive
agents in the treatment of vasculitis. In an open-label study of
low-dose methotrexate (0.15–0.3 mg/kg/week) in combination
with corticosteroids, marked improvement was noted in 76% of
patients with Wegener’s granulomatosis and remission occurred
in 69%.1239 Azathioprine, cyclosporine, tacrolimus, and chlo-
rambucil may be tried in refractory cases.169 Several prospective
but uncontrolled series have suggested that IVIG can be benefi-
cial in the treatment of systemic vasculitis.704,805 However, other
studies failed to demonstrated much improvement with
IVIG.1101
Patients with hepatitis B- or C-related PAN require special
treatment. Conventional treatment with high-dose cortico-
steroids and cyclophosphamide may allow the virus to persist
and replicate, thus increasing the risk of liver failure. Some sug-
gest using corticosteroids only during the first few weeks of
treatment to manage life-threatening manifestations of systemic
vasculitis.519 Afterward the corticosteroids are abruptly discon-
tinued. Plasma exchange and antiviral agents such as vidarabine
or α-interferon are used to control the course of the illness.
Using this protocol, the 7-year survival rate of hepatitis B-re-
lated PAN was 83%, HBeAG/HBeAB conversion rate was 51%,
and total viral clearance was seen in 24% of cases—a substantial
968 — PART IV CLINICAL APPLICATIONS
improvement from that seen with corticosteroids with or with-
out cyclophosphamide or plasma exchange.518
As noted above, hepatitis C has been implicated in most cases
of mixed cryoglobulinemia. Several studies have reported that α-
interferon (3 million units 3 times/week) is efficacious in treating
hepatitis C-related mixed cryoglobulinemia.62,122,175,294,317,343,455,682
As with PAN due to hepatitis B or C, a short course of corticos-
teroids may be required to control the initial manifestations of
systemic vasculitis. Plasma exchange may be beneficial in pa-
tients who continue to deteriorate on α-interferon.
NEUROPATHIES ASSOCIATED WITH AUTOIMMUNE
CONNECTIVE TISSUE DISEASES
Sjögren’s Syndrome
Clinical Features. The central feature of Sjögren’s syndrome
is the sicca complex, characterized clinically by xerophthalmia
(dry eyes), xerostomia (dry mouth), and occasional dryness of
other mucous membranes. There is a significant female predom-
inance, and onset is typically in middle adult life. The CNS man-
ifestations can mimic transverse myelitis or multiple sclerosis.
Peripheral neuropathy occurs in 10–50% of patients with
Sjögren’s syndrome.451,490,492,504,678,826,883,1125a,1336 Peripheral neu-
ropathy or neuronopathy can be the presenting feature of
Sjögren’s syndrome and may occur before any sicca symptoms.
Most patients have an axonal sensorimotor neuropathy char-
acterized by numbness and tingling in the distal portions of the
limbs.451,490,883 A burning sensation and paresthesias can also
occur. Muscle weakness may be present but is milder than the
sensory symptoms. Necrotizing vasculitis is uncommon in
Sjögren’s syndrome but may be responsible for as many as one-
third of the cases of neuropathy associated with the disorder.
Rarely, autonomic neuropathy is the primary manifestation.481a
A particularly interesting complication of Sjögren’s syndrome
is sensory neuronopathy or ganglionitis.39,451,490,492,504,546,758,1125a,1336
Patients develop progressive numbness and tingling of the
limbs, which may also involve the face. The onset can be acute
or insidious. Symptoms can involve the arms more than the legs,
and involvement can be quite asymmetric or even unilateral.
Physical examination demonstrates reduced sensation to all
modalities, especially position sense and vibration. A sensory
ataxia with pseudoathetosis is often evident. A positive
Romberg sign is noted in patients with lower limb involvement.
Sensation also may be diminished in the trigeminal nerve distri-
bution. Many patients have signs of autonomic insufficiency
with Adie’s pupils, anhidrosis, fixed tachycardia, and orthosta-
tic hypotension. Decreased or absent deep tendon reflexes are
seen. Muscle strength testing is usually normal, although the ex-
amination may reveal some “weakness” secondary to impaired
sensory modulation of motor activities.
Laboratory Features. Most patients with Sjögren’s syn-
drome have antinuclear, SS-A/Ro, and SS-B/La antibodies in
the serum. The CSF is usually normal. Schirmer’s test and
Rose-Bengal stain are useful for diagnosing keratocunjuctivitis.
The diagnosis is confirmed by demonstrating a lymphocytic in-
vasion of salivary glands on a biopsy of the parotid gland or
lips.650
Histopathology. Peripheral nerve biopsies in patients with
the more typical symptoms of sensorimotor polyneuropathy
demonstrate axonal degeneration and some degree of secondary
segmental demyelination.451,490,883 Rarely, necrotizing vasculitis
can be seen. Nonspecific perivascular inflammation involving
perineurial or endoneurial blood vessels is more commonly
seen. A decreased density of small unmyelinated fibers may
also be seen.
In patients with a sensory neuronopathy, biopsy of sensory
nerves reveals a reduction in the total number of myelinated
fibers, particularly those of larger caliber.451,490,504 Perivascular
lymphocytic (CD8 T-cells) inflammation of the endoneurial or
perineurial vessels also may be found.504 Biopsy of the dorsal
root ganglion has demonstrated lymphocytic (mainly CD8 T-
cells) infiltration and degeneration of cell bodies.504
Pathogenesis. The pathogenetic basis of the distal sensory or
sensorimotor polyneuropathy is unknown but is presumably au-
toimmune. Some cases may be caused by necrotizing vasculitis.
The sensory neuronopathy appears to be caused by an autoim-
mune attack directed against the sensory ganglia. The specific
antigen(s) and trigger of the autoimmune attack are not known.
Electrophysiologic Findings. In patients with the distal sen-
sorimotor form of peripheral neuropathy, there is marked abnor-
mality in the SNAPs as evidenced by a significant reduction in
amplitude and mild to moderate reductions in velocity.451,490,883
Some degree of abnormality in motor conduction can also be
detected with mild reductions in amplitude and slowing of con-
duction velocity. Distal latencies are not usually altered to a sig-
nificant degree. Needle EMG examination reveals some degree
of fibrillation potentials and positive sharp waves with MUAP
alterations suggestive of motor unit remodeling (i.e., increased
amplitude and duration with reduced recruitment).
In patients with sensory neuronopathy, nerve conduction stud-
ies also show preferential involvement of the SNAPs with signif-
icant reductions in amplitude or complete absence of the
response in both upper and lower limbs.39,451,490,504,546,758,826 In con-
trast to length-dependent axonopathies (e.g., the distal sensori-
motor neuropathy associated with Sjögren’s syndrome), the
upper limbs can be more severely affected than the lower limbs
in sensory neuronopathies. There can be asymmetric involve-
ment electrophysiologically. Motor conduction studies are mini-
mally affected, if at all. EMG is normal. If the trigeminal nerve
is affected, blink reflexes are also abnormal.52 In fact, an abnor-
mal blink reflex is more suggestive of a sensory neuropathy due
to Sjögrens syndrome as opposed to a paraneoplastic etiology.52
An important electrophysiologic feature that helps to distinguish
an axonal sensory neuropathy from a sensory neuronopathy or
ganglionopathy is the preservation of the masseter reflex or jaw
jerk in the latter.51 The masseter reflex is unique among the
stretch reflexes in that the cell bodies of the afferent limb lie in
the mesencephalic nucleus within the CNS. In contrast, sensory
cell bodies innervating the limbs reside in the dorsal root ganglia
of the PNS. Furthermore, the gasserian ganglion, which is re-
sponsible for conveying sensory nerves responsible for facial
sensation and the blink reflex, lies outside the CNS as well.
Treatment. There is no specific treatment for neuropathies
related to Sjögren’s syndrome. When vasculitis is suspected,
immunosuppressive agents may be beneficial. Unfortunately,
the sensory neuronopathy is poorly responsive to immunother-
apy. Once the cell body has degenerated, recovery is unlikely.
However, some investigators have suggested mild improvement
or at least some stabilization of function with various forms of
immunotherapy.39,504
Rheumatoid Arthritis
Rheumatoid arthritis (RA) affects approximately 1% of the pop-
ulation, and peripheral neuropathy is evident in at least one-half
of cases. Vasculitis is present in 8–25% of patients with RA,

making it the third most common cause of vasculitic neuropathy
after PAN and isolated PNS vasculitis.196,1052,1125a,1187,1247,1401
Vasculitic neuropathy develops in 40–50% of patients with
RA.1187,1401 The vasculitic neuropathy usually manifests 10–15
years after manifestations of other symptoms of RA, although
in rare patients the neuropathy is the presenting fea-
ture.495,1075,1187 Rheumatoid vasculitis can present with mononeu-
ropathy multiplex, overlapping mononeuropathy multiplex, or
generalized symmetric pattern of involvement. Laboratory ele-
vation is remarkable for the presence of antinuclear antibodies
(ANA), elevated ESR, and rheumatoid factor in the serum.
Electrophysiologic features are similar to those in other forms
of necrotizing vasculitis. As many as 75% of patients with RA
have clinical or electrophysiologic evidence of a mild sensory
neuropathy without definite necrotizing vasculitis on nerve
biopsies. Nerve histopathology in such cases reveals thickening
of the epineurial and endoneurial blood vessels as well as
perivascular inflammation. Some of these cases may be related
to a low-grade vasculitis that was missed on biopsy because of
sampling error. However, the mechanism may be related to
other undefined factors or toxic medications.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a common connec-
tive tissue disease with a prevalence in adults of 1 in 2000. The
diagnosis is based on the presence of multiple organ system in-
volvement and laboratory criteria.1286 Central nervous system
complications are more common, but peripheral neuropathies
also occur. Anywhere from 2–27% of patients with SLE clini-
cally develop a peripheral neuropathy.60,162,193,467,606,607a,863,878,997,
1125a,1178,1226,1430a Most patients manifest with slowly progressive
distal sensory loss. Many patients have a mild autonomic neu-
ropathy.1430a Large prospective series have reported electrophys-
iologic abnormalities in 24–56% of patients with SLE.607a,878,1226
Nerve conduction studies generally demonstrate a generalized,
primarily sensory axonopathy with absent or diminished SNAP
amplitudes. Mild reduction in CMAP amplitudes and a slight
slowing of motor conduction velocities also can be seen.
Endoneurial mononuclear inflammatory infiltrate and increased
expression of class II antigens within nerve fascicles and on en-
dothelial cells have been demonstrated on nerve biopsies in
some cases, suggesting an autoimmune pathogenesis.863
A few patients present with multiple mononeuropathies pre-
sumably secondary to necrotizing vasculitis.377,606,697 The longer
the disease progresses, the more likely the multiple mononeu-
ropathies are to fuse and overlap, creating an increasingly sym-
metric neuropathy. Electrophysiologic features are similar to
those with any form of necrotizing vasculitis.
Rare patients display a generalized sensorimotor polyneu-
ropathy quite similar to AIDP or CIDP.508,1090 Such patients can
have demyelinative features on nerve conduction studies and
nerve biopsies.
Immunosuppressive therapy is beneficial in SLE patients
with neuropathy related to vasculitis. Immunosuppressive
agents are less likely to be effective in patients with a general-
ized sensory or sensorimotor polyneuropathy without evidence
of vasculitis. Patients with an AIDP or CIDP-like neuropathy
should be treated accordingly (see sections on AIDP and
CIDP).
Systemic Sclerosis (Scleroderma)
Scleroderma manifests as progressive fibrosis of the skin, gas-
trointestinal tract, kidney, and lung.319,392,579,772,773,1290 Peripheral
Chapter 23 ACQUIRED NEUROPATHIES — 969
neuropathy occurs in 5–14% of patients and usually manifests
as a distal symmetric, mainly sensory polyneuropathy. The
pathogenic basis of the neuropathy is not known, but true vas-
culitis is quite rare, if it occurs at all. Cranial mononeuropathies
also can develop. The most commonly affected cranial nerve is
the trigeminal, as demonstrated by numbness, dysesthesias, and
electric shock-like or pricking/tingling sensations involving the
face. Occasional involvement of the seventh and ninth cranial
nerves also can occur. One investigation found a number of dif-
ferent disorders associated with involvement of the trigeminal
nerve: undifferentiated connective tissue disease (47%), mixed
connective tissue disease (26%), scleroderma (19%), rheuma-
toid arthritis (2%), Sjögren’s syndrome (2%), systemic lupus
erythematosus (2%), and dermatomyositis (1%).532
The CREST syndrome (calcinosis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly, and telangiectasis) is
considered a limited form of scleroderma. Multiple mononeu-
ropathies have been described in a small percentage (1–2%) of
patients with CREST syndrome. The clinical, electrophysio-
logic, and histologic features suggest a necrotizing vasculitis as
the cause of the neuropathy.366
Mixed Connective Tissue Disease
Mixed connective tissue disease (MCTD) represents an over-
lap syndrome of SLE, scleroderma, and polymyositis. There has
been no detailed study of neuropathy in patients with MCTD,
although one small study reported a mild distal axonal sensori-
motor polyneuropathy in 10% of patients.87
SARCOIDOSIS
Clinical Features. Sarcoidosis is a multisystem granulo-
matous disorder affecting the liver, spleen, mucous mem-
branes, parotid gland, muscle tissue, and central and
peripheral nervous system.307,707,850,1402,1407,1454 The cause is un-
known. Women are affected more commonly than men. The
clinical presentation of sarcoidosis is highly individualized
and ranges from an incidental observation on chest radi-
ographs with hilar adenopathy to profound functional incapac-
itation and death. Nonspecific constitutional symptoms of
fever, weight loss, and fatigue are the presenting complaints of
most patients. Hilar adenopathy is noted on chest radiographs
with transient erythematous subcutaneous nodules about the
pretibial region accompanied by arthralgias. Palpable periph-
eral lymph nodes may be noted. A common finding on presen-
tation is acute granulomatous uveitis, which can progress to
significant visual impairment or even blindness. Mucosal le-
sions of the nose and sinuses are common.
The peripheral or central nervous system is involved in about
5% of patients with sarcoidosis.307,707,850,1402,1407,1454 The most
commonly affected regions of the central nervous system are
the meninges, hypothalamus, and pituitary gland. The periph-
eral aspects of the nervous system frequently affected are the
cranial and peripheral nerves, especially about the nerve root
region. A common presentation is a mononeuropathy multiplex
pattern of remitting cranial nerve palsies. Essentially any cra-
nial nerve can be involved in the remitting and relapsing course
of the disease. The most commonly involved cranial nerve is the
seventh nerve, which can be affected bilaterally. The second and
eighth cranial nerves are also frequently affected.
Some patients may present with a clinical pattern quite simi-
lar to a radiculopathy of single or multiple nerve roots. With
generalized root involvement, patients may present with signs
970 — PART IV CLINICAL APPLICATIONS
and symptoms quite similar to AIDP or CIDP. The most
common involvement of the peripheral nervous system is a sub-
clinical mononeuropathy multiplex, which can be demonstrated
by electrodiagnostic medicine evaluation. Less commonly,
some patients present with symptoms and signs suggestive of a
slowly progressive primarily sensory, motor, or sensorimotor
peripheral neuropathy.
Histopathology. The major histopathologic finding is non-
caseating granulomas in various tissues. When the peripheral
nerves are affected, nerve biopsy can reveal profuse infiltration
of the nerve by multiple sarcoid tubercles, affecting all regions
of the supporting neural structures (endoneurium, perineurium,
and epineurium) associated with lymphocytic angiitis. There is
a combination of axonal loss and demyelination.
Pathogenesis. Sarcoidosis is an autoimmune disorder al-
though the cause and pathogenic mechanism are unclear.
Peripheral neuropathy may result from direct compression, is-
chemia, a combination of these two insults, or other ill-defined
factors. The cranial nerves and mononeuropathies of the periph-
eral nervous system are likely to result from direct neural inva-
sion and compression. The AIDP and CIDP-like neuropathies
may result from diffuse infiltration of nerve and nerve roots or
poorly defined immunologic compromise related to sarcoidosis
itself.
Electrophysiologic Findings. In patients with subclinical
neuropathy, the most common finding is an absence or reduction
in SNAP amplitudes in a mononeuropathy multiplex pattern.195
Such patients have normal motor conductions and CMAP ampli-
tudes. The needle EMG examination is also normal.
In patients with the symmetric sensorimotor peripheral neu-
ropathy, the SNAPs may be absent or reduced in ampli-
tude.446,941,981 Sensory nerve conduction velocities are mildly to
moderately slow but usual do not exceed more than 20% slow-
ing of the lower limit of normal. A few patients may have more
profound slowing, which indicates a demyelinating as opposed
to axonal component of nerve damage. Motor nerve conduction
studies also reveal reduced or absent CMAPs amplitudes in the
lower limbs with decreased or borderline normal CMAPs in the
upper limbs. The nerve conduction velocities are usually within
75–80% of the lower limit of normal. Patients with a
polyradiculopathy may have normal SNAPs but abnormal
CMAPs, as expected.707
Needle EMG examination in patients with long-standing dis-
ease and evidence of a clinical sensorimotor peripheral neuropa-
thy or polyradiculopathy is consistent with axonal loss lesions.
There are significant degrees of positive sharp waves and fibril-
lation potentials. MUAP duration, amplitude, and polyphasia
are increased, whereas recruitment is decreased.
Despite the frequent occurrence of cranial neuropathies, es-
pecially the facial nerve, there is a lack of information about
electrodiagnostic medicine evaluation of cranial nerves. One ex-
pects to see reduced facial nerve CMAPs amplitudes and some
degree of abnormal spontaneous activity on needle EMG. Blink
reflexes also may demonstrate either absence or amplitude re-
ductions in R1 and possibly R2.
Treatment. Patients with neurosarcoidosis, particularly of
the cranial nerves, may respond well to corticosteroid treat-
ment.707,980 If patients are resistant to corticosteroids, other im-
munosuppressive agents can be tried (e.g., cyclosporine). The
electrophysiologic abnormalities may resolve to various degrees
with treatment. Unfortunately, after cessation of treatment, pa-
tients appear to return to a propensity for developing compro-
mise of the nervous system.
IDIOPATHIC PERINEURITIS
Perineuritis is a nonspecific histologic abnormality with in-
flammation and thickening of the perineurium. Perineuritis can
be seen on nerve biopsies of patients with neuropathies associ-
ated with diabetes mellitus, connective tissue diseases, ulcera-
tive colitis, vasculitis (including cryoglobulinemia), and
lymphoma and other malignancies.190,394,714,1215,1251,1436 Peri-
neuritis also has been described in patients who fulfill clinical
and electrophysiologic criteria for AIDP or CIDP.190,955a,1251 In
these various conditions, perineuritis evident on biopsy does not
imply a distinct neuropathic disorder. However, there have been
several reports of patients without an underlying systemic disor-
der in whom perineuritis was the most prominent feature on
biopsy.42,849 Such cases with idiopathic perineuritis may repre-
sent a distinct neuropathic disorder.
Clinical Features. The clinical presentation is variable.
Patients with perineuritis related to diabetes or vasculitis de-
velop a mononeuropathy multiplex picture with sensory loss,
dysesthesias, hyperpathia, and weakness in the distribution of
multiple individual nerves. Other patients develop chronic, pro-
gressive, symmetric motor and sensory loss indistinguishable
from AIDP or CIDP. Finally, a subgroup of patients may have a
distinct neuropathy, which we term the idiopathic perineuritis
group. Wartenberg was the first to allude to this group of pa-
tients, who complain of migrating areas of sensory loss.1386 Pa-
tients described pain when the nerves where stretched.
Unfortunately, no histology was described in these cases.
Matthews reported a patient with “migratory sensory neuritis
of Wartenberg”; however, the nerve biopsy did not mention
features of perineuritis.848 Asbury et al. first coined the term
perineuritis in their detailed description of two patients who
developed pain and dysesthesias in the distribution of cutaneous
nerves, affecting mainly the distal upper and lower limbs.42 The
predominant histologic abnormality was inflammation confined
to the perineurium. Of note, the authors did not believe that their
patients had the sensory neuritis described by Wartenburg be-
cause of their less prominent pain. Other idiopathic cases have
been described with similar features.849,1251 The course can be
remitting and relapsing. Hypesthesia and hyperpathia are noted
on examination. A positive Tinel’s sign is often present over in-
volved nerves. Large-fiber sensory functions are typically less
affected than small-fiber modalities. Muscle strength is usually
preserved, but cases with generalized weakness, suggestive of
AIDP or CIDP, have been reported.190,1251 Deep tendon reflexes
are typically normal in patients with pure sensory symptoms.
Laboratory Features. Laboratory evaluation is usually
normal in patients with idiopathic perineuritis, including ANA,
ESR, liver function tests, serum protein electropheresis, and
vasculitic profile.42,849 In addition, CSF protein is usually normal
in patients with pure sensory symptoms. The presence of an ab-
normal laboratory work-up should lead to the consideration of
an underlying systemic disorder, such as vasculitis. Patients
who fulfill the clinical and electrophysiologic criteria for CIDP
typically have elevated CSF protein.190,1251 Likewise, elevated
CSF protein may be seen in diabetic patients with multiple
mononeuropathies or lumbosacral polyradiculoplexopathies.
Histopathology. The most prominent histologic abnormal-
ity is thickening and fibrosis of the perineurium.42,849,1251 Chronic
inflammatory cell infiltrates composed of lymphocytes and
macrophages should be confined to the perineurium. Mild perivas-
cular inflammation may be evident. Some investigators have re-
ported deposition of immunoglobulins in the epi-, peri, and

endoneurium190,955a; however, this subsequently was demon-
strated to be a nonspecific finding and can be seen in normal
controls. A loss of myelinated nerve fibers due to axonal degen-
eration may be seen. Perineuritis, thickened perineurium, and
the loss of nerve fibers can be asymmetric between and within
fascicles, suggesting a possible ischemic basis.
Pathogenenesis. Whether perineuritis is a distinct disorder
is debatable. The pathogenic basis is unknown but probably au-
toimmune. Perineuritis may cause damage via ischemia, impair-
ment of nutrient and toxin flow to and from nerve fibers in the
endoneurium, or direct humoral or cellular autoimmune attack
against the nerve fibers.
Electrophysiologic Findings. The major electrophysiologic
abnormality in idiopathic perineuritis is reduced or absent
SNAPs.42,849,955a Motor nerve conductions and EMG are normal
unless patients have mononeuropathy multiplex or radiculo-
plexopathy with motor and sensory involvement (as is the case
in patients with diabetes vasculitis or CIDP).190,1215,1251
Treatment. The small number of patients studied and the
retrospective nature of such reports limits conclusions about
treatment. Patients have variable responses to immunotherapy.
Patients with true vasculitis or CIDP should be treated with im-
munosuppression, IVIG, or PE. Prednisone appears to diminish
pain in patients with idiopathic pure sensory neuritis, although
this positive effect does not necessarily persist. Furthermore,
the natural history of the disorder may be one of remissions and
relapses. We have tried prednisone and IVIG in such idiopathic
cases with variable success but have not used more aggressive
immunosuppression (e.g., cyclophosphamide) in patients with
mainly sensory disturbances.
HYPEREOSINOPHILIC SYNDROME
Hypereosinophilic syndrome is characterized by eosino-
philia associated with various skin, cardiac, hematologic, and
neurologic abnormalities.223,331,914,1405 A vasculitic component
usually is not involved with this disease except for the skin.
The multiple organ dysfunction, including the peripheral ner-
vous system, is believed to result from the eosinophilia or some
byproducts of the eosinophils. A peripheral neuropathy may
occur in 6–14% of patients, manifesting as either generalized
peripheral neuropathy or mononeuropathy multiplex. Some pa-
tients have an associated inflammatory myopathy. Clinical and
electrophysiologic evidence clearly suggests that the disorder
is characterized by an axonal sensorimotor peripheral neuropa-
thy. The pathogenic basis for the neuropathy is not known but
may be autoimmune.
ISAACS’ SYNDROME
Isaacs’ syndrome (also know as neuromyotonia or syn-
drome of continuous muscle fiber activity) may be inherited,
but the sporadic form is more common. The disorder manifests
clinically by muscle twitching (myokymia) at rest, muscle stiff-
ness and cramps that are worse after activity, and excessive
sweating. The syndrome can occur with or without other signs
or symptoms of a peripheral neuropathy. The acquired disorder
may be associated with other autoimmune conditions (e.g.,
myasthenia gravis, CIDP), thymoma, and cancer (e.g., lym-
phoma, small cell carcinoma of the lung)—the latter perhaps on
a paraneoplastic basis. Some patients with the acquired form of
neuromyotonia have autoantibodies directed against the volt-
age-gated potassium channels of peripheral nerves. Mutations
Chapter 23 ACQUIRED NEUROPATHIES — 971
in potassium channels have been demonstrated in hereditary
episodic ataxia, in which patients also experience generalized
myokymia. The clinical and electrodiagnostic features as well
as the treatment of Isaacs’ syndrome are discussed in greater
detail in Chapter 16.
NEUROPATHIES ASSOCIATED
WITH INFECTIONS
LEPROSY (HANSEN’S DISEASE)
Clinical Features. The microorganism Mycobacterium
leprae (an acid-fast bacteria) causes leprosy. It is most commonly
found in Southeast Asia, Africa, South America, and Europe, but
it is endemic in certain areas of the United States (i.e., Hawaii,
Texas), and its prevalence may be increasing with the rise in HIV
infection. Three primary clinical manifestations of the disease are
commonly recognized: tuberculoid, lepromatous, and borderline
leprosy (Table 23-8).20,635,938,1111,1148 The host’s immunologic status
determines which form of the disease develops.
In tuberculoid leprosy, the cell-mediated immune response
is intact, leading to focal, circumscribed inflammatory lesions
involving the skin or nerves.20,906,938,1103 The skin lesions appear
as well-defined, scattered hypopigmented patches and plaques
with central anesthesia and raised, erythematous borders. The
organism has a predilection for the cooler regions of the body
(e.g., face, limbs) rather than warmer regions such as the groin
or axilla. The more superficial nerves in the vicinity of the skin
lesions also may be affected. In addition, there is a predilection
for involvement of specific nerve trunks, including the ulnar
nerve at the medial epicondyle, the median nerve at the distal
forearm, the peroneal nerve at the fibular head, the sural nerve,
the greater auricular nerve, and the superficial radial nerve at
the wrist.1390 These nerves can become encased within granulo-
mas, leading them to be thickened and easily palpable. The most
common neurologic manifestation of tuberculoid leprosy is
mononeuropathy or mononeuropathy multiplex.
In lepromatous leprosy, cell-mediated immunity is signifi-
cantly impaired, resulting in an extensive infiltration of the
bacilli process.20,906,938,1103 Clinical manifestations tend to be
more severe in the lepromatous subtype, but as in the tubercu-
loid form, cooler regions of the body are more susceptible. The
organisms multiply virtually unchecked and disseminate
hematogenously, producing confluent and symmetrical areas of
rash, anesthesia, and anhidrosis.336 Facial involvement fre-
quently causes madarosis (loss of eyebrows and eyelashes) and
deepening of the natural skin folds to produce the so-called
“leonine facies.” Typically, a slowly progressive symmetric sen-
sorimotor polyneuropathy develops over time. In early disease,
the superficial cutaneous nerves of the pinnae and distal limbs
are affected. Continued multiplication and infiltration of the or-
ganism into the epi-, peri-, and endoneurium result in the ap-
pearance of a progressive stocking-glove neuropathy. Distal
weakness ensues as the motor nerves become involved in the in-
filtrative process. Large sensory fiber modalities are relatively
spared, as are the muscle stretch reflexes. As with the tubercu-
loid subtype, nerve trunks can be affected with time, leading to
superimposed mononeuropathies. In advanced disease, facial
neuropathies can occur.
Patients with borderline leprosy have the highest incidence
of neurologic complications.20,906,938,1103 They can show clinical
and histologic features of both lepromatous and tuberculoid
972 — PART IV CLINICAL APPLICATIONS

Table 23-8. Clinical, Laboratory, Immunological, and Histopathological Features of Leprosy

Tuberculous Leprosy (TT)
Lepromin test Positive (> 5-mm induration)
Bacterial index 0 2–4
Morphologic index Low (down to 0)
Immunology Cell-mediated immunity: intact
Th1 > Th2 lymphocytes
Cytokines expressed: IL2, γ-IF
Skin lesions Few localized and well-demarcated
large skin lesions; erythematous
macules and plaques with
raised borders
Centers of lesions may be
hypopigmented
Histopathology Localized granulomas and giant
cells encompassed by dense
lymphocytic infiltrate extending
to epidermis
Fite stain: negative for bacteria
Neuropathies Mononeuropathy of superficial
cutaneous nerves or large
nerve trunks (i.e., ulnar, median,
peroneal nerves), multiple
mononeuropathies
Pure neuritic leprosy may be seen
Treatment* Dapsone: 100 mg/day
Rifampin: 600 mg/day
Duration: 12 months
* Treatment recommended by Hansen’s Disease Center, Carville LA.
Mid-Borderline Leprosy (BB)
Positive or negative (2–5-mm induration
Moderate
Cell-mediated immunity: unstable (can
range and switch from intact to
absent)
Size, number, and appearance of skin
lesions are intermediate between
those seen in TT and LL poles
Granulomas with epithelioid cells but
no giant cells
Not localized by zones of lymphocytes
Lymphocytes, if present, are diffusely
infiltrating
Fite stain: slight positive
Neuropathies can range in the spectrum
seen in TT to LL
As for LL
Lepromatous Leprosy (LL)
Negative (0–2-mm induration)
5–6
High (up to 10)
Cell-mediated immunity: absent
Th2 > Th1 lymphocytes
Cytokines expressed: IL4, 5, 10
Multiple, symmetric small macules
and papules; older lesions form
plaques and nodules
Scant lymphocytes, but if present
they are diffuse along with
organism-laden foamy macro-
phages
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

The features of the borderline tuberculoid (BT) form range between the TT and BB forms.The features of the borderline lepromatous (BL) form range between BB
and LL forms of leprosy.
From Altman D,Amato AA: Lepromatous neuropathy. J Clin Neuromusc Dis 1999;1:68–73, with permission.

forms of leprosy (Fig. 23-8). The impaired cellular immunity of
borderline patients results in mycobacterial spread but is still
active enough to generate an inflammatory response. The im-
munologic state is considered unstable in borderline patients in
that the immune response and clinical manifestations can shift up
and down the spectrum. Thus, patients can develop generalized
symmetric sensorimotor polyneuropathies, mononeuropathies,
and mononeuropathy multiplex, including multiple mononeu-
ropathies in atypical locations, such as the brachial plexus.
Rarely, patients with leprosy present with an isolated periph-
eral neuropathy without skin lesions.1111 Lepromatous neuropa-
thy should be suspected in patients without skin lesions who live
in endemic areas. Virtually all cases of pure neuritic leprosy have
the tuberculoid or borderline tuberculoid subtypes of the disease.
Diagnosis of leprosy has traditionally been made through
skin lesion biopsy with the Fite method of acid-fast bacilli stain-
ing.938 The morphologic index (MI), a ratio of viable to nonvi-
able organisms, has been used as a measure of treatment
efficacy. The MI, which is between one and ten at treatment
onset, often falls to zero within 3–4 months of successful ther-
apy. More recently, polymerase chain reaction and serum anti-
body testing have been used for diagnosis.
Histopathology. Histopathology depends on the host’s
immune response (see Table 23-8).635,938,1148 Histologically, the
tuberculoid form is characterized by granulomatous centers
formed by macrophages and Th1 cells, which are surrounded by
Th2 cells.906 Caseation may or may not be present, and typical
lesions extend throughout the dermis. Of note, bacilli cannot be
demonstrated. In the lepromatous form, the lesions demonstrate
large numbers of infiltrating bacilli, Th2 lymphocytes, and or-
ganism-laden, foamy macrophages with minimal granuloma-
tous infiltration. As the name suggests, patients with borderline
leprosy can have histologic features of both tuberculoid and lep-
romatous leprosy.
Pathogenesis. The clinical and pathologic spectrum of the
disease depends on the host’s immune response to M. leprae
and reflects the relative balance between Th 1 (helper) and Th2
(suppressor) T cells (see Table 23-8).20,906,938,1103,1148 Tuberculoid
leprosy and lepromatous leprosy represent the two extremes of
disease manifestation.20 In addition, three subtypes bridge these
polar extremes: the borderline tuberculoid, borderline, and bor-
derline lepromatous forms of the disease. The tuberculoid form
defines one end of the spectrum, in which the Th1 cells predom-
inate. The Th1 cells produce interleukin-2 and gamma inter-
feron, which in turn lead to activation of macrophages. On the
other extreme, the lepromatous form is dominated by Th2 cells,
which produce interleukins 4, 5, and 10, thereby downregulat-
ing cell-mediated immunity and inhibiting macrophages. The
 Chapter 23 ACQUIRED NEUROPATHIES — 973

borderline subtypes exhibit immune responses, spanning the

spectrum between the tuberculoid and lepromatous forms.
Electrophysiologic Findings. Sensory evaluations demon-
strate a whole spectrum of findings with a general impression
that SNAPs are usually absent in the lower limb, and reduced in
amplitude in the upper limb.20,642,700,1126,1246,1274 When the SNAPs
are present, the latencies are usually not significantly pro-
longed. The SNAP conduction velocities are moderately re-
duced but usually not less than 60% of normal. It is not unusual
for some patients to have a mononeuropathy multiplex pattern
of abnormal SNAP findings.
Motor nerve conduction velocities are usually reduced, with
the lower limbs slightly more affected than the upper limbs. The
reduction in velocity is usually 60–70% of the lower limit of
normal, but a few patients may demonstrate values less than 20
m/s in both upper and lower limbs.29,525,635,642,681,870,1126,1274,1349
Some patients may reveal a pattern of abnormality more consis-
tent with a mononeuropathy multiplex as opposed to diffuse pe-
ripheral nerve involvement. Within the upper limb, the proximal
segment may reveal slightly lower velocities than the forearm
segment. Some reports include a suggestion of conduction
block, but these notations are made only in passing; no criteria
are defined and no waveform traces provided. The CMAP may
be reduced in various nerves, approximating the mononeuropa-
thy multiplex pattern, whereas in other patients a generalized
lower worse than upper limb pattern is obvious. Distal motor la-
tencies are normal or only mildly prolonged. The phrenic and
facial nerves can be involved and electrophysiologic studies in
Figure 23-8. Borderline leprosy. A patient with borderline lep-
these nerves, when affected, are abnormal.287,870
rosy demonstrates numerous typical skin lesions on the trunk and
Needle EMG examination reveals mild to moderate degrees
limbs.The lesions have a depigmented center with raised erythema-
of positive sharp waves and fibrillation potentials, primarily in
tous borders.
the small muscles of the hand and feet as well as the ankle dor-
siflexors and evertors.58,287,652,1126,1190,1206 The MUAPs tend to be
reduced in number, firing at high rates with increased amplitude Prevention of leprosy is the ultimate goal and involves multi-
and durations as well as numbers of polyphasic potentials. ple strategies, starting with prompt diagnosis and treatment of
These findings are consistent with the pathologic observation of suspected cases, often with brief hospitalizations to ensure un-
mild to moderate degrees of axonal loss. derstanding and compliance with multidrug regimens.
Treatment. Multidrug therapy with dapsone, rifampin, and Chemoprophylaxis of childhood contacts with daily rifampin
clofazimine is presently the mainstay of treatment, although a for 6 months is currently recommended.20,938 Various vaccina-
number of other agents have recently demonstrated efficacy, in- tions are available, including BCG, killed leprae, and chemi-
cluding thalidomide, perfloxacin, ofloxacin, sparfloxacin, minocy- cally modified organism.
cline, and clarithromycin (see Table 23-8).20,906,938,1390 Treatment
typically requires two years of therapy to achieve full eradication LYME DISEASE
of the organism. A potential complication of therapy, particularly
in borderline leprosy, is the reversal reaction, which can occur at Clinical Features. The organism Borrelia burgdorferi, a
any time during treatment of the disease.20,938 The reversal reaction spirochete transmitted by ticks, is responsible Lyme disease
results from a shift to the tuberculoid end of the spectrum with an (named for the Connecticut town where it was first de-
increase in cellular immunity. Upregulation of the cellular re- tected).1010,1095 A hard-bodied tick known as Ixodes dammini
sponse is characterized by excessive release of tumor necrosis (deer tick) is responsible for the disease in most cases. This dis-
factor-alpha, gamma-interferon, and interleukin-2 with new gran- order is not localized to the continental United States but occurs
uloma formation. This can result in an exacerbation of the rash and world-wide. A tick acquires the spirochete by feeding on an in-
neuropathy as well as the appearance of new lesions. High-dose fected host animal and then transmits the spirochete to its next
corticosteroids appear to blunt this adverse reaction and may be host during feeding. Approximately 12–24 hours of tick attach-
used prophylactically in high-risk patients at treatment onset. ment is required to accomplish secondary host infection.
A second type of reaction to treatment is erythema nodosum Three stages of the disease are recognized: (1) early infection
leprosum (ENL), which occurs in patients at the lepromatous (erythema migrans: localized); (2) disseminated infection; and
pole of the disease.20,938 ENL is associated with the appearance (3) late-stage infection. Within one month after a bite from an
of multiple erythematous, sometimes painful, subcutaneous infected tick, an expanding erythematous circular region sur-
nodules; the neuropathy also may be exacerbated. ENL is due to rounding the original tick bite is noted. It then develops a some-
the slow degradation of antigens (bacterial debris), resulting in what variable appearance with a clear central region (erythema
antigen-antibody complex and complement deposition in af- migrans, also called bull’s eye) and resolves spontaneously by
fected tissue. ENL can be treated with corticosteroids or, if about one month. However, the erythema migrans is not noticed
available, thalidomide. by all patients. One or two weeks after the initial tick bite, systemic
974 — PART IV CLINICAL APPLICATIONS
symptoms of generalized fatigue, fever, chills, localized
adenopathy, headache, and painful neck motion can be ob-
served, thus defining the second stage of the illness. Additional
skin lesions may be detected about the body. The organism
spreads throughout the patient with a particular preponderance
for the skin, heart, nervous, and musculoskeletal systems. With
neurologic involvement, symptoms and signs of peripheral neu-
ropathy, radiculopathy, encephalitis and meningitis can be ob-
served.542–545,732,807,839,977,1010,1011,1094,1095,1175,1258,1325,1431 Pericarditis
and heart block can be detected with cardiac infection. During
the later portion of the second stage (weeks to years after the
first inoculation), knee, wrist, or shoulder attacks of inflamma-
tory arthritis become manifest. These symptoms may persist for
years, accompanied by overt fatigue in some patients. The third
stage is characterized by destructive joint changes due to the in-
flammatory changes in the synovium of affected joints, possibly
resulting in profound loss of function. A somewhat bluish dis-
coloration of the skin is located primarily on the distal limb re-
gions (acrodermatitis chronica atrophians), where active
spirochetes may be readily cultured.
With respect to peripheral nervous system manifestations, the
findings vary, depending on the stage of the disease. In stage 2
disease, cranial mononeuropathies can be documented. Facial
nerve dysfunction is believed to be the most commonly ob-
served disorder with respect to cranial neuropathies and can re-
semble Bell’s palsy, although it tends to be bilateral in about
one-half of cases (rare in idiopathic Bell’s palsy). Additional
cranial nerves can be affected but less frequently than the facial
nerve. Asymmetric polyradiculoneuropathies, plexopathies or
multiple mononeuropathies also can occur. Rarely, patients may
be misdiagnosed with AIDP. These symptoms eventually re-
solve with good return of function.
In stage 3, a distal glove-and-stocking distribution of al-
tered sensation and accompanying paresthesias can be noted
in roughly one-half of patients. Some patients experience
muscle weakness and cramps. Reductions in proprioception
and vibration are found in the feet as well as reduced deep
tendon reflexes.
Laboratory Features. Antibodies directed against the
spirochete can be measured using immunofluorescent or
enzyme-linked immunoabsorbent assay (ELISA). False-posi-
tive reactions are not uncommon. Therefore, Western blot
analysis is useful to confirm a positive ELISA.
Histopathology. Nerve biopsies can reveal perivascular in-
filtration of plasma cells and lymphocytes around small en-
doneurial, perineurial, and epineurial blood vessels without
clear necrotizing vasculitis. Axonal degeneration and secondary
demyelination can be seen. The spirochete has not been demon-
strated within the peripheral nerves themselves.
Pathogenesis. The pathogenic mechanism for Lyme neu-
ropathy is unknown. The neuropathy may result from an indi-
rect immunologic response and/or some form of vasculopathy.
Electrophysiologic Findings. The peripheral nerve mani-
festations of the disease, with different patients demonstrating
symptoms and signs that suggest a distal peripheral neuropathy,
mononeuropathy multiplex, painful polyradiculitis/plexitis, en-
trapment neuropathy (carpal tunnel syndrome), or AIDP pat-
tern, are rather diverse. These distinct patterns may be more
apparent than real. Careful neurophysiologic testing in a rela-
tively large group of patients with Lyme disease and the above
peripheral nervous system manifestations demonstrated not
only the preferential nerve dysfunction expected from the overt
clinical picture, but an underlying common electrophysiologic
thread.543,544 Specifically, most patients revealed evidence con-
sistent with a primarily axonal neuropathy.
In patients with an overt clinical presentation consistent with
mononeuropathy multiplex, for example, the electrophysiologic
findings are usually confirmatory of the preferential nerve in-
volvement suspected clinically; reduced CMAP and SNAP am-
plitudes as well as membrane instability suggest axonal
loss.542,544,693a,839,977,1011,1094,1175,1258,1325,1431 The same findings gen-
erally apply for all of the above disorders, even in patients who
present with preferential loss of seventh nerve function (i.e., re-
duced facial nerve CMAP, possibly prolonged distal motor la-
tency, and abnormal blink reflexes).732 However, in addition to
the confirmatory electrophysiologic evidence of a focal periph-
eral nerve lesion, all of these presentations have a number of ac-
companying findings, provided a careful search is made,
representative of the peripheral nervous system as a whole.
A reduction in both upper and in particular lower limb SNAP
amplitudes is found.543,544 Various nerves are preferentially in-
volved in different patients, but the sural nerve is typically af-
fected. A concomitant mild reduction in sensory nerve
conduction velocity is also detected. The tibial or peroneal nerve
may reveal reduced CMAP amplitudes with normal or border-
line distal motor latencies. F-wave latencies in the lower and oc-
casionally upper limb nerves (peroneal/tibial and median/ulnar)
are prolonged. Similarly, an absent or asymmetric tibial H-reflex
can be found. All of these findings indicate a patchy axonal neu-
ropathy in most patients with Lyme disease who present with
any form of neurologic complaint affecting the peripheral ner-
vous system.543,544 In patients with suspected Lyme disease, it is
important to examine the upper and lower limbs to document a
more widespread dysfunction of the peripheral nervous system
than may be suspected from the clinical presentation.
Rarely, a patient may present with symptoms and signs sug-
gesting a myopathy as opposed to neuropathy.1182 The nerve
conduction studies are essentially normal. Needle EMG exami-
nation demonstrates an alteration in MUAPs as characterized by
short-duration, small-amplitude potentials, with increased num-
bers firing rapidly at low levels of force.
Treatment. Adults with facial nerve palsies secondary to
Lyme disease are treated with amoxicillin, 500 mg PO QID,
plus probenecid, 500 mg q.i.d. for 2–4 weeks. If the patient is
allergic to penicillin, doxycycline, 100 mg PO b.i.d., should be
given for 2–4 weeks. Children less than 4 years of age can be
treated with amoxicllin, 20–40 mg/kg/day in 4 divided doses for
2–4 weeks. If allergic to penicillin, children can be treated with
erythromycin, 30 mg/kg/day in 4 divided doses for 2–4 weeks.
Adult patients with other types of peripheral neuropathy are
treated with intravenous (IV) penicillin, 20–24 million U/day
for 10–14 days, or ceftriaxone, 2 gm IV qd for 2–4 weeks.
Adults who are allergic to penicillin should receive doxycy-
cline, 100 mg PO b.i.d. for 30 days. Children with Lyme neu-
ropathy can receive IV penicillin G 250,000 U/kg/day in
divided doses for 10–14 days, or ceftriaxone, 50–80 mg/kg/day
IV for 2–4 weeks.
DIPHTHERITIC NEUROPATHY
Clinical Features. A neuropathy can arise in association
with the toxin produced by the organism Corynebacterium
diphtheriae.419,600,665,737,807a,923,1098,1248 After exposure to the organ-
ism, immunocompromised people usually demonstrate sys-
temic “flu-like” symptoms of generalized myalgias, lassitude,
headache, mild fever, and possible irritability within 1 week to

10 days of exposure. A whitish, membranous exudate may be
present in the throat region with or without cervical lymph node
involvement. In profound disease, autonomic disturbances of
heart rate and vascular tone may progress to cardiac arrhythmias
and eventual death. It is also possible for the organism to pro-
duce the above symptoms after entrance through a wound in the
body.
About 20–70% of patients develop a peripheral neuropathy.
By about the third or fourth week, patients may begin to com-
plain of difficulty in swallowing with a demonstrable reduction
in palatal sensation. Hoarseness or dysarthria, along with di-
aphragmatic weakness, may ensue. At the same time, patients
complain of blurred vision, particularly when looking at near ob-
jects. Pupils react to light but fail to accommodate. Additional
cranial nerves also may become involved. In patients with a less
fulminant form of the disease, a generalized peripheral neuropa-
thy may manifest 2 or 3 months after the initial infection. The
patient may note preferential loss of sensation in the distal as-
pects of the upper and lower limbs associated with paresthesias
and weakness in the same distribution. Physical examination re-
veals a reduction to all sensory modalities in the distal upper and
lower limbs. Manual muscle testing reveals reduced strength in
the hand intrinsics and ankle dorsiflexor/plantar flexor muscles.
Muscle weakness may progress over a period of weeks to the
degree that the patient is unable to ambulate independently.
Rarely, urethral and anal sphincters become compromised. Deep
tendon reflexes are diminished or absent throughout.
Laboratory Features. CSF protein can be elevated with or
without lymphocytic pleocytosis.255
Histopathology. The primary sites of pathologic reaction in
the nervous system are the dorsal root ganglia and the nearby
ventral nerve root and spinal nerve.419 However, the more distal
segments of the peripheral nerves are also affected. Segmental
demyelination is the major observation with relatively good
preservation of axons. Severely affected fibers are found in
close proximity to well-preserved nerve fibers. A small degree
of axonal loss and active degeneration also is noted.
Pathogenesis. The diphtheria toxin binds to Schwann cells
and inhibits synthesis of myelin proteins.1060 Demyelination is
believed to result from failure to replace myelin proteins during
normal metabolic turnover.
Electrophysiologic Findings. In most countries, the reduc-
tion of morbidity and mortality due to diphtheria occurred
before the development of sophisticated electrophysiologic
techniques. As a result, there is a paucity of information about
the electrodiagnostic medicine findings in patients with diph-
theria. Considerable information is available from animals, be-
cause diphtheria toxin is an excellent manner in which to study
demyelination experimentally.
In humans, the limited number of investigations have demon-
strated absent SNAPs.737 Motor nerve conduction studies reveal
about a 45% reduction in the mean nerve conduction velocity
expected for both upper and lower limbs.255,665,737,807a The distal
motor latencies are only mildly to moderately prolonged in
most cases. In a single patient, F-waves were attempted, but
they were absent in the median nerve. Nerve conduction studies
may be abnormal by 2 weeks after onset of symptoms sugges-
tive of a neuropathy, but the abnormalities tend to maximize by
5–8 weeks, after which there is a slow and steady recovery. In
most patients, the nerve conduction studies have normalized by
33 weeks after the initial clinical neurologic manifestations, but
they can persist for more than 1 year in patients with profound
weakness and muscle wasting. There is usually a disparity between
Chapter 23 ACQUIRED NEUROPATHIES — 975
the severity of nerve conduction studies and clinical presenta-
tion. Although nerve conduction studies worsen by 5–8 weeks,
the patient begins to demonstrate clinical recovery. Needle
EMG in only a few patients with muscle weakness and wasting
in the hand intrinsic muscles demonstrated fibrillation poten-
tials with a reduced MUAP recruitment pattern.
The above findings are certainly anticipated from the histo-
logic demonstration of primary demyelination with some
degree of axonal loss. In animal studies, a similar finding of re-
duced conduction velocities with prolongation of the distal
motor latencies is noted.600,923,959 Although not described in
humans, a considerable reduction in the CMAP amplitudes with
proximal stimulation has been demonstrated in animals. The
CMAPs not only are reduced in amplitude but also show signif-
icant temporal dispersion. This temporal dispersion is attributed
to segmental demyelination, with an asynchronous or differen-
tial slowing of neural conduction. This finding implies that
nerve conduction slowing is not uniform. The net result is an in-
crease in the temporal dispersion of arriving motor impulses
with the MUAP not summating temporally. There is a reduction
in amplitude for two reasons: (1) a spreading out of the electri-
cal activity associated with the motor units and hence not
adding up in time, and (2) increased phase cancellation with
positive and negative phases of motor units summating to cancel
each other. Additionally, there is also a suggestion that conduc-
tion block is likely across the demyelinated segment. Computer
models support the above assertions that temporal dispersion
and phase cancellation result in a reduction in CMAP ampli-
tude.708,1098 This is certainly likely, given the pathology; how-
ever, criteria have not been applied to animal studies, and this
finding has not been observed in humans.
Treatment. Antitoxin and antibiotics should be given within
48 hours of symptom onset to reduce the incidence and severity
of complications (i.e., cardiomyopathy). However, treatment
does not appear to alter the natural history of the associated pe-
ripheral neuropathy. Resolution of the symptoms may take sev-
eral months in severely affected patients.
HUMAN IMMUNODEFICIENCY VIRUS
At least 20% of patients with HIV develop some form of
polyneuropathy during the course of their illness.421,834,1024,1278
Six major types of peripheral neuropathy are associated with
HIV infection: (1) distal symmetric polyneuropathy (DSP), (2)
inflammatory demyelinating polyneuropathy (including both
AIDP and CIDP); (3) mononeuropathy multiplex (e.g., vas-
culitis, CMV-related); (4) progressive polyradiculopathy (usu-
ally CMV-related); (5) autonomic neuropathy; and (6) sensory
ganglionitis.75,244,250,278,306,438,539,764,857,1024
HIV-related Distal Symmetric Polyneuropathy
Clinical Features. DSP is perhaps the most common form
of peripheral neuropathy associated with HIV infection and
usually is seen in patients with AIDS.421,834,897,1221 Patients often
complain of numbness and painful paresthesias of the hands and
feet. Some patients are asymptomatic but are found to have di-
minished sensation to all modalities on examination. Atrophy
and mild weakness in foot intrinsic muscles may be noted. Hand
intrinsic strength is commonly well preserved until the disease
has progressed to affect more proximal leg muscles (i.e., rela-
tively late in the course of the disease). Deep tendon reflexes are
reduced at the ankles but are relatively preserved at the knees
and in the upper limbs.
976 — PART IV CLINICAL APPLICATIONS
Laboratory Features. CSF can reveal both increased pro-
tein and mild lymphocytic pleocytosis in patients with HIV in-
fection, regardless of the stage of the infection and the presence
or absence of peripheral neuropathy.77,837 Vitamin B12 deficiency
has been noted in some series,82,683 but other studies have sug-
gested that vitamin B12 metabolism does not play a significant
role in the neurologic complications of HIV infection.284,1110,1347
Histopathology. Autopsy studies and nerve biopsies have
demonstrated a reduction in the total number of both myelinated
and demyelinated axons due to axonal degeneration.61,211,435,
436,438,1085 A loss of cell bodies in the dorsal root ganglia can be
seen in addition to degeneration of the dorsal columns. Axonal
regeneration and secondary demyelination are more prominent
at the more proximal levels of the nerves. A small degree of
perivascular inflammation (mainly macrophages and T-cells)
can be observed, along with evidence of increased cytokine ex-
pression. Some degree of centrofascicular loss also can occur.
Skin biopsies may demonstrate a reduced density of small
myelinated nerve fibers in the epidermis.574
Pathogenesis. The pathogenic basis for DSP is unknown. It
is probably not due to actual infection of the peripheral nerves.
The neuropathy may be immune-mediated, perhaps caused by
the release of cytokines from surrounding macrophages. As
noted above, vitamin B12 deficiency may contribute to some
cases but is not a major cause of most cases. Various antiretrovi-
ral agents (e.g., dideoxycytidine, dideoxyinosine, stavudine) are
also neurotoxic and can cause a painful sensory neuropa-
thy.90,338,684 However, DSP can occur in patients not previously
exposed to antiretroviral agents.
Electrophysiologic Findings. The electrodiagnostic medi-
cine examination reveals evidence of a symmetric, axonal
polyneuropathy that affects sensory more than motor
nerves.61,212,338,421,436,570,762,1221,1237,1242,1278 Sural and superficial per-
oneal SNAP amplitudes are reduced with only mildly prolonged
latencies. The upper limb sensory studies are normal or only
mildly affected early in the course of AIDS. With disease pro-
gression, SNAPs in the lower limbs are no longer obtainable
with routine techniques, and there is a reduction in upper limb
SNAP amplitudes with a slight prolongation in the latency.
Table 23-9. Treatment of Painful Sensory Neuropathies
Therapy Route
First-line
Tricyclic antidepressants Oral
(e.g., amitriptyline,
nortriptyline)
Gabapentin Oral
Second-line
Carbamazepine Oral
Phenytoin Oral
Tramadol Oral
Third-line
Mexiletine Oral
Other agents
Lidocaine 2.5%/pylocaine Apply cutaneously
2.5% cream
Capsaicin 0.025–0.075% Apply cutaneously
cream
Motor nerve conduction velocities are usually not altered to a
great degree, but the CMAP amplitude may be reduced, espe-
cially when evaluated in the foot. Needle EMG examination can
reveal positive sharp waves and fibrillation potentials in the foot
intrinsic muscles that progress to the leg muscles. Occasionally,
the hand intrinsic muscles can demonstrate similar findings.
The MUAPs are reduced in numbers and recruitment with alter-
ations in morphology, suggesting motor unit remodeling (i.e.,
elevations in duration, amplitude, and phases).
Treatment. Antiretroviral agents have no demonstrable
affect on the course of DSP. Treatment is largely symptomatic
(Table 23-9). Neurontin may be beneficial in reducing the
painful symptoms.953,1323 However, a randomized trial of ami-
triptyline and mexiletine for painful neuropathy in HIV infec-
tion demonstrated no significant benefit.685
HIV-related Inflammatory Demyelinating
Polyradiculoneuropathy
Clinical Features. Patients with HIV infection can present
with symptoms and signs similar to those of AIDP and
CIDP.897,1222 AIDP can occur at the time of seroconversion,
whereas CIDP can occur at any point in the course of the infec-
tion but is more common in patient with AIDS.
Laboratory Features. A helpful feature in distinguishing
idiopathic AIDP or CIDP from HIV-related AIDP/CIDP is the
presence of pleocytosis in the CSF, along with elevated protein
levels.
Histopathology. The histologic features are identical to
those of AIDP and CIDP.211,242,895 There is no way to discrimi-
nate histologically idiopathic AIDP/CIDP from HIV-related
AIDP/CIDP.
Electrophysiologic Findings. The alterations noted for sen-
sory and motor fibers in idiopathic AIDP and CIDP are also op-
erational for cases associated with HIV infection.242,762,774,895,1074
Reduced motor and sensory conduction velocities are evident.
Conduction block and temporal dispersion can be seen. F-waves
are unobtainable or prolonged. The detailed discussions of the
electrophysiologic findings in idiopathic AIDP and CIDP
should be reviewed.
Dose Side Effects
10–100 mg qhs Cognitive changes, sedation, dry
eyes and mouth, urinary
retention, constipation
300–1200 mg tid Cognitive changes, sedation
200–400 mg q 6–8 hr Cognitive changes, dizziness,
leukopenia, liver dysfunction
200–400 mg qhs Cognitive changes, dizziness,
liver dysfunction
50 mg qid Cognitive changes, GI upset
200–300 mg tid Arrhythmias
qid
qid Painful burning skin

Treatment. Patients with HIV-associated AIDP or CIDP
can be treated with IVIG or plasmapheresis. 242,774,825 Pred-
nisone also can be effective, but we try to avoid steroids and
other second-line immunosuppressive agents in patients with
HIV-related CIDP because of the long-term implications of
immunosuppression.
HIV-related Progressive Polyradiculopathy
Clinical Features. Patients with advanced AIDS can de-
velop an acute, progressive lumbosacral polyradiculopathy sec-
ondary to cytomegalovirus (CMV) infection.897,898,1222 Patients
have severe numbness, pain, and weakness in the legs, which
usually are asymmetric. They also note a reduction in perineal
sensation with painful paresthesias. Incontinence of urine and
stool are common. Occasionally, the upper limbs and cranial
nerves become involved. Diminished or absent deep tendon re-
flexes in the legs can be found. Plantar responses are flexor.
Patients may have evidence of CMV infection in other parts of
the body (e.g., CMV retinitis)
Laboratory Features. CSF reveals an increased protein and
neutrophilic pleocytosis. CSF glucose concentration may be de-
creased. CMV can be cultured from the CSF, blood, and urine.
Histopathology. Biopsies of the ventral and dorsal root re-
gions demonstrate significant degrees of inflammatory infil-
trates associated with varying degrees of axonal loss. These
findings are most evident in the lumbar regions. Occasionally,
the cranial nerve root exit from the brainstem may be involved
with a minimal degree of adjacent myelitis. CMV inclusions
have been demonstrated in endothelial cells and macrophages
on nerve biopsy specimens.1132,1158
Pathogenesis. The polyradiculopathy is caused by the direct
infection of neurons by CMV.
Electrophysiologic Findings. The clinical presentation and
biopsy findings suggest the type of abnormalities anticipated on
electrodiagnostic medicine examination.279,898,1243 When the ven-
tral roots are affected, a progressive decline in the CMAP am-
plitudes is noted, coincident with the progressive loss of axons
and ensuing Wallerian degeneration. Concomitantly, needle
EMG examination reveals profuse fibrillation potentials and
positive sharp waves. There is a profound reduction in MUAPs
(reduced recruitment) with some muscles demonstrating a com-
plete absence of MUAPs. These abnormalities extend to essen-
tially all muscles in the lower limbs bilaterally. The conduction
velocities are normal until there is a complete absence of the
motor CMAPs or sensory SNAPs, confirming the primary
pathology as axonal loss with little demyelination. As expected
from the lesion location, F-waves are hard to obtain and laten-
cies can be prolonged. The above combination of findings is
quite distinct from findings in both CIDP and DSP and helps to
differentiate the various disorders.
Treatment. There may be a limited response to ganciclovir
or foscarnet in some patients.689,898,899 However, the prognosis in
most patients is poor; most patients with this complication die
within several weeks or months.
HIV-related Multiple Mononeuropathies
Clinical Features. Some patients with HIV infection, usu-
ally those with AIDS, develop multiple mononeurop-
athies.762,897,1222 They have weakness and reduced sensation and
paresthesias in a distribution suggestive of multiple peripheral
nerve involvement. Single or multiple cranial nerve dysfunction
also has been described. Examination is similar to that for other
causes of multiple mononeuropathies.
Chapter 23 ACQUIRED NEUROPATHIES — 977
Laboratory Features. An elevated CSF protein with some
degree of mononuclear cells is common.
Histopathology. Nerve biopsies can reveal perivascular in-
flammation or frank necrotizing vasculitis.1159 Axonal degenera-
tion is prominent, although secondary demyelination also may be
seen. In some cases, CMV inclusions were evident in endothelial
cells and macrophages on the nerve biopsy specimens.1132,1158
Pathogenesis. The pathogenic basis for this disorder is proba-
bly multifactorial. The neuropathy may be caused by deposition of
HIV antigen-antibody complexes in the walls of blood vessel.
Some cases may be related to vasculitis due to concomitant hepati-
tis B or C infection and antigenemia. In addition, CMV infection
probably plays a role in some cases of multiple mononeuropathy.
Electrophysiologic Findings. The electrodiagnostic medi-
cine findings are similar to those described with other forms of
multiple mononeuropathies caused by vasculitis.799,1160,1165 It is
not uncommon to find electrophysiologic evidence of a general-
ized symmetric distal polyneuropathy due to overlapping
mononeuropathies.
Treatment. It is difficult to draw firm conclusions about
treatment options, given the scarcity of relevant literature.
Patients with multiple mononeuropathies and hepatitis B or C
infection can be treated with plasma exchange, antiviral agents
(e.g., vidarabine), or α-interferon. Short courses of prednisone
and cyclophosphamide may be used. If CMV is suspected,
treatment with ganciclovir or foscarnet should be initiated.
HIV-related Autonomic Neuropathy
Clinical Features. Patients with HIV infection, usually those
with AIDS, also can develop an autonomic neuropathy, which
manifests as orthostatic hypotension, impaired sweating, diar-
rhea, impotence, and bladder dysfunction.228,254,429,798 The auto-
nomic neuropathy often occurs in patients who also have DSP.
Laboratory Features. There are no distinguishing labora-
tory features. As with any patient with HIV infection, the CSF
can reveal pleocytosis and increased protein.
Histopathology. There are no reports of histopathology data
in patients with autonomic neuropathy due to HIV infection.
Pathogenesis. The pathogenic basis for autonomic neuropa-
thy is unknown but probably multifactorial, as in DSP.
Electrophysiologic Findings. Most patients have the elec-
trodiagnostic features noted above for DSP. In addition, auto-
nomic function testing is usually abnormal.218,254
Treatment. Only symptomatic treatment of autonomic
problems is currently available.
HIV-related Sensory Neuronopathy/Ganglionopathy
Sensory ataxia due to ganglionitis is a rare complication of
HIV infection.278,372,1244 The clinical features are similar to those
of idiopathic sensory neuronopathy or ganglionopathy. The sen-
sory neuronopathy may be the presenting manifestation of HIV
infection. Autopsies have demonstrated degeneration of neurons
and inflammatory infiltration in the dorsal root ganglia, along
with the loss of myelinated nerve fibers in the peripheral
nerves.278 The pathogenic mechanism is not known. Because of
the rarity of the disorder, there are limited discussions of the
electrophysiologic features. However, one expects to find de-
creased amplitudes or absence of SNAPs.
HUMAN T-LYMPHOCYTE TYPE 1 INFECTION
HTLV-1 infection can cause a peripheral neuropathy, but the
most common manifestation is the tropical spastic paraparesis,
978 — PART IV CLINICAL APPLICATIONS
which is discussed in detail in Chapter 16. HTLV-1 infection
also can cause on inflammatory myopathy (discussed in Chap-
ter 28).
CYTOMEGALOVIRUS
CMV can cause an acute lumbosacral polyradiculopathy or
multiple mononeuropathies in patients with HIV infection, as
discussed above.
EPSTEIN-BARR VIRUS
EBV has been implicated as causing some cases of AIDP, cra-
nial neuropathies, mononeuropathy multiplex, brachial plexopathy,
lumbosacral radiculoplexopathy, and sensory neuronopathies.1138
HEPATITIS VIRUSES
Hepatitis B and C can cause multiple mononeuropathies,
AIDP, or CIDP.
HERPES VARICELLA ZOSTER VIRUS
Clinical Features. Herpes varicella zoster (HVZ) infection
can result from reactivation of latent virus or from primary infec-
tion. Primary acquired HVZ infection is frequently associated
with severe disseminated zoster in immunocompromised pa-
tients. The incidence of HVZ infection is approximately 480 per-
sons per 100,000 population.70 The peak age of developing the
disease is between 55 and 75 years of age. Two-thirds of infec-
tions are manifested by dermal zoster.24 Pain and paresthesias in
the dermatome region may precede the vesicular rash by 1 week
or more. Initially, the vesicular skin lesions are clear but form a
crusty mass by 2 weeks and heal with dermal scar formation. A
variable degree of pain is associated with the skin lesion; how-
ever, roughly 25% of affected patients have significant residual
pain, called postherpetic pain, which can be quite disabling.24
This complication is more common in older patients. In a large
series of patients, approximately 50% experienced the eruption
in the thoracic region (T1–T12) with an equal number develop-
ing skin lesions in the first division of the trigeminal (18%) and
L2–S4 aspects of the lumbosacral (18%) regions.1296 Cervical
(C2–C8) eruptions are the least frequently encountered.
Of note is the rarely appreciated possibility of developing
concomitant involvement of the associated motor nerves. From
5–30% of patients with typical cutaneous herpes zoster can de-
velop some form of motor weakness that affects the myotomal
muscles corresponding to the dermatomal distribution of skin
lesions.497,524,904,1296 The weakness usually develops within the
first 2 weeks of the skin eruption but can vary between several
hours to 1 month. The most commonly affected region of pare-
sis involves the cranial nerves; the facial nerve (herpes zoster
oticus, Ramsay-Hunt syndrome) has the highest likelihood of
being affected. Cervical and lumbosacral myotomal regions are
equally likely (26% each) to be affected. Thoracic weakness is
difficult to determine and most likely accounts for only 3% of
patients with motor paresis. Cervical weakness, particularly
with upper myotomal involvement, may be associated with
phrenic nerve dysfunction. Rarely, patients with a typical skin
eruption develop AIDP.298,1166 Additional neurologic manifesta-
tions of herpes zoster infection include encephalitis and stroke.
Physical examination reveals the expected loss of sensation
and hyperpathia in the dermatomal distribution of the disease.
With motor paresis, a loss of strength is noted in the corre-
sponding myotomal distribution. Decreased or absent deep
tendon reflexes are also expected in the appropriate regions.
Unilateral phrenic nerve involvement can lead to hemidiaphrag-
matic paralysis.346,1034 Herpes zoster oticus begins with vesicular
eruption in the ear canal, and secondary facial paralysis can
appear to be Bell’s palsy if ear lesions are missed. When the
thoracic myotomes are involved, protrusion of the abdominal
wall can suggest an abdominal wall hernia.460,483 Fortunately, the
prognosis for most patients with any type of focal motor in-
volvement is relatively good.521
Laboratory Features. CSF may demonstrate a mild to
moderate protein elevation with variable pleocytosis. The virus
is difficult to culture from the CSF, but polymerase chain reac-
tion can be used to confirm the presence of the virus in the CSF.
Histopathology. The basic pathologic neural reaction is
axonal degeneration with some degree of secondary segmental
demyelination. With respect to the sensory system, severe infec-
tions can result in the destruction of dorsal root ganglion cells
with secondary loss of posterior column fibers.
Pathogenesis. After initial infection, HZV migrates up the
sensory nerves and resides in the sensory ganglia, where it ap-
pears to be insulated from the host’s immune defense mecha-
nisms.70 After a reduction in the immune system’s capacity, the
virus can be reactivated with the above symptoms. HZV travels
down the sensory nerves and results in the typical skin lesions.
Motor paresis is postulated to develop when the virus causes
local neuritis in the spinal nerve and subsequently gains access
to the motor axons.
Electrophysiologic Findings. When regions of the body are
affected with available peripheral nerves amenable to SNAP
measurements, the potentials’ amplitudes may be reduced or, in
severe disease, completely absent.448,1128,1149 SNAP distal sen-
sory latencies and conduction velocities are only mildly af-
fected, if at all. Of course, when the thoracic dermatomes are
involved, it is not possible to evaluate a corresponding SNAP.
However, it is possible to use somatosensory evoked potential
techniques to evaluate more fully the extent of the intercostal
nerve involvement as subclinical regions amenable to neural
blockade may also be detected.
Motor nerves affected by the infection demonstrate reduced
CMAP amplitudes, which at times can be clearly abnormal or
reduced toward the lower limits of normal.448,524,904,1149 Nerve
conduction velocities may be mildly reduced and distal motor
latencies little affected, as anticipated for a primarily axonal
insult.
The needle EMG examination demonstrates a reduction in
the number of voluntary MUAPs in the affected my-
otome.448,489,526,904,1149,1296,1399 After the appropriate period, vari-
able degrees of positive sharp waves and fibrillation potentials
can be observed, depending on the extent of axonal loss in the
examined muscle. Examination of the paraspinal regions also
demonstrates membrane instability, confirming the impression
that the lesion is at least as proximal as the spinal root level (i.e.,
proximal to the bifurcation of the spinal nerve into the ventral
and posterior primary rami).
The findings of relatively preserved nerve conductions and
evoked response latencies apply equally, no matter what aspect
of the peripheral nervous system is affected. For example, if the
facial nerve is involved, a reduced CMAP from a facial muscle,
little change in distal motor latency, reduced recruitment of
MUAPs, and fibrillation potentials/positive sharp waves may be
observed.673 The same findings can occur if the virus damages a

nerve root supplying the upper or lower limb. If a patient devel-
ops 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 sever-
ity of acute pain of herpes zoster, but neither acyclovir alone nor
acyclovir in combination with corticosteroids reduces the fre-
quency 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, al-
though none is uniformly successful. Neurontin has been noted to
be effective in postherpetic neuralgia.1193 A number of placebo-
controlled studies have demonstrated that tricyclic antidepres-
sants reduce the pain in many patients.855 Carbamazepine can be
helpful in some patients who have intermittent lancinating as op-
posed to constant burning pain.1109 Topical capsaicin ointment,
applied 3 or 4 times daily for 2–4 weeks, is of benefit to some pa-
tients.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
NEUROPATHIES ASSOCIATED
WITH ENDOCRINOPATHIES
DIABETES MELLITUS
Diabetes mellitus (DM) is the most common metabolic dis-
ease 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 mel-
litus (NIDDM or type 2 DM). Several distinct types of periph-
eral neuropathy are associated with DM, including distal
symmetric sensory or sensorimotor polyneuropathy, autonomic
neuropathy, diabetic neuropathic cachexia, polyradiculoneu-
ropathies, 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 neuropa-
thy 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%; asymp-
tomatic 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 cuta-
neous neuropathy, diabetic amyotrophy), 3%. In patients with
type 2 DM, the following percentages had neuropathy: general-
ized polyneuropathy, 45%; asymptomatic carpal tunnel syn-
drome, 29%; symptomatic carpal tunnel syndrome, 6%;
autonomic neuropathy, 5%; and other mononeuropathies/multi-
ple 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
Chapter 23 ACQUIRED NEUROPATHIES — 979
Table 23-10. Diabetic Neuropathies
1. Distal symmetric sensory or sensorimotor polyneuropathy
2. Autonomic neuropathy
3. Diabetic neuropathic cachexia
4. Diabetic polyradiculoneuropathy
• Asymmetric, painful lumbosacral radiculoplexopathy (Bruns-
Garland syndrome, diabetic amyotrophy)
• Symmetric, relatively painless, polyradiculopathy (may resemble
or be a variant of chronic inflammatory demyelinating polyradicu-
loneuropathy—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 medi-
cine findings in individual types of peripheral neuropathy.573
Distal Symmetric Sensory
or Sensorimotor Polyneuropathy
Clinical Features. The most common form of diabetic neu-
ropathy 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-and-
stocking 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, signifi-
cant weakness is uncommon. Even in patients without motor
symptoms or signs on clinical examination, there is often elec-
trophysiologic evidence of subclinical motor involvement (see
below). Thus, the term distal symmetric sensorimotor periph-
eral 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 nephropa-
thy.362,1032 Nevertheless, DSPN can be the presenting manifesta-
tion of DM.
Histopathology. Nerve biopsies demonstrate axonal degen-
eration and segmental demyelination.352,356,1303 The axonal de-
generation is more pronounced distally, as expected in a
length-dependent process. An asymmetric loss of axons be-
tween and within nerve fascicles can sometimes be appreciated.
Clusters of small regenerated axons also can be appreciated.
Microangiopathy is evident as well, with endothelial hyperpla-
sia of epineurial and endoneurial arterioles and capillaries along
with redundant basement membranes around small blood ves-
sels. In addition, inflammatory cells sometimes can be appreciated
980 — PART IV CLINICAL APPLICATIONS
on nerve biopsies of patients with DSPN.245,1444 These perivas-
cular inflammatory cells consist predominantly of CD8+ T-cells.
Skin biopsies demonstrate a reduction of small myelinated epi-
dermal 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 myo-
inositol are similar in structure, and hyperglycemia may reduce
myoinositol uptake into peripheral nerves. Streptomycin-in-
duced 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 myo-
inositol.498 Myoinositol depletion may alter the function of
Na+/K+ ATPase or cause axon damage by some other mecha-
nism. 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 metabo-
lism.458 Hyperglycemia activates the enzyme aldose reductase,
which in turn causes the accumulation of sorbitol in nerves.
Sorbitol is relatively impermeable and hypertonic, thereby lead-
ing 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 demon-
strated that various aldose reductase inhibitors prevent or signif-
icantly alter the progression of DSPN.499,1053
Hyperglycemia also may cause glycosylation of neuronal
proteins, which may alter the functions of tubulin and neurofila-
ments.1365 This may lead to abnormal axonal transport.
Perturbations in lipid metabolism associated with chronic hy-
perglycemia 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 ap-
pearance of a generalized symmetric polyneuropathy.
Immunologic/Inflammatory Hypothesis. The presence of in-
flammatory 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 pa-
tients 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% demon-
strate reduced SNAP amplitudes and conduction velocities, and
up to 80% of symptomatic patients have such sensory conduc-
tion abnormalities. As expected, the abnormalities are first de-
tected in the distal lower limbs (i.e., sural and plantar
nerves).226,787,1093 The sensory alterations are noted prior to sig-
nificant 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 pro-
longation 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 cen-
tral conduction times of brainstem and somatosensory path-
ways.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 se-
verely 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, particu-
larly 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 seg-
mental demyelination in diabetic patients, conduction block
and/or temporal dispersion occurs in only 10% or less of pa-
tients with DSPN.2,1322 F-waves studies have revealed that
motor nerve slowing is rather diffuse; the proximal nerve seg-
ments are slowed but not to as great a degree as the distal por-
tions of the nerves.413,693,936 The standard F-wave parameters of
minimal latency and chronodispersion are among the most sen-
sitive 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 electrodiagnos-
tic evaluations to reveal peripheral nerve abnormalities in pa-
tients 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-stand-
ing 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 in-
creased 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 mea-
sures, nerve conduction studies, or quantitative sensory test-
ing.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, an-
tidepressants, 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 antide-
pressant medications help to reduce the pain.854 The side effect

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 ap-
pears safe and effective and may have an additive benefit when
given with gabapentin (anecdotal experience). The average ef-
fective 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 typi-
cally is seen in combination with DSPN. Patients develop ab-
normal 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 ejacula-
tion, incontinence).
Histopathology. Appenzellar and Richardson noted en-
larged sympathetic neurons containing PAS-positive material.34
Others have demonstrated degeneration of sympathetic and
parasympathetic neurons and inflammatory infiltrates in auto-
nomic ganglia.339,817 In addition, segmental demyelination has
been appreciated on teased fiber studies.
Pathogenesis. The pathogenic basis for autonomic neuropa-
thy 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 auto-
nomic function are generally abnormal, including sympathetic
skin responses and QSART.229,366,687,1044,1391 To evaluate impo-
tence or incontinence, one can perform nerve conduction stud-
ies 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, how-
ever, treatment of autonomic neuropathy is largely sympto-
matic.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 gastropare-
sis, 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 end-
organ 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 pre-
sent with an abrupt onset of severe generalized painful paresthe-
sias 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
Chapter 23 ACQUIRED NEUROPATHIES — 981
loss is generally mild. Deep tendon reflexes are usually sym-
metrically decreased. Some patients have weakness and atro-
phy, perhaps related to profound weight loss, whereas in others
muscle strength testing is normal. The neuropathy tends to im-
prove spontaneously, usually within 2 years. Weight gain typi-
cally precedes resolution of painful dysesthesias. Rarely, DNC
can recur.617
Laboratory Features. CSF protein is increased in some pa-
tients with DNC.
Histopathology. There are only a few reports of nerve his-
tology in patients with DNC. Sural nerve biopsies in a few pa-
tients demonstrated severe loss of large myelinated nerve fibers
due to axonal degeneration.38,617 Small myelinated and unmyeli-
nated 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 ve-
locities also can be observed. The limited reports of needle
EMG studies have been normal.617
Treatment. As noted above, the neuropathy usually im-
proves 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 cate-
gories 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 polyradicu-
loneuropathy 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 polyradiculoneu-
ropathy (also known as diabetic amyotrophy, Burns-Garland syn-
drome, 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 ap-
proximately 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 pares-
thesia. 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 un-
common 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 in-
volvement is generally asymmetric. As with DNC, the poly-
radiculoneuropathy is often heralded by severe weight loss. The
neuropathy progresses gradually or in a stepwise fashion, usu-
ally over several weeks or months, but cases of worsening over
982 — PART IV CLINICAL APPLICATIONS
18 months have been documented.74 There is an erroneous mis-
conception that only proximal muscles are affected. However,
examination reveals weakness of both proximal and distal lower
limb muscles.74 A mild stocking-glove sensory loss secondary
to superimposed DSPN is sometimes noted. Deep tendon re-
flexes are reduced in the affected leg. Eventually the disorder
stabilizes and slow recovery ensues. In many cases, however,
residual weakness is significant.
Thoracic mono- or polyradiculopathies also can present
with or without involvement of the lumbosacral roots/
plexus.375,810,1026,1260,1273,1392 The pain can radiate from the postero-
lateral chest wall anteriorly to the abdominal region with associ-
ated loss of sensation anterolaterally. On rare occasions, it is
possible to observe abdominal wall protrusion secondary to
muscle weakness. Although even less common, some patients de-
velop weakness in the upper limbs,1033 perhaps due to a superim-
posed cervical polyradiculoneuropathy/brachial plexopathy.
Laboratory Features. CSF protein concentration usually is
elevated, but cell count is normal. Erythrocyte sedimentation
rates may be increased. MRI scans of the lumbosacral roots and
plexus can reveal inflammatory changes.74,999
Histopathology. Sural, superficial peroneal, and lateral
femoral cutaneous nerve biopsies reveal a loss of myelinated
nerve fibers, which is often asymmetric between and within
nerve fascicles.74,368,729,1033,1161,1162,1444 Active axonal degeneration
and clusters of small, thinly myelinated, regenerating fibers can
be seen. Mild perivascular inflammation of epineurial and per-
ineurial blood vessels have been noted on some nerve biopsies.
Findings suggesting microvasculitis have been described in lat-
eral femoral cutaneous, superficial peroneal, and sural nerve
biopsies.368,1033 A polymorphonuclear small-vessel vasculitis as-
sociated with IgM and complement deposition on affected
epineurial vessels has also been reported.665a
Pathogenesis. The histopathology and presumed response to
immunomodulating therapies has led some to suggest an
immune-mediated microangiopathy as the basis for diabetic amy-
otrophy.665a,729,1444 This may be the case, but much more informa-
tion is needed. The histologic abnormalities are not specific for
vasculitis or ischemia. Most biopsy specimens do not demon-
strate frank vasculitis. Mild perivasuclar inflammation, which is a
nonspecific abnormality, is more common. Asymmetric loss of
axons between and within fibers certainly is seen with ischemic
neuropathies, but it is not specific for vasculitis. The fact that pa-
tients with diabetic amyotrophy may improve with various forms
of immunotherapy (see below) also does not prove that the patho-
genic basis for the neuropathy is immunologic. Remember that
the natural history of the disorder is spontaneous improvement.
Patients with “vasculitis” on lateral femoral cutaneous nerve
biopsies became pain-free and began to improve in strength after
the biopsies without the addition of immunotherapy.1033 Such
spontaneous improvement is not the natural history of other
forms of “true” vasculitis. More studies are necessary to unravel
the pathogenic nature of diabetic amyotrophy.
Electrophysiologic Findings. In patients with underlying
DSPN, electrophysiologic features of a generalized axonal
sensorimotor polyneuropathy, as described above, are evi-
dent. The nerve conduction studies and EMG of diabetic
amyotrophy reflect multifocal axonal damage to the roots and
plexus.43,74,177,215,217,627,688,1033,1263,1267,1272,1415 As expected, SNAPs
are absent or low in amplitude. When obtainable, the distal la-
tencies of the SNAPs are normal or slightly prolonged.
Likewise, CMAPs are diminished in amplitude in affected mus-
cles, whereas distal latencies are normal or slightly prolonged.
F-waves are unattainable or slightly increased in latency.
Conduction velocities in the affected limbs are normal or mildly
slow. Autonomic studies usually reveal abnormal sudomotor,
cardiovagal, and adrenergic functions.627,1033
Needle EMG demonstrates positive sharp waves and fibrilla-
tion potentials in proximal and distal muscles in the affected
limbs and paraspinal muscles.43,74,177,215,217,627,688,1033,1263,1267,1272,1415
Recruitment of MUAPs is reduced in weak muscle groups. As
reinnervation occurs over time, large-amplitude, long-duration,
polyphasic MUAPs can be appreciated.
Treatment. Small retrospective studies have reported that
IVIG, prednisone, and other forms of immunosuppressive ther-
apy are effective in patients with diabetic amyotrophy.138,627,729,1444
Anecdotally, we have been impressed that short courses of corti-
costeroids can help to ease the pain associated with severe
polyradiculoneuropathy. This may allow patients to undergo
physical therapy. However, as noted above, the natural history of
this neuropathy is gradual improvement so the actual effect, if
any, of these immunotherapies on the polyradiculoneuropathy is
not known. Prospective, double-blinded, placebo-controlled trials
are necessary to define the role of various immunotherapies.
Symmetric, Painless, Diabetic Polyradiculoneuropathy
Clinical Features. This second major group of diabetic
polyradiculoneuropathy presents with a progressive, relatively
painless, symmetric proximal and distal weakness evolving over
weeks to months.24a,241,479,627,729,1033,1106,1261,1322 This form of poly-
radiculoneruopathy resembles idiopathic CIDP. In fact, it is con-
troversial whether this neuropathy represents the coincidental
occurrence of CIDP in a patient with DM or is a distinct form of
diabetic neuropathy. Some have suggested an increased risk of
CIDP in diabetics. This type of polyradiculoneuropathy occurs in
both type I and type II DM but may be more common in the latter.
Weakness is most prominent distally and in the lower limbs;
however, proximal leg and upper limb muscles also are affected.
In addition, the arms are generally affected, particularly the
distal muscles. In contrast to classic diabetic amyotrophy, pa-
tients with this form of diabetic polyradiculopathy do not usu-
ally have severe back and proximal leg pain and the motor
weakness is relatively symmetric. However, distal dysesthesias,
perhaps secondary to a superimposed DSPN, are occasionally
present. A stocking-glove sensory loss to all modalities can be
demonstrated along with reduced deep tendon reflexes. Most
patients gradually improve over time regardless of treatment.
Laboratory Features. As with idiopathic CIDP, CSF pro-
tein concentration usually is increased.
Histopathology. Sural nerve biopsies have demonstrated a
loss of large and small myelinated nerve fibers, which can be
asymmetric.479,627,729,1033,1261,1322 Axonal degeneration and clusters
of small regenerating fibers are seen. Occasionally, demyeli-
nated fibers and onion-bulb formations are evident. In addition,
scant perivascular mononuclear inflammatory cells may be
demonstrated in the perineurium and epineurium. Nevertheless,
these nerve biopsy abnormalities are not specific for symmetric
diabetic polyradiculopathy or CIDP; similar findings can be
seen in DSPN and diabetic amyotrophy.
Pathogenesis. The pathogenic basis for this form of
polyradiculoneuropathy is quite controversial.24a The neuropathy
may represent the coincidental occurrence of CIDP in patients
with DM. Alternatively, it may represents a spectrum of diabetic
amyotrophy. Finally, the disorder may be a distinct form of dia-
betic neuropathy. It may be that patients with DM, especially
those with autoimmune type I DM, are more prone to developing

CIDP. The clinical features, increased CSF protein, electrophys-
iologic features (see below), and histopathology can be indistin-
guishable from idiopathic CIDP. Furthermore, some patients
appear to benefit from various immunotherapies. However, the
nerve histopathologic abnormalities, including immunohisto-
chemistry, are not specific for this form of diabetic polyradicu-
lopathy and have been noted in DSPN and diabetic amyotrophy.
The apparent response to various types of immunotherapies
does not imply that patients have CIDP, because they can im-
prove spontaneously without treatment.627,1033,1322 Obviously,
more work needs to be done to unravel the pathogenic nature of
this form of neuropathy. The authors believe that painless, sym-
metric diabetic polyradiculoneruopathy is likely to be multifac-
torial with some cases representing CIDP; others may be
unusual cases of diabetic amyotrophy or caused by a distinct
metabolic neuropathy related to the DM.
Electrophysiologic Findings. The electrodiagnostic medi-
cine examination reveals a significant generalized sensorimo-
tor polyneuropathy. The nerve conduction studies demonstrate
absent or reduced SNAP and CMAP amplitudes combined
with slowing of nerve conduction velocities, prolongation of
distal latencies, and absent or prolonged latencies of F-
waves.80,242,479,729,1033,1261,1322,1412 Conduction block and temporal
dispersion are uncommon but may be seen.479,1033 Occasionally,
the electrophysiologic features fulfill research criteria for de-
myelination, but there are generally more axonal abnormalities
than in idiopathic CIDP.479,626,1261 The needle EMG examination
reveals fibrillation potentials and positive sharp waves diffusely,
including multiple levels of the paraspinal musculature.80,1412
Autonomic studies demonstrate abnormalities in sudomotor,
cardiovagal, and adrenergic functions.627,1033
Treatment. A number of retrospective studies have demon-
strated that various forms of immunotherapy (i.e., IVIG, PE,
corticosteroids, cyclophosphamide) appear to be beneficial in
the symmetric, diabetic polyradiculoneuropathy.24a,242,479,627,729,
1033,1261,1322 This observation has led to the belief that this type of
diabetic neuropathy is immune-mediated and perhaps repre-
sents CIDP in diabetic patients. In many instances, however, the
magnitude of the response is not as robust as in idiopathic CIDP.
It has been suggested that the axonal loss associated with con-
current DSPN may account for the diminished response to im-
munosuppressive agents.479 In addition, patients with
symmetric, diabetic polyradiculoneuropathy also can improve
spontaneously without treatment.627,1033 Therefore, it is by no
means certain that this form of polyradiculopathy is immune-
mediated. Double-blind, placebo-controlled trials are needed
for better assessment of treatment options.
Diabetic Mononeuropathies or
Multiple Mononeuropathies
Patients with DM are particularly prone to both focal neu-
ropathies and multifocal neuropathies.12,45,637 One of the focal
neuropathies likely to be observed in diabetics is a cranial
mononeuropathy.894,1453 Of the cranial mononeuropathies, a
seventh nerve palsy is most common. The extraocular nerves
also can be affected: a focal lesion of the third nerve is the most
common, followed by sixth nerve palsies and, less frequently,
fourth nerve palsies. Pain in the form of a headache or located
within or about the eye can precede the onset of the palsy by
hours to days. There is usually complete loss of function within
hours to one day; however, sparing of pupillary function is
common, and resolution is noted by 3–5 months. Ischemia is
the primary cause for the dysfunction.
Chapter 23 ACQUIRED NEUROPATHIES — 983
Focal limb mononeuropathies are commonly observed in
diabetic patients superimposed on a more mild generalized pe-
ripheral sensorimotor peripheral neuropathy. Some of the more
frequently encountered isolated limb neuropathies include
carpal tunnel syndrome, cubital tunnel syndrome, femoral neu-
ropathy, peroneal neuropathy at the fibular head, and lateral
femoral cutaneous neuropathies. Any of these isolated nerve in-
sults can occur in combination within a similar time frame, cre-
ating a clinical presentation of mononeuropathy multiplex.
Perhaps the most challenging form of diabetic neuropathy is the
combined neuropathy in which any of the above patterns of periph-
eral nerve dysfunction occur in various combinations. Although
this “form” of neuropathy is not a single disease entity, it is a useful
clinical designation because it is quite descriptive of the patient’s
symptoms and signs. The common presentation is a generalized
sensorimotor peripheral neuropathy (i.e., DSPN) associated with
one or more focal mononeuropathies such as carpal tunnel, cubital
tunnel, foot drop, or oculomotor palsy. Clinical delineation of indi-
vidual peripheral nerve insults can be difficult. Of some help in
better defining all of the individual and combined peripheral nerve
dysfunctions is a carefully performed electrodiagnostic medicine
examination. It must be recognized, however, that at times doubt
may persist as to the true nature of the patient’s complaints because
of the limited manner in which the peripheral nervous system
reacts to insult (i.e., demyelination, axonal loss, or both).
The median and ulnar nerves are the most commonly af-
fected, followed by peroneal mononeuropathy at the fibular
head.426,658 Sciatic, femoral, and cranial (e.g., oculomotor, ab-
ducens, facial) nerves are affected less frequently. The electro-
diagnostic medicine evaluation should include a generalized
evaluation of the peripheral nervous system in addition to the
focal problem. Abnormalities consistent with axonal loss (re-
duced or absent SNAP and CMAP amplitudes, mild reduction
in conduction velocities) as well as demyelination (reduced
conduction velocities, temporal dispersion, and prolonged distal
latencies) can be expected out of proportion to the more gener-
alized neuropathy, indicating a superimposed focal lesion. In
profound disease, the complete absence of multiple responses
can make it virtually impossible to define separate nerve lesions
by electrophysiologic means. These mononeuropathies may
occur with or without concomitant significant clinical or elec-
trophysiologic evidence of a generalized peripheral neuropathy.
HYPOGLYCEMIA/HYPERINSULINEMIA
Clinical Features. Persistent hypoglycemia secondary to an
islet cell tumor of the pancreas or persistent injection of ele-
vated levels of insulin may lead to a peripheral neuropa-
thy.286,551,566a,628,926 Patients may note progressive numbness and
paresthesias in the hands and feet. Over a variable course of
time, motor weakness may develop. Manual muscle testing can
reveal significant muscle wasting in the distal aspects of the legs
and hand intrinsic muscles, accompanied by weakness. Deep
tendon reflexes are generally reduced. Correction of the hypo-
glycemic problem usually results in clinical improvement, espe-
cially with respect to the subjective sensory symptoms;
however, patients with long-standing muscle wasting and weak-
ness may have less than satisfactory recovery.
Histopathology. Few nerve biopsies have been performed
on affected patients with modern histologic techniques, thus
limiting the available information. There is a suggestion, how-
ever, that the primary lesion is axonal loss primarily affecting
the large myelinated fibers.628 Segmental demyelination is not a
984 — PART IV CLINICAL APPLICATIONS
prominent feature, and this observation tends to be supported by
electrodiagnostic findings (see below).
Pathogenesis. The basis for the polyneuropathy is not
known but is felt to be directly attributable to reduced glucose
levels in neurons.
Electrophysiologic Findings. The small number of patients
reported in the past, combined with prompt recognition of the
disorder, has limited the number of patients available for de-
tailed electrodiagnostic testing. The little available information
has shown a generalized reduction or absence in sensory nerve
responses.628 When present, the sensory conduction velocity is
reduced, but by no more than 30% of the lower limit of normal.
Motor nerve conduction velocities are normal or only mildly re-
duced. The CMAP amplitudes are slightly decreased in the
distal muscles of the hands and feet, as anticipated, given the
overt muscle wasting. F-waves are prolonged in both upper and
lower limbs, as are H-reflexes in the lower limbs.
Needle EMG reveals reduced recruitment with MUAPs sug-
gesting chronic motor unit remodeling in the distal limb mus-
cles.286,551,628,926 Fibrillation potentials and positive sharp waves
often accompany these changes. Some investigators have sug-
gested an associated anterior horn cell disorder, but pathologic
evidence of this supposition is lacking.551,92621 There are insuffi-
cient long-term electrophysiologic studies to define resolution
after appropriate medical intervention.
Treatment. Patients are treated for the underlying cause of
the hyperinsulinemia.
ACROMEGALY
Clinical Features. There are a number of neuromuscular
manifestations of acromegaly.1056 A proximal myopathy can be
readily found in acromegalic patients with long-standing dis-
ease and lack of treatment (see Chapter 28).679,1056 Several dif-
ferent types of peripheral neuropathies also may occur.1306 The
most common mononeuropathy in acromegaly is carpal tunnel
syndrome.817,1056,1181 A generalized sensorimotor peripheral neu-
ropathy, characterized by reduced sensation and paresthesias
beginning in the feet and progressing to the hands, is less fre-
quent. Some patients develop mild distal weakness. When clini-
cal and electrophysiologic studies are combined, evidence of
carpal tunnel syndrome is noted in 82% of patients and a gener-
alized sensorimotor peripheral neuropathy in 73% of patients.817
Finally, the bony overgrowth in or about the spinal canal and
neural foramens can result in spinal cord compression, poly-
radiculopathies, or cauda equina compression.
Histopathology. Nerve biopsies in patients with generalized
polyneuropathy are abnormal,817 showing an increase in en-
doneurial and subperineurial connective tissue and an overall
increase in the fascicular area. A reduction in myelinated and
unmyelinated nerve fibers also is evident. Teased nerve fiber
preparations demonstrate changes suggestive of axonal degen-
eration and segmental demyelination.
Pathogenesis. The cause of the neuropathy in patients with
acromegaly is not clear. In some cases, the neuropathy may be
attributable to superimposed DM. Mitogenesis induced by in-
creased growth hormone and upregulation of insulin-like
growth factor receptors is probably responsible for the prolifer-
ation of connective tissue elements in peripheral nerves.1306
These hypertrophic changes may render the nerve fibers more
susceptible to pressure and trauma.
Electrophysiologic Findings. Nerve conduction studies in
patients with generalized polyneuropathy demonstrate reduced
amplitudes of SNAPs.817 When SNAPs are obtainable, the distal
latencies may be prolonged and conduction velocities are slow.
The amplitudes of the CMAPs are usually normal. However,
there may be slightly prolonged distal latencies and slow motor
conduction velocities.
Treatment. Data about the response of peripheral neurop-
athies associated with acromegaly to treatment are insufficient.
HYPOTHYROIDISM
Clinical Features. In patients with hypothyroidism, two major
forms of peripheral nerve dysfunction can be observed as well as
proximal myopathy.346a,681a,956,1063 The most common form of pe-
ripheral nerve disease is carpal tunnel syndrome.346a,681a,930,1076 Less
common are symptoms and signs suggestive of tarsal tunnel syn-
drome.1186 A few series of cases suggest that generalized periph-
eral neuropathies also can complicate hypothyroidism.346a,681a,880,943
Patients develop symmetric painful paresthesias and dysesthesias
in both hands and feet. Reduced sensation in a glove-and-stocking
distribution is noted as well as reduced or absent ankle reflexes.
Documentation of frank weakness is less common despite the con-
current complaint of sensory symptoms.
Histopathology. Nerve biopsy demonstrates primarily seg-
mental demyelination with small onion-bulb formation over
time in untreated patients.312,349,838,956,1062,1210 A general reduction
in large myelinated fibers may be seen. Evidence of mild de-
grees of active axonal degeneration also can be found in some
patients.321,322,817
Pathogenesis. Carpal tunnel syndrome most likely results
from reduced space within the flexor retinaculum as a result of
associated edematous changes. The cause of the generalized
neuropathy associated with hypothyroidism is not known.
Electrophysiologic Findings. Electrophysiologic evaluation
demonstrates evidence consistent with carpal tunnel syndrome,
mono/polyentrapment syndromes, or generalized sensorimotor
polyneuropathy.312,322,346a,681a,817,838,880,943 In patients with a gener-
alized neuropathy, the SNAP amplitudes are reduced and may
have mildly prolonged latencies.349,415,1062,1210 Motor nerve con-
duction velocities are usually 70–80% of the lower limit of
normal with mild prolongation of distal motor latencies. CMAP
amplitudes are relatively well preserved, with some degree of
reduction compared with normal mean values in most patients.
Needle EMG examination reveals variable degrees of fibrilla-
tion potentials and positive sharp waves, primarily in the intrin-
sic foot and hand muscles. In patients with myopathies,
proximal muscle examination can demonstrate short-duration,
small-amplitude potentials firing at rapid rates during low levels
of force production (i.e., early recruitment).
Treatment. Appropriate medical treatment usually arrests
progression of the peripheral neuropathy with variable degrees
of compensation, depending on the amount of peripheral nerve
reserve at the time of medical intervention.
NEUROPATHIES ASSOCIATED
WITH SYSTEMIC DISEASE
UREMIC NEUROPATHY
Clinical Features. Patients with renal failure develop an
excess of urea and other nitrogenous waste products in the
blood secondary to an inability to eliminate these substances be-
cause of failing glomeruli. Both central (encephalopathy) and

peripheral (peripheral neuropathy) nervous system abnormali-
ties can result from renal failure.47,118,121,1123 Approximately 60%
of patients with renal failure develop a peripheral neuropathy.
Patients usually complain of bilateral numbness, tingling, and
feet that are extremely sensitive to normally nonpainful stimuli.
Patients may note muscle cramps in the distal legs and occa-
sional restless leg syndrome, but these symptoms are most
likely not related to the neuropathy.957,958 A few patients may de-
velop a clinical syndrome that is rapidly progressive, much like
AIDP, and improves with an increase in renal dialysis or trans-
plantation.121,1123 Physical examination demonstrates an early
depression or abolition of the ankle reflexes with an accompa-
nying reduction in the foot vibratory threshold. A small number
of patients also experience a reduction in the thermal threshold,
especially as the neuropathy progresses.
In addition to the sensorimotor peripheral neuropathy, a
number of mononeuropathies can occur. The most common
mononeuropathy in patients with chronic renal failure is carpal
tunnel syndrome. This syndrome is related to a particular type
of hemodialysis instrument that uses a Cuprophan membrane,
which may predispose patients to tissue damage. The
Cuprophan membrane fails to remove completely a small ß2 mi-
croglobulin, which is normally catabolized by the healthy
kidney.118 This substance forms a type of amyloid deposit
throughout the body, with particularly adverse consequences
when deposited in the carpal tunnel about the transverse carpal
ligament. Carpal tunnel syndrome is the end result of this form
of amyloid accumulation. Because of their general debilitation,
patients with renal failure are also prone to developing other
mononeuropathies, such as ulnar neuropathy at the elbow and
peroneal nerve injury about the fibular head. During renal trans-
plant surgery, damage to the brachial plexus or peripheral
nerves may result from improper limb positioning or traction.
Ischemic monomelic neuropathy, affecting the median, ulnar,
and radial nerves, may result from ischemia to the nerve(s) sec-
ondary to the creation of an arteriovenous shunt in the arm for
dialysis.113,785,1410
Histopathology. Sural nerves in patients with generalized
sensorimotor polyneuropathy demonstrate a loss of nerve fibers,
particularly large myelinated nerve fibers.47,118,350,632 Evidence of
active axonal degeneration is more prominent in the distal than
proximal regions of the peripheral nervous system. Segmental
and paranodal demyelination also can be prominent but gener-
ally is believed to be a secondary result of axonal degeneration.
Evaluation of autopsy spinal cord specimens in patients with
renal disease and peripheral neuropathy demonstrates anterior
horn cell chromatolysis consistent with axonal loss of motor
fibers. Degeneration of the fasciculus gracilis at the cervical
level also has been noted.
Pathogenesis. Some evidence suggests that as long as the
glomerular filtration rate exceeds roughly 12 ml/minute, the ad-
verse effects on the peripheral nervous system are minimal. At
glomerular filtration rates below this value, nerve conduction
studies become abnormal, and when about 6 ml/minute is
reached, patients begin to demonstrate clinical signs of periph-
eral nerve dysfunction. Whether the Schwann cell or the axon is
the primary target of the essential metabolic or toxic abnormal-
ity in uremia is still debated. The primary pathophysiology of
the uremic neuropathy remains unknown, but according to one
theory, some slowly dialyzable substance(s) of intermediate
molecular weight alters the peripheral nerve in a manner that re-
sults in axonal and possible Schwann cell dysfunction and even-
tual degeneration.
Chapter 23 ACQUIRED NEUROPATHIES — 985
Electrophysiologic Findings. In general, the electrophysio-
logic findings in uremic patients tend to follow the clinical
symptoms and signs.4,15 The lower limbs are more involved than
the upper limbs. The sural SNAPs are reduced in amplitude or,
more commonly, unobtainable. When present, the distal laten-
cies are prolonged, and sensory conduction velocities are slow.
Some patients display temporally dispersed SNAPs with an in-
crease in phases. In one study, the sural SNAPs were abnormal
in 100% of patients examined.3 In the upper limbs, median and
ulnar SNAP abnormalities are detectable with respect to conduc-
tion velocities, amplitudes, and distal latencies.273,630,959,962 Most
patients have either prolonged or absent H-reflexes, even when
the lower limb motor studies are considered normal.512,538,1057
Somatosensory evoked potential studies reveal slowing of neural
conduction along both peripheral and central pathways.1130
Motor conduction studies have been the mainstay of electro-
diagnostic evaluation of uremic patients for years, primarily be-
cause of ease of performance and relatively good intertrial
reproducibility, provided good technique is used.227,597 However,
motor nerve conductions still may vary to some degree.711 The
tibial and peroneal nerves usually demonstrate some degree of
slowing but typically are not reduced below 70% and 60% of
the lower limit of normal for upper and lower limb nerves, re-
spectively.1298 Median and ulnar nerve conduction velocities
tend to be abnormal later in the course of the disease process
compared with lower limb conductions. The mean CMAP am-
plitudes for uremic patients are within the low normal range,
particularly early in the course of the disease. The amplitudes
become abnormal and eventually disappear in the lower limbs
and decrease much later in the upper limbs. F-waves are usually
absent or demonstrate delayed latencies.
There is some debate about whether the proximal portions of
the peripheral nerves are affected to a greater degree than the
distal aspects. Studies using disparate methods have arrived at
opposite conclusions—i.e., no difference and more proximal
than distal slowing.216,835,974,1019 This discrepancy most likely re-
sults from a more diffuse metabolic process that is not de-
tectable over the short nerve segments that are routinely used. If
mild disease is present, the proximal segments, as measured
through F-waves and H-reflexes, appear to be preferentially in-
volved. When only short segments are used in patients with ob-
vious clinical neuropathy, the proximal nerve conduction does
not appear to be as affected as the more distal segments. The
concept that a metabolic derangement other than demyelination
and axonal loss results in dysfunctional neural conduction is a
postulated cause for improvement in nerve conduction within 1
week after renal transplant—an interval too brief for remyelina-
tion or axonal regeneration.
Needle EMG findings support a generalized axonopathy.
Proximal and distal muscles in the upper and lower limbs
should be examined, especially the foot intrinsic muscles in
early disease, because the distal muscles of the lower limbs are
the first to demonstrate abnormalities. Positive sharp waves and
fibrillation potentials of varying degrees are evident first in the
foot intrinsic muscles and later in the gastrocnemius, soleus,
and tibialis anterior muscles. When the tibialis anterior demon-
strates easily obtainable membrane instability, the intrinsic hand
muscles begin to show the same abnormal potentials. With dis-
ease progression, reduced recruitment becomes evident in the
affected muscles, again first in the lower and then with upper
limb muscles.
Of interest, several single-fiber investigations of uremic pa-
tients demonstrate that fiber density is relatively normal.713,1292
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.
This is the likely explanation for reduced motor CMAP ampli-
tudes relatively early in the disease process compared with other
neuropathies. As axons are lost, the CMAP amplitudes drop be-
cause the remaining axons do not reinnervate the denervated
fibers. For this reason, SNAP amplitudes are important indica-
tors of axonal loss because there is no compensatory mecha-
nism to repair the lost axons, and amplitude is a good indicator
of the total number of functional axons. Furthermore, when col-
lateral sprouting is defective, the CMAPs become a good indi-
cator of axonal loss in the chronic phase of the disease and are
noted as an abnormality relatively early in course of the disease.
There are few detailed quantitative needle EMG examinations
in uremic patients, but based on the presumably reduced ability
of muscle fibers to be reinnervated, the MUAP parameters (am-
plitude and duration) should not be as abnormal as in the more
commonly observed axonal loss lesions. This assumption re-
mains to be documented.
In patients with mononeuropathies, electrodiagnostic find-
ings are compatible with focal demyelination and/or axonal
loss. If the patient has sustained an ischemic monomelic neu-
ropathy, the electrophysiologic findings are commensurate with
the degree of ischemic neural insult.113,785,1310 The median,
radial, and ulnar SNAPs may be absent or reduced in amplitude,
depending on the degree and duration of ischemia. If CMAPs
are present, the distal motor latencies are relatively normal, as
are the conduction velocities. Conduction block may be seen as
well. Needle EMG demonstrates a marked reduction in MUAPs
with abundant positive sharp waves and fibrillation potentials
along with decreased recruitment.
Treatment. The sensorimotor peripheral neuropathy is usu-
ally held in check by hemodialysis and almost completely re-
versed if the patient receives a successful renal transplant before
large numbers of axons are lost. When hemodialysis is insti-
tuted, the peripheral neuropathy and nerve conduction studies
may not necessarily improve. However, hemodialysis appar-
ently has the ability to stabilize and prevent further peripheral
nerve functional deterioration.111,114,309,960 Some nerve conduc-
tion parameters may improve after hemodialysis over a short
time incompatible with remyelination.1255 The peripheral neu-
ropathy and electrodiagnostic abnormalities also improve after
a successful renal transplant.110,112,961,978 Patients demonstrate an
increase in both motor and sensory nerve conduction velocities,
reductions in distal latencies, and increases in amplitude.
Individual entrapment neuropathies also may improve. Positive
sharp waves and fibrillation potentials are difficult to detect and
may disappear completely. Of course, in patients with profound
axonal loss and significant muscle atrophy, the ability of the pe-
ripheral neuromuscular system to repair itself is limited, and
only minimal to modest gains may be made.
After renal transplantation a biphasic mode of functional
gains occurs. The first and more rapid return of function
(weeks to months) is probably due to the above-noted meta-
bolic effect combined with remyelination of demyelinated seg-
ments.978 Later (months to 1 year or more), improvement
probably results from functional axonal regrowth and reinner-
vation of previously denervated muscle fibers by collateral
sprouting. It is not presently possible to state definitively
whether nerve conduction studies are sufficiently sensitive to
determine if renal dialysis frequency and duration are adequate
in individual patients.1054
Surgical release is helpful in patients with carpal tunnel syn-
drome. Median neuropathy at the wrist related to amyloid depo-
sition 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. If treated early enough, motor and sensory symptoms can
resolve quickly, indicating an ischemia-induced conduction
block rather than peripheral nerve infarction. Severe ischemia re-
sulting in infarction leads to delayed and incomplete recovery.
GASTROINTESTINAL DISEASES
Celiac Disease (Gluten-induced Enteropathy
or Nontropical Sprue)
Clinical Features. Intolerance to gluten, a protein found in
wheat and wheat products, results in a malabsorption syndrome
(weight loss, abdominal distention, steatorrhea). Diagnosis of
celiac disease is based on the documentation of (1) malabsorption,
(2) blunting and flattening of jejunal villi, and (3) clinical and his-
tologic improvement after the institution of a gluten-free diet.1046
Patients with gluten intolerance can develop neurologic complica-
tions related to vitamin B12 or vitamin E deficiencies caused by
malabsorption. Patients complain of distal paresthesias and some
loss of sensation associated with gait ataxia.233,239,528,528a,654,696,822a,
1046,1384 Generalized sensorimotor polyneuropathy, motor neuropa-
thy, mononeuropathy multiplex, and neuromyotonia have been re-
ported. Dementia can be seen in some patients. Physical
examination demonstrates a distal muscle weakness, which can be
in a mononeuropathy multiplex pattern or generalized, absent
deep tendon reflexes, Romberg sign, and ataxic gait. Spasticity
and upper motor neuron weakness can be seen in patients with
subacute combined degeneration related to vitamin B12 deficiency.
Laboratory Features. Anti-gliadin and anti-endomysial an-
tibodies are often detected in the serum of patients with celiac
disease.1364b
Histopathology. Nerve biopsy reports are conflicting with
respect to axonal loss vs. segmental demyelination. The most
likely pathologic insult to the peripheral nervous system is
axonal degeneration of the large myelinated fibers. Autopsy
studies have revealed atrophy of the cerebellum with loss of
Purkinje cells.239,528a,696 Cortical atrophy and degeneration of
neurons in the thalamus, basal ganglia, and brainstem are also
apparent. In addition, degeneration of the posterior columns and
corticospinal tracts has been described.
Pathogenesis. The neuropathy may be secondary to malab-
sorption of vitamins B12 and E. However, some patients have no
appreciable vitamin deficiencies.1384 The pathogenic basis for
the neuropathy is unclear but may be autoimmune.
Electrophysiologic Findings. Limited electrophysiologic
data are available for celiac disease.528,528a,654 Electrodiagnostic
medicine evaluation reveals a significant reduction in the
SNAP amplitude or complete absence of the SNAP. Sensory
conduction velocity is only mildly reduced, even in nerves with
significant amplitude reductions. Motor conduction studies
demonstrate a mild reduction in the nerve conduction velocity
with preservation of distal motor latencies and CMAP ampli-
tudes. Needle EMG examination can demonstrate features typ-
ical of any other type of axonal neuropathy. One case has been
described with neuromyotonia.528
Treatment. The neuropathy does not appear to be respon-
sive to a gluten-free diet.1046 In patients with vitamin B12 or vita-
min E deficiency, replacement therapy may improve or stabilize
the neuropathy.

Whipple’s Disease
Whipple’s disease is a rare disorder characterized by abdomi-
nal pain, diarrhea, malabsorption weight loss, arthralgias, and
other systemic involvement.266,541,1046,1229 Associated symptoms
and signs include fever and peripheral lymphadenopathy, accom-
panied by enlargement of the celiac, mesenteric, and periaortic
lymph nodes. CNS involvement can result in dementia.
Supranuclear ophthalmoparesis, convergence nystagmus, my-
oclonus, oromandibular myorhythmia, insomnia, hyperphagia,
and polydipsia have been described. Rarely, patients exhibit prox-
imal weakness and atrophy suggestive of a myopathic process.
Some patients develop a sensorimotor polyneuropathy.266
Laboratory Features. The CSF examination in patients
with CNS involvement typically demonstrate inflammatory
changes, including a polymorphonuclear response and periodic
acid-Schiff (PAS)-positive macrophages.1046 MRI scan of the
brain can reveal signal changes correlating with the sites of
pathologic involvement and gadolinium enhancement sugges-
tive of ependymitis.
Histopathology. Small bowel mucosa has PAS-positive
macrophages containing the bacilli Tropheryma whippeli. The
organism also can be identified in the CNS. There have been no
reports of peripheral nerve or muscle histopathology in patients
with suspected neuropathy or myopathy.
Pathogenesis. Whipple’s disease is caused by a gram-posi-
tive actinomycete, T. whippeli. Intestinal mucosal changes lead
to malabsorption. Although the pathogenic basis of the neuropa-
thy is not known, it may result from malabsorption of necessary
vitamins. Alternatively, the neuropathy may be caused by bacte-
rial infiltration and subsequent inflammatory involvement of the
peripheral nerves.
Electrophysiologic Findings. A detailed electrodiagnostic
medicine report of a single patient with Whipple’s disease re-
vealed evidence of a sensorimotor peripheral neuropathy, espe-
cially prominent in the lower limbs.266 Additionally, proximal
muscle weakness on clinical examination suggested a superim-
posed myopathic process. Sensory nerve conduction revealed
reduced SNAP amplitudes with mild impairment of conduction
velocities. Similar findings were noted for the motor nerves
with the exception of the peroneal nerve, which yielded evi-
dence suggestive of conduction block. Needle EMG examina-
tion demonstrated a reduced recruitment pattern distally with
positive sharp waves and fibrillation potentials. The proximal
muscles, however, demonstrated short-duration, low-amplitude
potentials consistent with a myopathic process. Single-fiber
EMG failed to demonstrate significant abnormalities.
Treatment. Chloramphenicol and trimethoprim-sulpha-
methoxazone are efficacious in the treatment of CNS disease
associated with Whipple’s disease.1046 Because of the rarity of
PNS involvement, it is not known whether antibiotic treatment
improves or arrests the progression of peripheral neuropathy.
Obviously, if a vitamin deficiency is documented, replacement
therapy should be started.
Inflammatory Bowel Disease
Inflammatory bowel disease refers to ulcerative colitis and
Crohn’s disease. Both disorders are thought to have an immuno-
logic basis and are associated with various neurologic abnormali-
ties, including peripheral neuropathy. In a large series of 638
patients with inflammatory bowel disease, 6 developed a periph-
eral neuropathy (3 AIDP, 1 mononeuropathy multiplex, 1
bibrachial plexopathy, 1 recurrent facial nerve palsy).812 All of the
patients with neuropathy had ulcerative colitis. However,
Chapter 23 ACQUIRED NEUROPATHIES — 987
polyneuropathy can complicate Crohn’s disease as well as ulcera-
tive colitis and may manifest as AIDP,73,190,471,607,712,812,1450 general-
ized axonal sensorimotor polyneuropathy, 939 brachial
plexopathy,230,812 multiple mononeuropathies,812 and cranial neu-
ropathies.595,812 The clinical, laboratory, histologic, and electro-
physiologic features of the specific types of peripheral
neuropathies associated with inflammatory bowel disorders are
no different from the idiopathic forms. In addition to neuropathy,
patients with inflammatory bowel disease can develop weakness
secondary to myasthenia gravis or myositis (including
polymyositis, dermatomyositis, and granulomatous myositis).812
LIVER DISEASE
Chronic Liver Disease
Patients with chronic liver disease from various causes can
develop a mild, generalized sensorimotor peripheral neuropa-
thy characterized by numbness, tingling, and minor weakness
primarily in the distal aspects of the lower limbs.210,655,706,1198
Sural nerve biopsies reveal both segmental demyelination and
axonal loss. Electrodiagnostic medicine evaluations have
demonstrated a reduction in SNAP amplitudes as the major
abnormality, with some prolongation of sensory and motor
distal latencies. Motor nerve conduction studies are usually
normal, although needle EMG examinations have not been
well described. Quantitative sensory testing is abnormal in
62% of patients in large series, with cooling thresholds more
abnormal than vibratory thresholds.210 Autonomic testing re-
veals dysfunction in nearly 50% of patients.210,994 Whether he-
patic failure itself can cause peripheral neuropathy is unclear.
Toxins that could damage peripheral nerves may accumulate
as a result of liver disease. However, most patients have he-
patic failure secondary to other disorders, such as alcoholism
or viral hepatitis, that can cause peripheral neuropathies.
Alcoholics may develop neuropathy secondary to the direct
toxic effect of alcohol or because of nutritional deficiencies.
Hepatitis B and C can cause mononeuropathy multiplex (sec-
ondary to vasculitis or cyroglobulinemia), AIDP, or CIDP.
Furthermore, EBV-related hepatitis can be associated with
AIDP. Obviously more work needs to be done before we can
conclude that liver failure is the direct cause of associated pe-
ripheral neuropathies.
Primary Biliary Cirrhosis
Clinical Features. Primary biliary cirrhosis (PBC) is an au-
toimmune disorder directed against the biliary ducts in the
liver. Patients develop progressive liver failure, which is often
fatal. Patients with PBC can develop a peripheral neuropathy
characterized by distal numbness and tingling.202,210,820 Physical
examination demonstrates a reduced ability to perceive touch
and vibration, along with diminished proprioception. Pain and
temperature perception can be diminished to a minor degree in
the most distal aspects of the limbs. Deep tendon reflexes may
be reduced or absent. Muscle strength is typically normal.
Although documentation is poor, it would not be surprising to
find a CIDP-like neuropathy in PBC because autoimmune dis-
orders frequently occur together. When weakness is present,
other autoimmune neuromuscular disorders, such as myasthe-
nia gravis, Lambert-Eaton syndrome, and myositis, need to be
considered.
Laboratory Features. Liver function tests are obviously el-
evated. Antimitochondrial antibodies can be detected in the sera
of some patients.
988 — PART IV CLINICAL APPLICATIONS
Histopathology. Nerve biopsy demonstrates a reduction
in the large myelinated fibers without evidence of segmental
demyelination.
Pathogenesis. The cause of peripheral nerve damage is un-
known. The neuropathy may have an immunological basis.
Additionally, the neuropathy may be related to unknown toxins
that accumulate as a result of liver failure.
Electrophysiologic Features. Electrodiagnostic medicine
evaluation demonstrates reduced or absent SNAPs. The motor
conduction and needle EMG portions of the evaluation are
normal. The electrophysiologic and histopathologic findings
support the clinical impression of a primary sensory neuropathy.
Treatment. PBC is treated with immunosuppressive ther-
apy and, ultimately, liver transplantation. Whether transplanta-
tion affects the peripheral neuropathy has not been adequately
addressed.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
In a single study, 87% of patients with chronic obstructive
pulmonary disease had electrophysiologic evidence of a sub-
clinical sensorimotor peripheral neuropathy.385 Only 17% of the
total study population had clinical findings suggestive of a pe-
ripheral neuropathy. Similarly, 17% of patients had needle
EMG evidence of axonal loss as demonstrated by a combination
of positive sharp waves, fibrillation potentials, and reduced re-
cruitment of MUAPs. Additional findings of long-duration,
high-amplitude potentials suggested chronic disease with motor
unit remodeling.
GOUT
Rarely, patients with gout may develop a sensorimotor pe-
ripheral neuropathy preferentially localized to the lower limbs
or neural entrapments at the wrist and elbow.308 Patients with
peripheral neuropathies may complain of progressive loss of
sensation in the feet with difficulty in walking. Physical exami-
nation can reveal a wide-based gait with a positive Romberg
sign. Deep tendon reflexes are depressed in the upper limbs and
absent in the lower limbs. Despite a lack of overt muscle atro-
phy, a loss of about one grade of strength may be documented in
the distal lower limb muscles. Decreased sensation to all modal-
ities can be observed in the legs.
Sensory nerve conductions in the lower limbs can be absent,
whereas those in the upper limbs reveal reduced amplitudes with
mild alterations of conduction velocity or distal latencies.
Similar findings are noted for motor nerve studies. Needle EMG
studies have not been detailed in patients with gouty neuropathy.
CRITICAL ILLNESS POLYNEUROPATHY
As opposed to AIDP and myasthenia gravis, which are the
most common neuromuscular causes for admission to intensive
care units (ICU), weakness in critically ill patients in the ICU
setting121a,312a usually is secondary to critical illness polyneu-
ropathy,115,116,117,776,1414,1424,1449a,1451 or critical illness myopathy
(also known as acute quadriplegic myopathy [AQM]; see
Chapter 28),310,752–754,1099,1100,1452 or, much less commonly, pro-
longed neuromuscular blockade.76 From a clinical and electro-
physiologic standpoint, it can be quite difficult to distinguish
these disorders. Critical illness neuropathy was more common
than critical illness myopathy in some series of ICU pa-
tients.776,1000,1424 However, other institutions and the authors’
own anecdotal experiences suggest that critical illness myopa-
thy is more common than critical illness neuropathy.754,1100 In
the largest series involving 88 patients who developed weakness
in the ICU, critical illness myopathy was three times as
common as critical illness neuropathy (42% vs. 13%); pro-
longed neuromuscular blockade occurred in only one patient,
who also had AQM.754 From a practical standpoint, morbidity
and mortality appear to be similar in critical illness neuropathy
and critical illness myopathy.754 In patients who survive the un-
derlying sepsis and multiorgan failure, muscle strength recovers
slowly over several months.
Clinical Features. Critical illness polyneuropathy occurs in
patients in the ICU with sepsis and multiple organ fail-
ure.115,116,117,121a,312a,776,1185,1424,1449a,1451 The peripheral neuropathy is
often first suspected when the patient cannot be weaned from a
ventilator. Neurologic examination can be limited by en-
cephalopathy related to sepsis and organ failure. It is often difficult
to ascertain the degree of sensory loss and modalities if the pa-
tient’s mental status is altered. Nevertheless, generalized weakness
of the limb muscles can be appreciated. Cranial nerve musculature
is usually comparatively well preserved, although mild facial
weakness may occur. As noted above, respiratory muscle involve-
ment is prominent. Deep tendon reflexes are absent or reduced.
A subset of patients sustaining burn injury to 20% or more of
the total body surface may develop a number of different types
of neuropathies in the critical care setting.569,570,572,1164 Focal neu-
ropathies of the median, radial, ulnar, and peroneal nerves can
result from poorly applied compression dressings or malposi-
tioning of limbs. Patients may develop a mononeuropathy mul-
tiplex (69% of patients in one series), possibly secondary to
vascular insult of the vasa nervora.833 A generalized sensorimo-
tor peripheral neuropathy that is less severe than critical illness
polyneuropathy may occur in 6–52% of burn patients . Burn pa-
tients also may develop the complete critical illness polyneu-
ropathy described above.174,833 Delayed paraparesis may result
from electrical injuries (see Chapter 16).710
Laboratory Features. CSF is usually normal or only mildly
elevated, whereas in AIDP and CIDP in CSF protein is usually
significantly increased.1451 Of note, some patients have in-
creased serum creatine kinase (CK) levels, which were attrib-
uted to myocardial infarction in some cases.1451 However, the
elevated serum CKs may be secondary to critical illness myopa-
thy rather than critical illness neuropathy.
Histopathology. Nerve biopsies reveal significant axonal
degeneration with little demyelination.1451 Autopsies have
demonstrated chromatolysis of anterior horn cells, loss of dorsal
root ganglion cells, and axonal degeneration of motor and sen-
sory nerves.1451 Muscle biopsies show grouped atrophy and
targetoid fibers suggestive of acute neurogenic process.1451
However, scattered muscle fiber necrosis and increased central
nuclei, which are nonspecific myopathic features, also have
been noted. AQM is usually associated with necrotic fibers and
loss of myosin thick filaments.
Pathogenesis. The pathogenic basis of critical illness neu-
ropathy is not clear. One can speculate that circulating toxins
and metabolic abnormalities associated with sepsis and multior-
gan failure lead to axonal degeneration of the peripheral nerves,
perhaps by interfering with axonal transport mechanisms or mi-
tochondrial function.1451
Electrophysiologic Features. An electrodiagnostic medi-
cine examination in critical care units is usually fraught with
technical difficulties secondary to interference from multiple
lifesaving and monitoring equipment. In addition, units are located

on the upper floors of the hospital, thus predisposing recording
of electrical signals from radio and television stations. Despite
these adverse conditions, good technique can demonstrates sig-
nificant abnormalities in patients with critical illness polyneu-
ropathy.115,116,117,121a,312a,776,1185,1414,1424,1449a,1451 CMAPs are profoundly
reduced in amplitude or absent. Phrenic nerve studies often
reveal absence or reduction of the diaphragm’s CMAP ampli-
tude. Motor nerve conduction velocity and distal motor latency
are normal or only slightly abnormal. There is no conduction
block or increased temporal dispersion. F-waves may be unob-
tainable, but when they are present, the latencies are normal or
only mildly prolonged. Repetitive stimulation studies fail to
reveal electrophysiologic evidence of neuromuscular junction
failure.
The SNAPs also should be significantly diminished in ampli-
tude or absent. When SNAPs are recordable, the sensory con-
duction velocities are normal or only mildly reduced, and the
distal sensory latencies are normal or only slightly prolonged. If
the SNAPs amplitudes are normal or only slightly reduced in
comparison with loss of CMAP amplitudes, the diagnosis of
critical illness myopathy or motor axonal neuropathy must be
considered. Of importance, low-amplitude SNAPs do not nec-
essarily imply that the patient’s weakness is secondary to criti-
cal illness neuropathy. Patients with critical illness myopathy
may have an age-related decrease in SNAP amplitudes, or the
SNAPs may be abnormal secondary to an underlying condition
(e.g., diabetes mellitus). Furthermore, patients may have a mix-
ture of critical illness neuropathy and myopathy; thus SNAPs
would be abnormal, but the muscle weakness may be more re-
lated to the superimposed myopathy.
Needle EMG examination reveals profuse positive sharp
waves and fibrillation potentials. In patients with severe weak-
ness, it is not unusal to be unable to recruit MUAPs. When
MUAPs are recruited, they are often small and polyphasic in
morphology. These small units have been attributed to early
reinnervation. Unfortunately, discussion of the recruitment pat-
tern often has been neglected. One would expect to see de-
creased recruitment of small MUAPs in a neurogenic process.
However, if one sees early recruitment of small-duration,
polyphasic MUAPs, AQM should be considered. Increased
jitter on single-fiber EMG has also been noted,1185 but in-
creased jitter can be caused by remodeling of the motor termi-
nal due to a neuropathic, myopathic, or neuromuscular junction
defect.
Direct muscle stimulation has been advocated to help distin-
guish critical illness neuropathy from myopathy.1099,1100 Direct
muscle stimulation bypasses the distal motor nerve and neuro-
muscular junction. In a neuropathic process or prolonged neuro-
muscular blockade, the muscle membranes should retain
excitability, and the direct muscle stimulation CMAP
(dmCMAP) theoretically should be near normal despite a low
or absent nerve stimulation-evoked CMAP (neCMAP). In con-
trast, if the muscle membrane excitability is reduced, as in
AQM, both the neCMAP and dmCMAP would be expected to
be very low. Rich and colleagues suggest that the ratio of
neCMAP to dmCMAP should be close to 1:1 (> 0.9) in a disor-
der of muscle membrane inexcitability and approach zero (0.1
or less) in a neuropathy or neuromuscular junction disor-
der.1099,1100 However, a large control group is needed to confirm
the statistical value of this ratio.
Treatment. There is no specific therapy for critical illness
neuropathy other than supportive care and treatment of the un-
derlying sepsis and organ failure.
Chapter 23 ACQUIRED NEUROPATHIES — 989
NEUROPATHIES ASSOCIATED
WITH MALIGNANCY
Peripheral neuropathies can develop in a patient with malig-
nancy as (1) a direct effect of the cancer by invasion or compres-
sion of nerves, (2) a remote or paraneoplastic effect, (3) or an
iatrogenic effect of treatment (chemotherapy, immunosuppres-
sion, radiation, bone marrow transplantation).24 Estimating the
frequency of peripheral neuropathies associated with malignan-
cies is difficult because the frequency depends on a number of
factors, including the type, stage, and location of the cancer, dura-
tion of disease, degree of malnutrition, and neurotoxic effects of
various therapies. However, clinically evident peripheral neu-
ropathy has been reported in 1.7–5.5%261,262,876,1313 of patients with
malignancy, and quantitative sensory testing can detect peripheral
neuropathy in 12%.801 Furthermore, nerve conduction studies
have demonstrated peripheral neuropathy in 30–40% of patients
with cancer.876,919 Peripheral neuropathy is most common in carci-
noma of the lung but also is associated with carcinoma of the
breast, ovaries, stomach, colon, rectum, and other organs, includ-
ing the lymphoproliferative system.191,259,261,262,493,604,784,874,1264
PARANEOPLASTIC NEUROPATHIES
The remote effects of carcinoma on the peripheral nervous
system (so-called paraneoplastic neuropathies) are quite di-
verse.24,163,172,262,382,564,580,876,1183,1291,1313,1435 These neuropathies
result from indirect carcinomatous insult to the peripheral ner-
vous system, not from direct nerve infiltration or compression.
Paraneoplastic Sensory Neuronopathy/Ganglionopathy
Clinical Features. Subacute sensory neuronopathy was the
first neuropathy described as a complication of carcinoma.312
Because the site of the lesion is at the level of the sensory cell
body, the disorder is also called a ganglionopathy. Small cell lung-
carcinoma (SCLC) is the most commonly associated malignancy,
but cases associated with carcinoma of the esophagus, breast,
ovaries, and kidney and lymphoma also have been re-
ported.24,26,261,283,491–493,602,1151,1232,1324,1366 The disorder is rare and
most commonly affects women in late-middle life (mean age of
onset: 59 years).192,263 The predominant symptoms—numbness,
dysesthesia, and paresthesia—begin distally and spread proxi-
mally. Symptoms begin in the arms in over 60% and are asymmet-
ric in approximately 40% of cases.192 The onset can be acute or
insidiously progressive. Diminished touch, pinpoint, and tempera-
ture sensation and prominent loss of vibratory and position sense
result in sensory ataxia and pseudoathetosis. Deep tendon reflexes
are diminished or absent. Alterations in mental status, autonomic
dysfunction, and cranial nerve abnormalities occur in about two-
thirds of patients as a result of a superimposed paraneoplastic en-
cephalomyelitis.602 Although most cases of sensory neuronopathy
have only sensory abnormalities, mild weakness is occasionally
evident and may reflect an associated sensorimotor neuropathy or
a superimposed myasthenic (Lambert-Eaton) syndrome.
The neuropathy generally evolves over a few months, then
stabilizes. Symptoms of the neuropathy may precede symp-
toms of the cancer by several months or years. Discovery of a
sensory neuronopathy should lead to an aggressive evaluation
for an underlying malignancy. We obtain a chest CT scan,
mammogram, pelvic CT, and antineuronal nuclear antibodies
(anti-Hu) for all patients in addition to performing a complete
physical examination.
990 — PART IV CLINICAL APPLICATIONS
Laboratory Features. CSF may be normal or demonstrate
mild lymphocytic pleocytosis and elevated protein.26,283,602 Type
1 antineuronal nuclear antibodies (ANNA-1), also known as
anti-Hu, can be demonstrated in serum and CSF in patients with
small cell carcinoma of the lung complicated by paraneoplastic
sensory or sensorimotor polyneuropathy, encephalitis, and cere-
bellar degeneration.26,283,491,492 The antibodies are directed
against a 35–40 kD nuclear protein and are highly specific for
SCLC.194 We advise chest radiograph every 3 months and chest
CT or MRI every 6 months in patients who initially have no
identifiable cancer but a sensory neuronopathy with a positive
ANNA-1.
Histopathology. Pathologic features of the disease include
inflammation and degeneration of the dorsal root ganglia with
secondary degeneration of sensory neurons and the posterior
columns. Sural nerve biopsies may demonstrate perivascular in-
flammation.194 The inflammatory infiltrate is comprised of both
B- and T-lymphocytes.629 In addition, autopsies reveal degener-
ation and inflammation involving neurons in the brainstem and
limbic system.283,491,1366
Pathogenesis. The cause of the neuronopathy is unclear.
Perhaps an antigenic similarity between proteins in tumor cells
and neuron cells leads to an immune response directed against
both.491,1127,1366
Electrophysiologic Findings. Nerve conduction studies in
pure sensory neuronopathy reveal low-amplitude or absent
SNAPs with normal CMAPs.26,283,602 A small reduction in the
sensory conduction velocity may result from loss of large
myelinated nerve fibers. Of importance, the SNAPs can be
asymmetrically affected, reflecting clinical involvement. Fur-
thermore, one can see abnormal SNAPs in the hand when they
are normal in the legs. This feature suggests a ganglionopathy
as opposed to the much more common length-dependent ax-
onopathies, in which sural SNAPs are affected earlier and more
severely than upper limb SNAPs. Blink and masseter reflexes
are generally normal.51,52 Motor conduction studies are normal
in pure sensory neuronopathies, but many patients have motor
involvement. In particular, some patients have superimposed
Lambert-Eaton syndrome. Thus, low-amplitude CMAPs, with
low rates of repetitive stimulation (2–3 Hz), can reveal a decre-
ment, whereas 10 seconds of exercise or fast rates of repetitive
stimulation (20–50 Hz) may demonstrate facilitation of CMAP
amplitudes. Needle EMG findings usually are normal. Some pa-
tients with subclinical motor nerve involvement may have a few
positive sharp waves and fibrillation potentials in the distal limb
musculature. Furthermore, variability in MUAP morphology
and increased jitter may be seen in patients with superimposed
Lambert-Eaton syndrome.
Treatment. Treatment of the underlying cancer may pro-
long survival but generally does not affect the course of the un-
derlying neuronopathy.283 Remission after treatment of the
tumor is rare.
Paraneoplastic Sensorimotor Polyneuropathy
Clinical features. Sensorimotor polyneuropathies also may
have an immunologic pathogenesis as part of a paraneoplastic
syndrome.24 From a clinical and electrophysiologic standpoint,
it is usually easy to distinguish neuropathy caused by direct
tumor infiltration from a paraneoplastic or idiopathic variant by
its local character, but rarely—in widespread cases—the dis-
tinction may be difficult. Although sensory symptoms predomi-
nate in the paraneoplastic anti-Hu syndrome, mild weakness is
evident in many patients.283 Multiple mononeuropathies attributed
to paraneoplastic vasculitis are described in patients with lym-
phoma, SCLC, and adenocarcinoma of the lungs, endometrium,
prostate, and kidneys.24,443,558,639,739,846,985,1307,1357,1430
Histopathology. Histologic examination of the peripheral
nervous system in patients with clinical signs and symptoms of
a sensorimotor peripheral neuropathy reveal a general reduction
in all myelinated fibers.172,262,564,580,876,1291,1313,1435 Perivascular in-
flammation as well as changes due to necrotizing vasculitis
have been described within peripheral nerves.
Pathogenesis. The pathogenic basis of the neuropathy is not
known. Perhaps an immune response is directed at both sensory
and motor components of peripheral nerves.
Electrophysiologic Findings. Patients with a generalized
sensorimotor peripheral neuropathy demonstrate findings con-
sistent with the above histopathologic observations.172,262,564,580,
876,1291,1313,1435 Sensory nerve conduction studies show absent or
low-amplitude SNAPs with normal or borderline-slowing con-
duction velocities and slightly prolonged distal latencies. Motor
conduction studies reveal low normal or mildly slowed veloci-
ties. The CMAP amplitudes may be reduced in the intrinsic
muscles of the hands and feet. The distal motor latencies can be
mildly prolonged. Needle EMG examination may reveal evi-
dence of long-standing motor unit remodeling (increased
MUAP amplitudes, durations, and phases), decreased recruit-
ment, and fibrillation potentials and positive sharp waves of
varying degrees.
Paraneoplastic Autonomic Neuropathy
Autonomic dysfunction can occur as an isolated disturbance
or as part of the spectrum of the anti-Hu–associated en-
cephalomyelitis-neuropathy syndrome.283 Autonomic neuropa-
thy is most commonly described as a paraneoplastic effect of
SCLC but also has been described with adenocarcinoma and
carcinoid tumor of the lungs, testicular cancer, pancreatic ma-
lignancy, and Hodgkin’s lymphoma.214,283,453,777,1214,1245 The auto-
nomic neuropathy may manifest as orthostatic hypotension,
intestinal pseudo-obstruction, urinary retention, constipation,
dry eyes and mouth, and pupillary dysfunction. In a study of 71
patients with anti-Hu–associated encephalomyelitis-sensory
neuronopathy syndrome, 10% presented with severe orthostatic
hypotension, and 28% had varying degrees of dysautonomia
during the course of the illness.283 Autopsies have demonstrated
damage to neurons in the dorsal root ganglia in addition to those
of the myenteric plexus in patients with intestinal pseudo-ob-
struction. Lennon reported autoantibodies directed against a nu-
clear antigen of myenteric neurons in patients with this
syndrome.777
CRYPTOGENIC SENSORY OR
SENSORIMOTOR POLYNEUROPATHY
Clinical Features. Cryptogenic sensory or sensorimotor
polyneuropathy complicating cancer is much more common than
paraneoplastic neuropathies.262,263,564 The polyneuropathy is more
common in patients with SCLC but also can complicate carci-
noma of the breast, ovary, uterus, testes, kidney, and gastrointesti-
nal tract. The causes of sensorimotor neuropathy in malignancy is
multifactorial. A paraneoplastic basis for the sensorimotor
polyneuropathy, although often suspected, is actually uncommon.
In most cases, the cause of sensory or sensorimotor polyneuropa-
thy complicating cancer remains unknown or idiopathic.
The neuropathy in most patients manifests clinically with
slowly progressive, distal, symmetric numbness, beginning in

the feet and later progressing to the hands.24,262,263,564 All sensory
modalities can be affected, but the prominent sensory ataxia that
is seen in sensory neuronopathies is generally not observed.
Mild distal weakness of the distal lower and upper limbs may be
noted. Deep tendon reflexes are diminished or absent distally.
Laboratory Features. There are no specific laboratory
abnormalities.
Histopathology. Nerve biopsies and post-mortem tissue
analysis most commonly reveal axonal degeneration and regen-
eration, but segmental demyelination and remyelination have
been reported.261,263,312,876
Pathogenesis. The pathogenic basis is not known. Although
various chemotherapies are toxic to peripheral nerves, a sensory
or sensorimotor polyneuropathy can occur in untreated people
with cancer. Weight loss frequently accompanies malignancies,
but patients may not appear cachectic or malnourished when
neuropathy initially manifests.24,876,1313 Furthermore, vitamin
supplementation is of no benefit.876 The pathogenesis may be
related to toxic factors released by the tumor, which may some-
how result in axonal degeneration.876 Metabolic disturbances,
such as an alteration in protein and fat metabolism, that occur
with malignancies may be responsible for the neuropathy.
Electrophysiologic Findings. Nerve conduction studies
demonstrate features of a length-dependent, axonal, sensory or
sensorimotor polyneuropathy.24,262,1313 Sensory studies reveal de-
creased or absent sensory nerve action potentials. Compound
muscles action potentials are normal or only mildly reduced in
amplitude. Likewise, distal latencies and conduction velocities of
motor and sensory nerves are normal or only slightly prolonged
or slow. EMG may reveal mild denervation changes distally.
Treatment. There is no specific treatment for the neuropa-
thy other than treating the underlying malignancy and maintain-
ing adequate nutrition.
NEUROPATHIES RELATED TO TUMOR INFILTRATION
Mononeuropathy Multiplex
Occasionally, the peripheral nerves can be invaded directly
by the tumor, particularly leukemia and lymphoma, resulting in
mononeuropathy, mononeuropathy multiplex, polyradiculopa-
thy, plexopathy, or even generalized symmetric distal or proxi-
mal and distal polyneuropathy.24 The onset and course of the
neuropathy can be acute, subacute, or chronic progressive. Of
importance, peripheral neuropathy may be the presenting clini-
cal manifestation of leukemia or lymphoma or the heralding
feature of a relapse.
Leukemia. Peripheral neuropathy has been reported in up to
5.5% of cases of leukemia.725,876,1068,1269,1362,1403 Mononeuropathy
or mononeuropathy multiplex may result from hemorrhage or
leukemic infiltration into cranial or peripheral nerves and spinal
roots. Symmetric peripheral neuropathy is unusual but has been
described. Acute, subacute, and chronic sensorimotor polyneu-
ropathies complicating chronic leukemia, especially chronic
lymphocytic leukemia, are well documented.256 The neuropathy
may respond to corticosteroids and treatment of the underlying
leukemia.
Electrophysiologic features are consistent with an axonal
sensorimotor polyneuropathy. Nerve biopsies can demonstrate
leukemic infiltration of the nerve, axonal degeneration, and seg-
mental demyelination. Vasculitis also has been suggested as a
cause of peripheral neuropathy in hairy cell leukemia.443,558
Angiotrophic Large-cell Lymphoma. Angiotrophic large-
cell lymphoma is a rare malignancy characterized by intravascular
Chapter 23 ACQUIRED NEUROPATHIES — 991
proliferation of large, atypical, lymphoid B-cells.786,1134,1364 The
CNS and skin are the most common sites of involvement. Of
note, malignant cells are absent in the peripheral blood or lym-
phoid tissues. Approximately 24% of patients have involvement
of the spinal cord or roots, and 5% have mononeuropathies.786
Intravascular vascular and endoneurial lymphocytic infiltration
(primarily B-cells) is evident on nerve biopsy.
Lymphomatoid Granulomatosis. Lymphomatoid granulo-
matosis is an angiocentric, immunoproliferative disorder with a
pleomorphic lymphoid infiltrate of blood vessels.24 The infil-
trate is composed of reactive T-cells, which are driven by
Epstein-Barr infected T-cells.1418 There is a predisposition for
evolution into lymphoma. Distal symmetric polyneuropathy,
mononeuropathy multiplex, polyradiculopathies, and cranial
neuropathies occur in 10–15% of patients.168,662,795 Nerve biop-
sies reveal perivascular lymphoplasmatoid infiltrates in the
epineurium that lead to necrosis or thrombosis of the vessels
and ischemic injury to the nerve fascicles. Electrophysiologic
studies suggest an axonopathy.
Cranial Neuropathies and Radiculopathies
Almost any type of cancer has the potential to invade the lep-
tomeninges, cranial nerves, and nerve roots.24 Polyradiculopathy
due to malignant invasion of the nerve roots manifests as radicu-
lar pain and sensory loss, weakness, and hypo- or areflexia.
Widespread involvement can mimic a generalized sensorimotor
polyneuropathy. Upper motor neuron dysfunction can also occur,
if the spinal cord is compressed. Multiple cranial neuropathies
may result from spread of a local tumor (i.e., nasopharyngioma)
or by metastasis. The sixth and fifth cranial nerves are most com-
monly affected in nasopharyngiomas, whereas the sixth cranial
nerve, followed by the third, fifth, and seventh, is most commonly
affected in metastatic processes. The so-called “numb chin syn-
drome,” characterized by numbness of the lower lip and chin, is
particularly worrisome for malignant invasion of the mental or
alveolar branches of the mandibular nerve.
MRI with gadolinium may demonstrate enhancement or
compression of the nerve roots by the tumor. CSF may be ab-
normal, revealing increased protein, an increased cell count, and
malignant cytology. It may take several weeks for evidence of
active denervation to appear on EMG. Asymetrically prolonged
or absent F-waves may be a sensitive early indicator of nerve
root involvement.
Patients with leukemia and lymphoma may respond to irradi-
ation and intrathecal chemotherapy. However, the response rate
is much lower in other types of tumors, with the possible excep-
tion of breast cancer.
Brachial Plexopathy
Damage to the brachial plexus usually results from metasta-
sis, regional spread of a local tumor (e.g., Pancoast tumor), or
radiation-induced injury.24 In a series of 100 patients with
cancer and brachial plexopathy, metastatic tumor was responsi-
ble for the plexopathy in 78%.717 The most common tumors are
lung or breast carcinomas. The cancer most often spreads via
the lymphatics to the region of the lateral group of axillary
lymph nodes, where divisions of the lower trunk of the brachial
plexus are located. Cancers in the apices of the lungs may grow
into the paravertebral space and posterior chest wall and invade
the extraspinal C8–T3 mixed spinal nerves, the sympathetic
chain, and the stellate ganglia (see Chapter 19).
The most common symptom, occuring in approximately 85%
of patients, is pain in the shoulder area that radiates into the
992 — PART IV CLINICAL APPLICATIONS
medial aspect of the arm and the fourth and fifth digits of the
hand. Sensory loss and weakness are usually present in the dis-
tribution of the lower trunk. Horner’s syndrome due to involve-
ment of the sympathetic chain or stellate ganglia is evident in
most patients. A few patients have lymphedema of the affected
arm. Signs and symptoms attributable to involvement of the
upper and middle trunk of the brachial plexus are much less
common and, when present, suggest epidural extension of the
tumor.
Radiation-induced brachial plexopathy usually occurs after
doses greater than 6000 rads and presents 3 months to 26 years
(mean: 6 years) after radiation treatment to the region.717 Unlike
metatastatic plexopathy, pain occurs in only 15% of patients and
usually is not as severe. Paresthesias and lymphedema are pre-
sent in 55% and 45% of patients, respectively. The upper plexus
is involved in 77%, and diffuse plexus involvement is seen in
23% of patients. The relative sparing of the lower trunk of the
brachial plexus may relate the shorter distance that the trunk
travels through the radiation port or a protective effect of the
overlying clavicle. However, other studies have reported that the
entire plexus is more commonly involved than just the upper
trunk.916
MRI or CT scan may demonstrate malignant invasion of the
plexus and perhaps extension to the epidural space. Although
myokymic discharges on EMG are highly suggestive of radia-
tion-induced damage, the absence of myokymia doses not ex-
clude radiation plexopathy. At times noninvasive testing cannot
differentiate between metastatic and radiation disease, and surgi-
cal exploration and biopsy are required for definitive diagnosis.
Neoplastic invasion of the brachial plexus can be treated with
radiation therapy. Although patients may experience pain relief,
there is usualy no notable improvement in strength. Treatment
of the pain with transcutaneuous stimulation, sympathetic
blockage, or dorsal rhizotomies has been disappointing.
Lumbosacral Plexopathy
Malignant invasion of the lumbosacral plexus may due to
direct extension of intra-abdominal neoplasms (73%) or metas-
tasis of a distant tumor (27%).620 The most comon tumors are
colorectal, cervical, lymphoma, sarcoma, and breast cancers.
The lumbar plexus is involved in 31%, the lumbosacral trunk in
51%, and the entire lumbosacral plexus in 18% of patients with
malignant invasion of the plexus.383,620 Patients present with in-
sidious onset of pain, numbness, weakness, and edema of the
lower limb. Bilateral lower limbs are involved in approximately
25% of cases. Incontinence or impotence develops in less than
10% of patients.
Radiation-induced lumbosacral plexopathy manifests 1–31
years (mean: 5 years) after completion of treatment as slowly
progressive weakness.24 Unlike plexopathy secondary to tumor
invasion, pain is present in only one-half of patients and typi-
cally is not as severe. Both lower limbs are typically involved,
although asymmetrically, and distal muscles are affected more
than proximal muscles. Bowel and bladder incontinence may
result from radiation-induced proctitis or cystitis.
MRI or CT of the lumbosacral spine and pelvis can demon-
strate tumor invasion of the lumbosacral plexus and, at times,
extension of the tumor into the epidural space. EMG reveals fib-
rillation potentials in the paraspinal muscles in approximately
50% of patients with radiation-induced damage, suggesting the
disorder is more appropriately termed a radiation radiculoplex-
opathy. Myokymia is evident in over 50% of patients with radi-
ation-induced lumbosacral radiculoplexopathy.24
NONINFILTRATIVE PERIPHERAL NEUROPATHIES
ASSOCIATED WITH LYMPHOPROLIFERATIVE
DISORDERS AND MONOCLONAL GAMMOPATHIES
Neuropathies associated with monoclonal gammopathies are
discussed under immune-mediated neuropathies, but the rela-
tionship between neuropathy, monoclonal gammopathies, and
malignancy deserves further comment. An increased incidence
of monoclonal gammopathies has been observed in patients
with peripheral neuropathy. About 10% of patients with idio-
pathic peripheral neuropathies have monoclonal gammopathies
compared with 2.5% of patients with peripheral neuropathies
secondary to other diseases.668,768 In addition, peripheral neu-
ropathies may be more common in patients with monoclonal
gammopathies than in the general population.1368 A causal rela-
tionship between monoclonal gammopathies and peripheral
neuropathies has been suggested by studies demonstrating bind-
ing of monoclonal IgM to peripheral and periaxonal regions of
nerve fibers.767,885 Antibodies directed against myelin-associated
glycoprotein (anti-MAG) are present in at least 50% of patients
with IgM monoclonal gammopathies and peripheral neu-
ropathies.661,704,768 However, what role, if any, these antibodies
play in the pathogenesis of peripheral neuropathies is unknown.
In IgA and IgG monoclonal gammopathies, immunoglobulin
deposition is generally not seen on nerve sheaths, and a causal
link is much less established.
All patients with peripheral neuropathies of unknown etiol-
ogy should be tested for the presence of monoclonal gam-
mopathies. Serum protein electrophoresis (SPEP) is a useful
screening test, but it is not as sensitive as immunoelectrophore-
sis (IEP) or immunofixation (IFE). Serum IEP or IFE should be
performed to identify the nature of monoclonal proteins and in
patients suspected of having a myeloproliferative disorder, even
with a normal SPEP, because a small monoclonal protein may not
be apparent. The presence of monoclonal gammopathies should
lead to an aggressive work-up for amyloidosis, multiple myeloma,
osteosclerotic myeloma, Waldenström’s macroglobulinemia, cryo-
globulinemia, leukemia, and lymphoma.669,671,702,744,768,1064,1361 If a
monoclonal gammopathy is detected, urine protein elec-
trophoresis and immunoelectrophoresis should be performed,
along with hematologic studies, bone marrow biopsy and aspi-
rate, and a radiographic skeletal survey. In most patients with
monoclonal gammopathies, no underlying disease is found;
such patients are designated as having a monoclonal gam-
mopathies of undetermined significance (MGUS). MGUS has
replaced the term benign monoclonal gammopathy because
approximately 20% of patients initially classified as having
MGUS eventually develop malignant disorders with long-term
follow-up.747,768,1064
Lymphoma
Clinical Features. Neuropathy in patients with lymphoma may
be secondary to direct endoneurial infiltration or direct compres-
sion of nerves by lymphoma24,727,877,921 but more commonly occurs
as a remote effect of the cancer.24,270,816,921,1381 Sensorimotor neu-
ropathy can complicate both Hodgkin’s disease (HD) and non-
Hodgkin’s lymphoma (NHL).123,170,262,270,803,921,1269,1381 The incidence
of peripheral neuropathy is generally thought to be lower in patients
with lymphoma (approximately 1–2%) than in patients with
SCLC.803,877 However, a prospective study reported clinically evi-
dent neuropathy in 8% and electrophysiologic evidence of neuropa-
thy in 35% of patients with lymphoma.1381 The clinical presentation
is variable. The neuropathy may be purely sensory602,1151 or motor1183

but most commonly is sensorimotor.1381 It may be symmetric,
asymmetric, or multifocal. Autonomic dysfunction also may occur.
The course may be acute,170,270,921,1269 subacute,803,921,1269 chronic
progressive,262,803,1381 or relapsing and remitting.123,170,262,803,921
Laboratory Features. CSF may reveal lymphocytic pleocy-
tosis and elevated protein.727,877,921,1381
Histopathology. Nerve biopsy may reveal axonal degenera-
tion along with segmental demyelination.170,877,1381 Inflammatory
cells within the endoneurium may be demonstrated in both infil-
trative and presumed paraneoplastic neuropathies complicating
lymphoma (Fig. 23-9). The presence of a monoclonal popula-
tion of inflammatory cells within the nerve fascicles suggests
infiltration of tumor cells rather than an immunologic paraneo-
plastic etiology.
Pathogenesis. The paraneoplastic neuropathy associated
with lymphomas is presumably autoimmune, but the exact anti-
gen(s) and triggers for the immune attack are not known.
Electrophysiologic Findings. Nerve conduction studies
may reveal changes compatible with an axonal sensorimotor
neuropathy1381 or demonstrates features of prominent demyeli-
nation270,1269 similar to that seen in AIDP and CIDP.
Treatment. The neuropathy may respond to treatment of the
underlying lymphoma.727,1151,1269
Multiple Myeloma
Multiple myeloma is the most common hematologic malig-
nancy associated with a monoclonal gammopathy. The disorder
typically manifests in the fifth-to-seventh decade of life with fa-
tigue, bone pain, anemia, and hypercalcemia. Peripheral neu-
ropathies associated with multiple myeloma are uncommon,
occurring in 3–13% of cases.667,668,702,748,1355,1380 Electrophysiogic
abnormalities, however, may be detected in 40% of cases, indi-
cating possible subclinical peripheral neuropathy.1380 Most pa-
tients have a distal, axonal, sensory or sensorimotor
neuropathy.667,1380 Less frequently, a demyelinating polyradicu-
loneuropathy may develop.667 A small-fiber neuropathy with
painful paresthesias and loss of pinprick and temperature dis-
crimination and autonomic dysfunction with superimposed
carpal tunnel syndrome suggest amyloid neuropathy.128 Epi-
dural cranial and spinal root compression by expanding plasma-
cytomas is common and may be superimposed upon and
overshadow the peripheral neuropathy.
Laboratory Features. Monoclonal proteins consisting of γ or
µ heavy chains or κ light chains are usually identified in the serum
or urine. Many patients are anemic, and hypercalcemia is evident
on routine chemistries. Skeletal survey typically reveals osteolytic
lesions. Diagnosis of multiple myeloma requires the demonstra-
tion of at least 10% plasmacytes on a bone marrow biopsy.
Histopathology. Amyloid deposition may be responsible for
up to two-thirds of neuropathies in patients with multiple
myeloma.667 Abdominal fat pad, rectal, or sural nerve biopsy
should be performed to look for amyloid deposition. In patients
without amyloidosis, nerve biopsies reveal prominent axonal
degeneration along with mild segmental demyelination/re-
myelination consistent with reinnervation.1380
Pathogenesis. The mechanism of the neuropathy in multiple
myeloma is multifactorial. The most common cause is primary
amyloidosis with infiltration of the nerves.667 Others may be due
to the metabolic or toxic effects of the systemic consequences
of multiple myeloma or amyloidosis (e.g., renal failure)
Electrophysiologic Findings. Nerve conduction studies
reveal low-amplitude or absent SNAPs with normal or only
mildly abnormal distal latencies and conduction velocities.295,667,1380
Chapter 23 ACQUIRED NEUROPATHIES — 993
Figure 23-9. Lymphoma. Sural nerve biopsy demonstrates marked
lymphomatous infiltration of endoneurium. (Paraffin section, H&E stain).
Likewise, CMAP amplitudes are reduced in patients with weak-
ness. The lower limbs have more profound changes than the
upper limbs. The needle EMG examination demonstrates positive
sharp waves and fibrillation potentials in the distal limb muscles.
Recruitment of long-duration, large-amplitude polyphasic
MUAPs may be reduced in the motor and sensorimotor forms of
the disease but not in pure sensory neuropathy.
Treatment. The treatment of the underlying multiple
myeloma usually does not affect the course of the neuropathy.
Osteosclerotic Myeloma (POEMS Syndrome)
Clinical Features. Osteosclerotic myeloma occurs in less
than 3% of patients with myeloma. However, unlike multiple
myeloma, polyneuropathy is present in almost one-half of cases
of osteosclerotic myeloma.670 Systemic manifestations are
common and include hepatosplenomegaly, cutaneous pigmenta-
tion, hypertrichosis, edema, ascitis, pleural effusion, leukony-
chia, finger clubbing, hypothyroidism, gynecomastia, testicular
atrophy with impotence in men, and ammenorhea in women.
This complex constitutes the Crow-Fukase or POEMS syn-
drome (Polyneuropathy, Organomegaly, Endocrinopathy,
Monoclonal gammopathy, Skin changes) (Table 23-7).69,702,749,
934,992,1355 Patients may display all or none of these features.
Some patients can have POEMS syndrome without osteoscle-
rotic myeloma. Other patients usually have Castleman’s disease
(angiofollicular lymphadenopathy), extramedullary plasmacy-
tomas, or a solitary lytic plasmacytoma. In still others, no tumor
is ever detected.
The neuropathy manifests as tingling, numbness, and weak-
ness of the distal lower limbs, which gradually progresses prox-
imally in the lower limbs and upper limbs like CIDP. These
alterations are bilateral and symmetric. The sensory modalities
mediated by large fibers are most affected, with decreased but
relative sparing of pain and temperature sensation. The cranial
nerves and respiratory muscles are usually spared but can be af-
fected. The peripheral neuropathy is usually present for several
years before the correct diagnosis is established.
Laboratory Features. Most patients have a IgG or IgA
lambda-chain monoclonal gammopathy.702 In up to 20% of pa-
tients, the monoclonal protein is demonstrated in the urine but
not in serum. In addition, various cytokines, including inter-
leukin (IL)-1β, IL-6, tumor necrosis factor-α, and vascular en-
dothelial growth factor, are elevated in the serum of patients
994 — PART IV CLINICAL APPLICATIONS
with POEMS syndrome.1388 CSF protein levels are often ele-
vated, as in CIDP.702 Skeletal survey reveals characteristic scle-
rotic (two-thirds of cases) or mixed sclerotic and lytic bony
lesions (one-third of cases), usually in the vertebral bodies,
pelvis, or ribs.702 In 50% of cases, these skeletal lesions, which
represent focal plasmacytomas, are multiple.
Histopathology. Sural nerve biopsy demonstrates a combi-
nation of segmental demyelination and Wallerian degenera-
tion.992 The number of myelinated fibers is reduced, with a shift
of fiber sizes toward the smaller end of the spectrum, and few
inflammatory cells are noted.
Pathogenesis. The pathogenesis of POEMS syndrome is not
clear, but an autoimmune mechanism is likely. Immunoglobulin
deposition similar to that seen in IgM-MGUS neuropathy has
not been demonstrated in patients with POEMS syndrome.
Electrophysiologic Findings. The electrodiagnostic medi-
cine examination is consistent with a demyelinating or mixed
axonal and demyelinative sensorimotor peripheral neuropa-
thy.295,323,326,667,670,992 Sensory studies reveal absent or markedly
reduced SNAP amplitudes with mild to moderate prolongation
of the peak latencies and similar reductions in conduction ve-
locity. Motor conduction studies demonstrate variable reduc-
tions in velocity, with some patients approaching 50–60% of the
lower limits of normal. The CMAP amplitudes are markedly re-
duced or absent in the lower limbs and mildly to moderately re-
duced in the upper limbs. Distal motor latencies are normal to
increased. Needle EMG examination can demonstrate fibrilla-
tion potentials and positive sharp waves with reduced recruit-
ment of MUAPs of long duration and increased amplitude.
These findings are worse in lower than upper limbs and more
pronounced in distal than proximal muscles. When patients are
examined early in the course of the disease, only a mild general-
ized peripheral neuropathy may be present, with few needle
EMG abnormalities. As the disease progresses, the above-noted
abnormalities become manifest.
Treatment. The neuropathy may respond to radiation, surgi-
cal excision of the isolated plasmacytoma, or chemotherapy.
The neuropathy also may improve with the usual treatment
given to patients with idiopathic CIDP (e.g., corticosteroids). In
one series of 38 patients, almost 50% reported that the neuropa-
thy responded to radiation and prednisone, with or without
some other form of chemotherapy. However, the neuropathy
and plasmacytoma can recur even in patients with an initial pos-
itive response to treatment.
Castleman’s Disease (Angiofollicular
Lymph Node Hyperplasia)
Castleman’s disease (angiofollicular lymph node hyperplasia)
is a lymphoproliferative disorder characterized by lymphoid hy-
perplasia associated with capillary proliferation.181,323 Castleman’s
disease may be associated with POEMS syndrome (absence of
the osteosclerotic lesions). The angiofollicular lymph node hy-
perplasia is characterized by marked vascular proliferation,
which may be related to increases in serum cytokine levels and
vascular endothelial growth factor.1,388
Waldenström’s Macroglobulinemia
Waldenström’s macroglobulinemia is an uncommon disorder
responsible for about 2% of cases of monoclonal gammopa-
thy.481,613,702,1073,1363 The disorder is caused by a malignant prolif-
eration of lymphoplasmacytoid cells, which produce an IgM
monoclonal protein, usually with a κ light chain. Waldenström’s
macroglobulinemia most commonly occurs in men aged 50–70
years. The disease is characterized clinically by insidious onset
of progressive fatigue, weight loss, lymphadenopathy, hemor-
rhagic diathesis (especially nosebleeds), anemia, and weakness.
Hepatomegaly and splenomegaly are commonly found on phys-
ical examination. Approximately 5% of patients with
Waldenström’s macroglobulinemia develop a symmetric sen-
sory or sensorimotor peripheral neuropathy, which is similar
clinically, electrophysiologically, and histologically to IgM-
MGUS neuropathies. Patients initially complain of numbness
and paresthesias that begin in the feet, progress proximally in
the lower limbs, and also affect the hands. Progressive difficulty
in ambulating independently may occur, along with reduced
fine motor coordination of the hands. Occasionally, a mononeu-
ropathy multiplex pattern of involvement is seen.
Laboratory Findings. Diagnosis requires demonstration of
an IgM monoclonal protein in a concentration greater than 3
gm/L. Over 80% of the monoclonal proteins are associated with
a κ light chain. The disorder is distinguished from IgM-
myeloma by the absence of lytic bone lesions and hypercal-
cemia and by the presence of hepatosplenomegaly and
lymphadenopathy. Antibodies directed against MAG can be de-
tected in the serum in as many as 38% of patients.702,964
Histopathology. Nerve biopsies reveal findings similar to
IgM-MGUS neuropathies with prominent demyelination and
immunoglobulin deposition on the outer myelin membranes and
occasionally in the periaxonal space, but not on the compact
myelin.
Pathogenesis. The mechanism of the neuropathy is unknown.
As with IgM-MGUS, the neuropathy may be related to anti-MAG
antibodies, although a causal relationship has not been estab-
lished. Some neuropathies are caused by secondary amyloidosis
or nerve fiber ischemia related to serum hyperviscosity.
Electrophysiologic Findings. Nerve conduction studies
most commonly reveal a demyelinating sensorimotor polyneu-
ropathy indistinguishable from IgM-MGUS neuropathy.
However, some patients have features more consistent with an
axonal sensorimotor neuropathy.481,613,702,964,1073,1363 Needle EMG
examination consistently reveals fibrillation potentials and posi-
tive sharp waves as well as reduced numbers of MUAPs firing at
high rates during a minimal contraction. These findings are
prominent in the distal muscles of the upper and lower limbs; less
dramatic changes are noted in proximal muscle examination.
Treatment. Some patients reportedly benefit form corticos-
teroids, chlorambucil, or plasma exchange.964 However, pros-
pective, blinded, controlled trials have not been performed.
ACQUIRED AMYLOIDOSIS
Amyloidosis is a relatively nonspecific name for a heteroge-
neous collection of various disorders, all with amyloid deposi-
tion in different organs.575,743,750,1141 Classification of amyloidosis
is based on the hereditary or acquired nature of the disease and
the identification of the major protein constituent of the accu-
mulating amyloid. Familial amyloidosis is caused by muta-
tions in the genes for transthyretin, apolipoprotein A-1, or
gelsolin. Familial amyloidosis is discussed in Chapter 22.
Secondary amyloidosis (AA) is seen in patients with rheuma-
toid arthritis and other chronic inflammatory diseases and is as-
sociated with the accumulation of protein A. Peripheral
neuropathy is uncommon in secondary amyloidosis. Primary
amyloidosis (AL amyloidosis) is the designation given when
the amyloid is composed of light chains; hence the term AL amy-
loidosis. Primary amyloidosis can occur in the setting of multiple

myeloma, Waldenström’s macroglobulinemia, lymphoma, other
plasmacytomas or lymphoproliferative disorders, or without any
other identifiable disease.
Amyloid is a proteinaceous substance composed of non-
branching fibrils, approximately 10–20 nanometers in diameter,
with a β-pleated sheet structure. The fibrils are not soluble in
aqueous solutions and are quite resistant to proteolytic decom-
position. Amyloid eventually damages the various organs and
peripheral tissues in which it is deposited. The arrangement of
amyloid fibrils results in the characteristic apple-green birefrin-
gence when they are stained with Congo red and observed under
conditions of polarized light. Metachromasia is seen when they
are stained with methyl violet or crystal violet. The appearance
of the Congo red or metachromatic staining does not distinguish
among the various subtypes of amyloidosis. Immuno-
histochemistry using antibodies directed against light chains,
protein A, gelsolin, and transthyretin are required to distinguish
histologically among the various forms.
Primary Amyloidosis
Clinical Features. Primary (AL) amyloidosis is a systemic
disorder that typically affects men after the sixth decade of
life.344,666 This later age of onset is helpful in distinguishing be-
tween AL and familial amyloidosis. Patients with AL amyloido-
sis may present with symptoms attributable to the major organ
systems preferentially affected. Organs that commonly are ren-
dered dysfunctional include the kidney (nephrotic syndrome),
heart (congestive heart failure), skin, lungs, gastrointestinal
tract (nausea, constipation, diarrhea, pain), and peripheral ner-
vous system. Patients with peripheral nervous system involve-
ment commonly complain of weakness, fatigue, and weight
loss. The general physical examination can demonstrate limb
edema, hoarse voice (amyloid deposit in vocal cords), he-
patomegaly, and macroglossia.
Peripheral neuropathy occurs in 15–30% of patients with AL
amyloidosis and may be the presenting manifestation in one-
sixth of cases.128,666,702,745,750 Initially small-fiber modalities are
affected, resulting in painful dysesthesias along with diminished
pain and temperature sensation. The neuropathy is slowly pro-
gressive, and eventually symmetric weakness develops, begin-
ning in the distal lower limbs and accompanied by large-fiber,
discriminatory sensory loss. Most patients develop autonomic
involvement with postural hypertension, syncope, impotence,
gastrointestinal disturbance, impaired sweating, and loss of
bladder control. Carpal tunnel syndrome occurs in 25% of pa-
tients and may be the presenting manifestation.750 Enlarged pe-
ripheral nerves are a rare finding. Although the peripheral nerve
symptoms are annoying, renal or cardiac failure is more serious
and has lethal consequences. The clinical and electrodiagnostic
findings are essentially the same in patients with primary amy-
loidosis and other lymphoproliferative disorders.666
Laboratory Features. The amyloid is composed of the
complete or variable portion of the monoclonal light chain.
Lambda (λ) is more common than κ light chain (2:1) in AL
amyloidosis, whereas in multiple myeloma κ light chains are
more common.750
Histopathology. Nerve biopsies may reveal amyloid deposi-
tion in either a globular or diffuse pattern within epineurial and
endoneurial connected tissue and blood vessel walls.745,750
Immunohistochemistry is helpful in demonstrating that the
amyloid is composed of λ or, less frequently κ, light chains.
Active axonal degeneration and severe loss of small myelinated
and unmyelinated fibers are observed. Degeneration of the large
Chapter 23 ACQUIRED NEUROPATHIES — 995
myelinated nerve fibers is less pronounced but obvious. Cranial
nerves also may demonstrate significant loss of axons, with
amyloid deposition the most likely cause. Amyloid deposition
also can be demonstrated in the sympathetic and dorsal root
ganglia.
Electrophysiologic Findings. Despite the various different
types of amyloidosis, similar histopathologic alterations form
the foundation for the rather common electrodiagnostic medi-
cine findings.27,348,666,1299 In patients with carpal tunnel syn-
drome, the electrophysiologic findings are the same as those
anticipated for preferential slowing of median nerve conduction
across the carpal tunnel region.
The generalized sensorimotor peripheral neuropathy in all
forms of amyloidosis demonstrates variable degrees of SNAP
abnormalities. The SNAP amplitudes are diminished or absent.
When obtainable, the distal sensory latencies are normal or only
mildly prolonged, and conduction velocities are similarly normal
or mildly reduced. In general, the lower limbs tend to be more
severely affected than the upper limbs; in long-standing and
severe disease, however, all sensory potentials may be absent.
Motor nerve conduction velocities are in low normal range or
slightly reduced. The distal motor latencies are normal or only
moderately prolonged in the upper limbs and usually prolonged
in the lower limbs. CMAP amplitudes are normal or only mildly
reduced during early disease and not as severely affected as the
SNAP. This finding is understandable when one considers that
collateral sprouting maintains the CMAP amplitude until it can
no longer compensate for lost axons, whereas the sensory
system does not have this capability to a significant degree.
Needle EMG usually reveals significant degrees of positive
sharp waves and fibrillation potentials in the distal muscles of
the lower limbs. Such findings usually are not observed in the
upper limbs until late in the disease process. Reduced recruit-
ment is noted in affected muscles. Motor unit remodeling
results in the eventual demonstration of long-duration, high-am-
plitude, polyphasic potentials. Fasciculation potentials also may
be observed in upper and lower limb muscles. Single-fiber
EMG examination also demonstrates findings consistent with
denervation and subsequent motor unit remodeling (i.e., ele-
vated jitter, blocking, and fiber density).
Treatment. The prognosis of patients with primary amyloi-
dosis is poor; the median survival is 2 years.750 Death generally
results from progressive congestive heart failure or renal failure.
Chemotherapy with melphalan, prednisone, or colchicine, all of
which reduce the concentration of monoclonal proteins, gener-
ally has been unsatisfactory.128,750
NEUROPATHIES ASSOCIATED WITH MONOCLONAL
GAMMOPATHY OF UNCERTAIN SIGNIFICANCE
Clinical Features. MGUS neuropathy is heterogeneic in its
clinical, laboratory, and electrophysiologic features.702,746–748,768
The neuropathies can be either demyelinating or axonal. As dis-
cussed in the CIDP section, neuropathies associated with an
IgM monoclonal protein are typically demyelinating, whereas
IgG and IgA monoclonal gammopathies may be axonal or de-
myelinating in nature.
Patients with a demyelinating neuropathy can present with
typical features of CIDP.152,661,671,672,702,969,972,1064,1168,1168a,1216,1217,
1218,1234,1235 Patients usually describe numbness and tingling in both
upper and lower limbs, beginning in the distal regions and pro-
gressing proximally. Significant reductions in sensation conveyed
996 — PART IV CLINICAL APPLICATIONS
by large myelinated fibers are noted, along with a reduction in
the ability to perceive pain and temperature. A positive
Romberg sign may be present. Weakness also can develop but
usually is restricted to the distal limbs in IgM-MGUS neu-
ropathies. Patients with IgG-MGUS and IgA-MGUS neu-
ropathies are more likely to have symmetrical proximal and
distal weakness typical of idiopathic CIDP. Deep tendon re-
flexes are reduced or absent throughout.
Patients with an axonal neuropathy present with distal sen-
sory loss in a length-dependent fashion. Clinical, laboratory,
histopathology, and electrophysiologic features are indistin-
guishable from idiopathic sensory or sensorimotor polyneu-
ropathies. The pathogenic relationship of the monoclonal
protein to the neuropathy is not clear.
Laboratory Features. At least 50% of the patients with IgM-
MGUS neuropathy have antibodies directed against myelin-asso-
ciated glycoprotein (MAG).661,748,768,1064,1256 Elevated CSF levels
are common in patients with a demyelinating neuropathy.
Histopathology. Nerve biopsy demonstrates a reduction in
the myelinated nerve fiber population with relative sparing of
unmyelinated fibers.702,748,947,1234 The remaining myelinated
fibers are usually of small fiber caliber. A combination of seg-
mental demyelination and remyelination as well as axonal loss
is found. In some patients, demyelination predominates,
whereas in others axonal loss may be somewhat more signifi-
cant. In patients with IgM-MGUS, immunohistochemistry re-
veals immunoglobulin deposition on the outer myelin
membranes and occasionally in the periaxonal space but not on
compact myelin.748,885,1256,1361 Deposition of complement (C1q,
C3d, C5, and C5b-9) along the myelin sheath also has been
demonstrated,911 although in some patients the presence of C5b-
9 deposits cannot be confirmed.699 Ultrastructurally, the myelin
sheaths appear to be separated and IgM deposits can be demon-
strated in zones of myelin splitting.
Pathogenesis. As described earlier, IgM-MGUS is usually
associated with a demyelinating neuropathy. Endoneurial injec-
tion or passive transfer of serum from patients with IgM anti-
MAG antibodies into animals leads to conduction block and
demyelination. However, response to plasmapheresis and other
immunotherapies is less satisfactory in this IgM-MGUS sub-
group than in IgG/IgA demyelinating neuropathies, in which a
causal link is even less well established.360
Electrophysiologic Findings. The electrophysiologic find-
ings depend on the pathogenic basis of the neuropathy. As pre-
viously noted, IgG and IgA MGUS neuropathies can be either
axonal or demyelinating. The IgM-MGUS neuropathies are typ-
ically demyelinating. When axonal loss predominates, SNAPs
are reduced in amplitude or absent. CMAP amplitudes can be
normal or reduced, but distal latencies and conduction veloci-
ties are normal or only mildly affected.
In demyelinating MGUS neuropathies, the SNAP amplitudes
are reduced or absent in most patients.275,327,329,668,942,969,972
Latencies are usually prolonged; hence conduction velocities are
variably reduced. Motor nerve conduction studies reveal
markedly prolonged distal latencies with moderate slowing of
conduction velocities.152,661,669,942,969,972,1089,1168,1168a,1234,1235 Lower
limb nerves are usually considerably more involved than upper
limb nerves. Distal accentuation of demyelination and thus slow-
ing of conductions are reflected by the lower terminal latency
index (TLI) in patients with IgM-MGUS neuropathy. CMAP
amplitudes are at least minimally reduced and often consider-
ably reduced. F-wave latencies are characteristically prolonged
and sometimes hard to elicit with every supramaximal stimulus.
Needle EMG quite commonly reveals positive sharp waves
and fibrillation potentials in the hand and foot intrinsic muscles,
with variable degrees of abnormal spontaneous activity in more
proximal muscles.152,275,329,669,942,1234,1235 The location of the ab-
normality obviously depends on the severity of disease. MUAPs
suggest extensive motor unit remodeling, with large-amplitude,
long-duration potentials predominating in distal muscles and
variable degrees of changes in more proximal muscles.
Treatment. Patients with MGUS neuropathy who fulfill
clinical and electrophysiologic criteria for CIDP can improve
with immunotherapy (discussed in greater detail in the CIDP
section). The demyelinating sensorimotor polyneuropathies as-
sociated with IgG-MGUS and IgA-MGUS are more amenable
to treatment than the IgM-MGUS neuropathies.
NEUROPATHY ASSOCIATED WITH BONE MARROW
TRANSPLANTATION AND GRAFT-VS-HOST DISEASE
Neuropathies can complicate bone marrow transplantation
(BMT) secondary to the toxic effects of chemotherapy, im-
munosuppressive agents, radiation, or infection and perhaps to
an autoimmune response directed against the peripheral
nerves.21,22,24 Cranial and peripheral neuropathies1425 are most
frequently related to herpes zoster infection or previous
chemotherapy.293,1425 Neuropathy may be due to hemorrhage
within the nerve or plexus. Other potential causes of neuropathy
include carcinomatous or infectious meningitis with infiltration
of nerves, toxicity from immunosuppressive medications, mal-
nutrition, and sepsis with multiorgan failure in critically ill pa-
tients. Another important cause of peripheral neuropathy in
patients with BMT is graft-versus-host disease (GVHD).21
Chronic GVHD has features associated with a variety of au-
toimmune disorders, and an immune-mediated response may be
directed against peripheral nerves.
Patients can develop a variety of cranial neuropathies, includ-
ing loss of olfactory and gustatory sensation,500 sensorimotor
polyneuropathy,488 multiple mononeuropathies,1425 and severe
generalized peripheral neuropathies resembling GBS79,533,931,1038
or CIDP21 have been well described. Electrophysiologic studies
may be consistent with a primary axonal, demyelinating, or
mixed pathogenic process. Some cases of GBS have been attrib-
uted to chemotherapy, CMV, or Campylobacter jejuni infections
and have improved with plasma exchange79,488 or IVIG.533 In
some patients, the neuropathy responds to increased immuno-
suppressive therapy and resolution of GVHD.21
TOXIC NEUROPATHIES
CHEMOTHERAPY
The commonly used anticancer drugs that can cause neu-
ropathy fall mainly into three groups: platinum agents (cis-
platin), vinca alkaloids (vincristine), and taxanes (paclitaxel,
docetaxel) (Table 23-11).24 The clinical manifestations of neu-
ropathy are somewhat different for various agents. When
symptoms first begin, nerve conduction studies are often
normal. With further doses, abnormalities eventually occur but
again may differ with the various chemotherapy drugs. These
agents generally produce neuropathy in a dose-dependent rela-
tionship; the higher the dose and the longer the time of expo-
sure, the more likely a neuropathy will occur. Age alone is
probably not a major factor that predisposes patients to develop
 Chapter 23 ACQUIRED NEUROPATHIES — 997

Table 23-11. Toxic Neuropathies Caused By Chemotherapy

Mechanism of
Drug Neurotoxicity Clinical Features Nerve Histopathology EMG/NCS
Vinca alkaloids Interfere with axonal micro- Symmetric, S-M, large/ Axonal degeneration of Axonal sensorimotor PN
vincristine, vin- tubule assembly small fiber PN myelinated and unmyelinated Distal denervation on EMG
blastine, vindesine, Impairs axonal transport Autonomic symptoms fibers Abnormal QST, particularly
vinorelbine) common Regenerating clusters vibratory perception
Infrequent cranial Minimal segmental
neuropathies demyelination
Cisplatin Preferential damage to Predominant large-fiber Loss of large > small mye- Low-amplitude or unobtain-
dorsal root ganglia sensory neuropathy linated and unmyelinated able SNAPs with normal
? Binds to and cross-links Sensory ataxia fibers CMAPs and EMG
DNA Axonal degeneration with Abnormal QST, particularly
? Inhibits protein synthesis small clusters of regenerat- vibratory perception
? Impairs axonal transport ing fibers
Secondary segmental
demyelination
Taxanes (paclitaxel, Promotes axonal micro- Symmetric, predominantly Loss of large > small mye- Axonal sensorimotor PN
docetaxel) tubule assembly sensory PN linated and unmyelinated Distal denervation on EMG
Interferes with axonal Large-fiber modalities fibers Abnormal QST, particularly
transport affected more than Axonal degeneration with vibratory perception
small-fiber small clusters of regenerat-
ing fibers
Secondary segmental
demyelination
Suramin
Axonal PN Unknown Symmetric, length- None described Abnormalities consistent
? Inhibition of neurotrophic dependent, sensory- with axonal S-M PN
growth factor binding predominant PN
? Neuronal lysosomal storage
Demyelinating PN Unknown Subacute S-M PN with Loss of large and small mye- Features suggestive of an
? Immunomodulating effects diffuse proximal and linated fibers with primary acquired demyelinating
distal weakness demyelination and secondary sensorimotor PN (e.g.,
Areflexia axonal degeneration slow CVs, prolonged distal
Increased CSF protein Occasional epi- and endoneu- latencies and F-wave
rial inflammatory cell latencies, conduction
infiltrates block, temporal
dispersion)
Ara-C Unknown GBS-like syndrome Loss of myelinated nerve Axonal, demyelinating, or
? Selective Schwann cell Pure sensory neuropathy fibers mixed S-M PN
toxicity Brachial plexopathy Axonal degeneration Denervation on EMG
? Immunomodulating effects Segmental demyelination
No inflammation
Etoposide Unknown Length-dependent, None described Abnormalities consistent
? Selective dosral root sensory predominant with axonal S-M PN
ganglia toxicity PN
Autonomic neuropathy
S-M = sensorimotor, PN = polyneuropathy, EMG = electromyography, NCS = nerve conduction studies, QST = quantitative sensory testing, GBS = Guillain-Barré
syndrome
From Amato AA, Collins MP: Neuropathies associated with malignancy. Semin Neurol 1998;18:125–144, with permission.

a neuropathy secondary to chemotherapy. Neurotoxicity is
more common and severe in patients with a preexisting neu-
ropathy (e.g., Charcot-Marie-Tooth disease, diabetic neuropa-
thy) and patients taking other potentially neurotoxic drugs
(e.g., nitrofurantoin, isoniazid, disulfiram, pyridoxine). The
mechanism by which degeneration of the ganglion cells or
axons occurs is different for various agents. The pathologic
process in chemotherapy-induced neuropathies is either distal
axonopathy due to axonal degeneration or ganglionopathy.
It is often a difficult to decide whether to stop chemotherapy
drugs in the setting of neuropathy if the tumor is responding to
therapy. Occasionally, a dose reduction can ameliorate some of
the neuropathy symptoms or stop them from progressing. In
general, withdrawal leads to some improvement of the neuropa-
thy. However, complete resolution of symptoms and signs is
more likely if the drug is stopped in the early stages of the pe-
ripheral neuropathy. After significant cumulative doses, some
symptoms and signs may persist, especially mild distal sensory
998 — PART IV CLINICAL APPLICATIONS
loss and hypo- or areflexia. The neuropathy also may continue
to progress for several weeks or even months after discontinua-
tion of the offending toxic agent because of the so-called coast-
ing-effect. Although the drug may be eliminated from the blood
stream, its toxic biologic effects on the peripheral nervous
system can continue. Nerve growth factor and other neu-
rotrophins may be beneficial in the future for preventing or
treating chemotherapy-induced neuropathies.24
Cisplatin
Clinical Features. Cisplatin is used widely for the treatment
of ovarian, testicular, and bladder cancer. Cisplatin produces a pre-
dominantly sensory neuronopathy (ganglionopathy) at cumulative
doses of 225–501 mg/m2.24,48,67,187,503,529,724,808,912,913,1112,1144,1304,1383
Large-fiber modalities are preferentially affected, resulting in
paresthesia, hypesthesia, diminished deep tendon reflexes, loss
of vibratory perception and proprioception with gait ataxia, and
pseudoathetoid movements. Deep tendon reflexes are reduced
or diminished throughout. Of interest, as many as 40% of pa-
tients can develop Lhermitte’s sign, perhaps due to demyelina-
tion and edema of the posterior columns. Weakness occurs in
only 2% of patients.187 The neuropathy can appear as late as 8
weeks after the drug has been discontinued and continue to
progress up to 6 months after discontinuation.24
Histopathology. Cisplatin given to rats produces changes in
the dorsal root ganglion and axonal degeneration on both cen-
tral and peripheral nerve processes.808 Sural nerve biopsies
reveal a predominant loss of large myelinated nerve
fibers.67,503,724,1112,1304 Axonal degeneration, segmental demyeli-
nation, and regenerating axonal sprouts also may be evident.
Pathogenesis. Cisplatin covalently binds DNA, creating in-
terstrand and intrastrand cross-links. Pathologic and electro-
physiologic studies suggest that neuronal cell bodies in the
dorsal root ganglion are preferentially affected. Binding of the
drug to neuronal DNA may inhibit transcription of important
proteins and impair axonal transport.24
Electrophysiologic Findings. Electrophysiologic studies
reveal low-amplitude or absent sensory nerve action potentials
with normal or only slightly prolonged distal latencies or slow
sensory conduction velocities.290,529,724,808,912,1096,1105,1112,1304 Quan-
titative sensory testing has demonstrated that vibratory percep-
tion is a sensitive indicator of early cisplatin-induced
neuropathy. Motor nerve conduction studies and needle EMG
are usually normal.373
Vincristine
Clinical Features. Vincristine, the most commonly used
vinca alkaloid, produces a sensorimotor and autonomic neu-
ropathy.24,136,179,513,592,775,869,1014,1155,1167 The earliest symptoms are
paresthesias and numbness, which at times occur in the fingers
before the toes. These symptoms have been reported as early as
2 weeks after a single dose of 2 mg/m2. The loss of ankle re-
flexes commonly precedes the subjective loss of sensation. With
further dose accumulation, distal weakness of the hands and feet
occurs in 25–35% of patients.592,1167 Cranial neuropathies, in-
cluding optic neuropathy, oculomotor palsies, facial weakness,
hearing loss, and laryngeal paralysis, are rare. Autonomic
nerves can become involved, leading to constipation, urinary re-
tention, impotence, and orthostatic hypotension.
Histopathology. Sural nerve biopsies reveal axonal degen-
eration and loss of myelinated and unmyelinated nerve
fibers.136,869 Scattered clusters of regenerating axonal sprouts
may be seen.
Pathogenesis. Vinca alkaloids inhibit microtubule formation
by binding to tubulin. The impairment in the microtubules inter-
feres with axoplasmic transport and subsequently causes cy-
toskeletal disarray and axonal degeneration.496,1155
Electrophysiologic Findings. Sensory and motor nerve con-
duction studies reveal diminished amplitudes or absent re-
sponses.869,1014,1105,1167 Normal or only mildly prolonged distal
latencies and slow conduction velocities are evident. Stopping
the drug results in improvement of SNAP and CMAP ampli-
tudes, but they do not commonly return to pretreatment levels.
Fibrillation potentials and positive sharp waves reflecting active
denervation can be seen in distal muscles. The MUAP recruit-
ment is reduced in the distal limb muscles. Over time, motor unit
remodeling leads to large-amplitude, long-duration MUAPs.
Vinorelbine
Clinical Features. Vinorelbine is a semisynthetic vinca al-
kaloid recently approved for treatment of various types of
cancer. It is less neurotoxic than vincristine, but a dose-related
peripheral neuropathy has been reported in 20–50% of pa-
tients.24,462,1004,1009 However, the neuropathy is severe in only 1%
of patients. The most common symptoms are distal sensory loss
and paresthesia. Weakness can develop after 3–6 months of
treatment. As with vincristine, autonomic neuropathy is less fre-
quent. Deep tendon reflexes are reduced or absent at the ankles
in most patients after 12 cycles of chemotherapy.1009
Histopathology. Nerve pathology has not been reported.
Pathogenesis. The pathogenesis is presumably similar to
that of vincristine-induced neuropathy.
Electrophysiologic Findings. A prospective study using
serial nerve conduction studies demonstrated a dose-dependent
reduction of sensory and compound muscle action potentials.1009
Distal latencies and conduction velocities were normal. The am-
plitudes of the sensory and compound muscle action potentials
improved after discontinuation of vinorelbine.
Etoposide (VP16)
Clinical Features. Etoposide, or VP16, is a semisynthetic deriva-
tive of podophyllotoxin and is used to treat patients with lymphoma,
leukemia, SCLC, and testicular cancer. A moderate to severe distal,
axonal, predominantly sensory polyneuropathy occurs in 4–10% of
patients.146,390,611 Severe autonomic dysfunction can result in orthosta-
tic hypotension and gastroparesis. The neuropathy gradually im-
proves over several weeks or months after discontinuation.
Histopathology. In mice, VP16 causes degeneration of cell
bodies within the dorsal root ganglion. However, histopathol-
ogy has not been described in humans with the neuropathy.
Pathogenesis. Presumably, VP16 also produces its neurotoxic
effects by inhibiting microtubule function, much like vincristrine.
Electrophysiologic Findings. Detailed descriptions are lack-
ing, but nerve conduction studies and needle EMG show changes
consistent with an axonal sensorimotor polyneuropathy.611
Paclitaxel (Taxol)
Clinical Features. Paclitaxel is used for treatment of cancer
of the ovaries, breasts, lungs, bladder, and head and neck as well
as lymphoma. It produces a dose-dependent, predominantly
sensory neuropathy.24,206,422,802,1066,1136,1156,1328,1339 A subclinical or
mild neuropathy develops in up to 85% of patients after 3–7
cycles at doses of 135–200 mg/m2. A severe neuropathy occurs
in 2% of patients at this lower dose range. However, in patients
treated with doses between 250–350 mg/m2, neuropathy devel-
ops after the first or second cycle—sometimes within 24 hours

of the initial infusion. As many as 70% of patients have severe
neuropathy after high doses.206,1066,1136 Cumulative doses above
1500 mg/m2, preexisting neuropathy, and prior or concurrent
exposure to neurotoxic agents are additional risk factors for de-
veloping a severe neuropathy.1136
The neuropathy manifests with numbness, paresthesias, and
dysesthesias that begin in the feet and later involve the arms and
face.206,422,802,1066,1136,1156,1328,1339 Symptoms can resolve before the
next scheduled dose, but with further therapy, the sensory symp-
toms persist. Vibratory perception is impaired more than pain
and temperature sensation, and some patients develop sensory
ataxia. Distal motor weakness is uncommon, even with large
cumulative doses, but weakness can occur in patients with an
underlying neuropathy or other risk factors (e.g., diabetic neu-
ropathy). Autonomic neuropathy is uncommon, unless these
risk factors are present. The neuropathy can continue to
progress for 1 month or more after the drug has been discontin-
ued because of the coasting effect.1328
Histopathology. There are only a few pathologic descrip-
tions of paclitaxel-induced neuropathy.1156,1328 Sural nerve biop-
sies reveal a greater loss of large- than small-diameter
myelinated nerve fibers. Axonal degeneration with secondary
demyelination and remyelination may be seen, but regenerating
axonal sprouts are uncommon. EM has demonstrated accumula-
tion of tubular and membranous structures within the axons.1156
Pathogenesis. Paclitaxel may have a toxic effect on the neu-
ronal cell body, axon, or both.24 In contrast to vinca alkaloids,
which disassemble microtubules, the taxanes promote micro-
tubule assembly by increasing tubulin polymerization. This
process leads to aggregation and accumulation of abnormal
bundles of microtubules in dorsal root ganglia, axons, and
Schwann cells.1137 Axoplasmic transport may be disrupted by
the mechanical obstruction caused by the abnormal accumula-
tion of microtubules.
Electrophysiologic Findings. Paclitaxel produces both sen-
sory and motor nerve conduction abnormalities and denervation
potentials in distal muscles, reflecting an axonal neuropa-
thy.206,422,802,1066,1136,1156,1328,1339 Reduction in amplitudes of the
sensory nerve and compound muscle action potentials correlate
with the cumulative dose. Distal latencies and conduction ve-
locities are usually normal, although two cases with demyeli-
nating features have been reported.802,1328 Quantitative sensory
testing reveals impairment of vibratory perception more often
than abnormal thermal thresholds.206,422,1339 The electrophysio-
logic motor involvement is more likely to be subclinical and
occur later in the course of the neuropathy. Needle EMG may
show fibrillation potentials in the distal limbs.802,1156
Docetaxel (Taxotere)
Clinical Features. Docetaxel is a semisynthetic analog of
paclitaxel, which is also used in the treatment of various malig-
nancies. As with paclitaxel, a dose-dependent, predominantly
sensory, peripheral neuropathy develops in 11–50% of patients,
although severe symptoms develop in only 4% of pa-
tients.430,581,951 Large-fiber modalities are more commonly af-
fected, with patients complaining of distal numbness. Some
patients describe pain in the hands and feet and also have
Lhermitte’s sign. Mild proximal and distal weakness can be
seen in 5–19% of patients. Deep tendon reflexes are absent at
the ankles in one-half of patients. The neuropathy may continue
to worsen for several months after discontinuation of the drug.
However, most patients improve 1–2 months after cessation of
chemotherapy.
Chapter 23 ACQUIRED NEUROPATHIES — 999
Histopathology. Sensory nerve biopsy in one patient re-
vealed a loss of large myelinated fibers with scattered fibers un-
dergoing axonal degeneration.951
Pathogenesis. The pathogenic mechanism is presumably
similar to that of paclitaxel (see above).
Electrophysiologic Findings. Electrophysiologic studies
have been reported in detail in only a few patients.430,951 Motor
nerve conduction studies reveal diminished amplitudes with
mild slowing of conduction velocities. Sensory nerve conduc-
tion studies demonstrate unobtainable or very low-amplitude
potentials. Fibrillation potentials and large-amplitude, long-du-
ration polyphasic MUAPs showing decreased recruitment can
be appreciated in distal muscles.
Suramin
Clinical Features. Suramin, a hexasulfonated naphthylurea,
was used initially for treatment of trypanosomiasis and onchcer-
ciasis and more recently for various cancers. Neurotoxicity is
the dose-limiting side effect. The reported incidence of periph-
eral neuropathy ranges from 25–90%.24,208,766,1250 Suramin ap-
pears to cause two distinct types of neuropathy: (1) a
dose-dependent, distal, axonal sensorimotor polyneuropathy
and (2) a subacute demyelinating polyradiculoneuropathy. The
subacute demyelinating polyradiculoneuropathy is much more
severe and is associated with peak plasma concentrations of
over 300 µg/L, exposure to greater than 200 µg/L for more than
25 days per month, or cumulative dose of 40,000 mg/hr/L.24
The distal axonopathy is more common and manifests with
distal numbness and paresthesias.24,208,1250 Diminished light
touch, pain, and vibratory perception are noticeable on exami-
nation. Mild weakness of the distal limbs (e.g., toe extensors)
and diminished ankle refelxes can be seen. The neuropathy is
reversible with suramin discontinuation.
A subacute sensorimotor demyelinating polyradiculoneu-
ropathy develops in 10–20% of patients after 1–5 months of
treatment.208,766,1250 Symptoms typically begin with numbness
and paresthesias of the distal limbs or face, followed by sym-
metric weakness (proximal > distal). The weakness progresses
over 2–21⁄2 months. As many as 25% of patients become bedrid-
den and require mechanical ventilation. Patients can continue to
deteriorate for 1 month after suramin discontinuation. Deep
tendon reflexes are decreased or absent throughout. Recovery
occurs over a few months, although some patients have residual
numbness and weakness. Plasma exchange has been tried in an
uncontrolled fashion with mixed results.
Laboratory Features. CSF protein has been elevated in
some patients with a subacute demyelinating polyradiculoneu-
ropathy.208,1250
Histopathology. Sural nerve biopsies have been performed
in a few patients with the subacute demyelinating polyradicu-
loneuropathy.208,766,1250 Biopsies demonstrated loss of large and
small myelinated nerve fibers, demyelination and remyelina-
tion, and secondary axonal degeneration. Epineurial and en-
doneurial mononuclear inflammatory infiltrates were present in
two biopsies.208
Pathogenesis. The mechanism of neurotoxicity is unknown.
Suramin may inhibit the interaction of neurotrophic factors with
peripheral nerve receptors1145,1268 or induce a form of lysosomal
storage disease.457 The demyelinating neuropathy may be re-
lated to the immunomodulating effects of suramin.271
Electrophysiologic Findings. The more common distal ax-
onopathy is associated with decreased amplitudes of sensory
and compound muscle action potentials.24,208,1250 Quantitative
1000 — PART IV CLINICAL APPLICATIONS
sensory testing has demonstrated increased vibratory and cool-
ing thresholds.208 Fibrillation potentials and neurogenic MUAPs
may be noted in distal muscles with needle EMG.
Electrodiagnostic studies in the subacute sensorimotor poly-
radiculoneuropathy reveal features of demyelination.208,766,1250
Prolonged distal latencies and F-waves, slow conduction veloci-
ties, temporal dispersion, and conduction block have been re-
ported. As in the distal axonopathy, quantitative sensory testing
shows increased vibratory and cooling thresholds.208 Needle
EMG demonstrates decreased recruitment in proximal and
distal muscles and increased insertion and spontaneous activity
(fibrillation potentials and positive sharp waves) in severe cases.
Cytosine Arabinoside (ARA-C)
Clinical Features. Cytosine arabinoside C is an antimetabolite
used in the treatment of leukemia and lymphoma. Several types of
peripheral neuropathy have been reported with cumulative doses
of 60–36g/m2. Cases of brachial plexopathy1179 and severe sensori-
motor polyneuropathy resembling GBS124,638,949,1003,1038 have been
attributed to the drug. These neuropathies may begin hours or
weeks after treatment.
Laboratory Features. Increased CSF protein has been
demonstrated in patients with a severe neuropathy resembling
GBS.1003
Histopathology. Sural nerve biopsies may reveal demyeli-
nation or axonal degeneration.124,1003,1038
Pathogenesis. The pathophysiologic mechanism for the
neuropathies is not well understood. Perhaps, the antimetabolite
action of cytosine arabinoside C inhibits proteins important in
myelin production or axonal transport. Alternatively, its im-
munomodulating effects may lead to dysinhibition of autoreac-
tive lymphocytes and an immune attack against the peripheral
nerves.
Electrophysiologic Findings. Electrodiagnostic studies
may be compatible with a primary axonal1038 or an acquired de-
myelinating sensorimotor polyneuropathy.636 Needle EMG may
reveal active denervation changes in distal muscles.124,638
Ifosfamide
Ifosfamide is a cyclophosphamide analog. Neuropathy has
been reported in patients receiving a total dose of 14 g/m2 or
more. 1037 Numbness and painful paresthesias begin in the
hands and feet 10–14 days after treatment. Symptoms gradu-
ally resolve but recur if patients are rechallenged with
chemotherapy. Electrodiagnostic and histopathologic data are
lacking, but occasional symptom onset in the hands rather than
the feet suggests a ganglionopathy.
OTHER MEDICATIONS
Misonidazole
Clinical Features. Misonidazole is a member of the ni-
troimidazole group of compounds and is used as an adjuvant
agent in the treatment of various carcinomas to sensitize neo-
plastic cells to the effects of radiation therapy.827,882,1040 After ap-
proximately 3–5 weeks of administration (total dose > 18 gm),
some patients may begin to complain of painful paresthesias in
the feet, followed by similar symptoms in the hands.
Ambulation may become impaired by a combination of sensa-
tion loss in the feet and pain. A few patients also may demon-
strate evidence of a reduction in strength in the distal muscles of
the lower limbs. Deep tendon reflexes are preserved, but vibration
sensation and pain/temperature discrimination are significantly
affected. Cessation of the drug usually results in symptom im-
provement, but a number of patients continue to have residual
deficits.
Histopathology. Sural nerve biopsies demonstrate a reduc-
tion in the large myelinated fibers with evidence of axonal de-
generation and segmental demyelination/remyelination. EM
may reveal an accumulation of neurofilaments with axonal
swellings.
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Sensory nerve conduction
studies demonstrate a mild to moderate reduction in upper limb
nerves with significant reduction to complete absence of lower
limb SNAPs. The distal sensory latencies and conduction veloc-
ities are normal or mildly abnormal. Motor conduction studies
reveal normal nerve conduction velocities and distal motor la-
tencies in the upper limbs with borderline abnormal values in
the lower limbs. The CMAP amplitudes are typically well pre-
served throughout. Needle EMG demonstrates increased ampli-
tudes, durations, and polyphasia of MUAPs. A reduction in
motor unit recruitment can be seen in weak limb muscles.
Metronidazole
Clinical Features. Metronidazole is used in the treatment of
various protozoan infections as well as in Crohn’s dis-
ease.137,253,1282 Like misonidazole, metronidazole is a member of
the nitroimidazole group, and a few cases have been reported in
which patients developed an axonal peripheral neuropathy with
primarily sensory symptoms. The major manifestations are hy-
peralgesia and hypesthesia in a glove-and-stocking distribution.
Deep tendon reflexes are well preserved except for a reduction
at the ankles. Muscle strength is usually normal throughout.
Histopathology. Nerve biopsies demonstrate evidence con-
sistent with axonal loss.
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Nerve conduction studies
reveal reduced or absent sural SNAPs with low-amplitude upper
limb SNAPs. The distal sensory latencies are usually at the upper
limits of normal. Compound muscle action potentials are well
preserved, and motor conduction velocities are at the lower end
of normal values. Needle EMG findings have not been reported.
Chloroquine
Clinical Features. Chloroquine is a quinoline derivative
used for treating malaria, sarcoidosis, systemic lupus erythe-
matosus, scleroderma, and rheumatoid arthritis.369,381,843 Chloro-
quine can cause a toxic myopathy (discussed in Chapter 28).
Patients with chloroquine myopathy develop slowly progres-
sive, painless, proximal weakness and atrophy, which are worse
in the legs than in the arms. Cardiomyopathy also may occur.
Sensation is diminished in some patients secondary to a super-
imposed neuropathy. Deep tendon reflexes may be diminished
particularly at the ankle. The “neuromyopathy” usually appears
in patients taking 500 mg for 1 year or more but has been re-
ported with doses as low as 200 mg/day. The neuromyopathy is
reversible after discontinuation of the medication.
Laboratory Features. Serum CK levels are usually elevated
because of the superimposed myopathy.
Histopathology. In addition to vacuolar myopathy, nerve
biopsies also demonstrate autophagic vacuoles.
Pathogenesis. Chloroquine has amphiphilic properties be-
cause it contains both hydrophobic and hydrophilic regions.

These properties account for the ability of the drugs to interact
with the anionic phospholipids of cell membranes and or-
ganelles. The drug-lipid complexes are resistant to digestion by
lysosomal enzymes, thus resulting in the formation of the au-
tophagic vacuoles filled with myeloid debris.
Electrophysiologic Findings. Patients with neuropathy
demonstrate mild slowing of both motor and sensory nerve con-
duction velocities associated with a mild to moderate reduction
in the amplitudes.381,843 Patients with only the myopathy usually
have normal motor and sensory studies.369 EMG reveals an in-
crease in insertional activity with significant amounts of posi-
tive sharp waves and fibrillation potentials primarily, but not
exclusively, in the proximal limb muscles. Voluntary MUAPs
are significantly decreased in amplitude and duration with a
predominance of polyphasic MUAPs. Myotonic potentials may
be seen despite a lack of clinical myotonia.
Hydroxychloroquine
Hydroxychloroquine is structurally similar to chloroquine
and also produces a neuromyopathy.381 Weakness and histologic
abnormalities are usually not as severe as in chloroquine my-
opathy. Vacuoles are typically absent on biopsy, but EM usually
demonstrates the abnormal accumulation of myeloid and curvi-
linear bodies.
Amiodarone
Clinical Features. Amiodarone is an antiarrhythmic med-
ication that causes a neuromyopathy similar to chloro-
quine.201,425,619,840,1042 Severe proximal and distal weakness,
combined with distal sensory loss, affects the legs more than the
arms. The drug is known to have a number of adverse effects in-
cluding tremor, thyroid dysfunction, keratitis, pigmentary skin
changes, hepatitis, pulmonary fibrosis, and parotid gland hyper-
trophy. Peripheral neuropathy usually occurs in patients taking
the medication for over 2–3 years. The initial complaint is re-
duced sensation and paresthesias in the feet with burning pains
and a feeling of coldness. Within several months, difficulty in
ambulation may be noted, accompanied by a tendency to fall
and cramping in some leg muscles. Physical examination
demonstrates a reduction in sensation to all modalities as well
as absent deep tendon reflexes, especially at the ankle.
Weakness is present in the distal regions of both upper and
lower limbs.
Histopathology. Muscle biopsies demonstrate autophagic
vacuoles with myeloid inclusions. Neurogenic atrophy also can
be appreciated, particularly in distal muscles. Sural nerve biop-
sies demonstrate a combination of segmental demyelination and
axonal loss. EM reveals myeloid inclusions in muscle and nerve
biopsies. These lipid membrane inclusions in muscle and nerve
biopsies have persisted for as long as 2 years after discontinua-
tion of the medication.
Pathogenesis. The pathogenesis is presumably similar to
other amphiphilic medications (e.g., chloroquine).
Electrophysiologic Findings. Nerve conduction studies
reveal variable findings among different nerves in the same pa-
tient.425,840,881,1042 The sural SNAPs are usually markedly reduced
in amplitude or reduced with some degree of nerve conduction
slowing. Most patients demonstrate a mild reduction (within the
70–80% range of the lower limit of normal) in nerve conduction
velocity throughout. Some patients, however, can have motor
conduction velocities as low as 11–12 m/s in the lower limb.
Distal motor latencies are mildly prolonged in some patients or
increased by 100% in others. Needle EMG examination usually
Chapter 23 ACQUIRED NEUROPATHIES — 1001
detects fibrillation potentials and positive sharp waves in the
hand and foot intrinsic muscles with reduced recruitment.
Perhexiline Maleate
Clinical Features. Perhexiline maleate has antiarrhythmic
properties and was used in the past to treat angina.131,793,1189,1408
Because of its significant side effects, such as liver dysfunction,
hypoglycemia, weight loss, and peripheral neuropathy with ele-
vated CSF protein, it is now rarely used. The peripheral neu-
ropathy is a generalized sensorimotor type manifesting with an
initial reduction in sensation and paresthesias in the feet. Later
weakness becomes apparent in the distal lower limb muscles,
and similar sensory disturbances are noted in the hands. With
time, significant weakness and muscle wasting are noted in the
legs with progressive loss of strength and coordination of the
hands. The neuropathy may develop over months to years. Its
exact incidence is unknown. Cessation of the drug leads to sig-
nificant clinical improvement in most patients, provided that
profound muscle wasting has not already occurred.
Histopathology. Nerve biopsies demonstrate significant
segmental demyelination with variable degrees of Wallerian
degeneration.391,1157 Osmiophilic inclusions are evident in
Schwann cells, fibroblasts, and endothelial cells.
Pathogenesis. Perhexiline is an amphiphilic drug, and the
mechanism of neuropathy may be similar to other such agents
(see above).
Electrophysiologic Findings. Nerve conduction studies
may demonstrate a reduction in both motor and sensory con-
duction velocities to less than 60–70% of the lower limit of
normal, whereas distal latencies may be increased by up to
100% of the upper limit of normal.131,793,1189,1408 The nerves are
affected to different degrees—some profoundly, others mildly
or moderately. The SNAP and CMAP amplitudes are signifi-
cantly reduced only in patients with long-standing disease of a
severe nature. The H-reflex may be of help in demonstrating
mild abnormalities of conduction in patients with early disease.
Needle EMG reveals fibrillation potentials and positive sharp
waves in patients with severe disease as well as reduced re-
cruitment of MUAPs. Alterations of MUAP morphology sug-
gesting motor unit remodeling can be anticipated in the distal
limb muscles.
Colchicine
Clinical Features. Colchicine, which is used primarily to
treat patients with gout, inhibits the polymerization of tubulin
into microtubules. Of note, colchicine is capable of generating
both a significant myopathy and a mild to moderately severe
polyneuropathy.734,735,1104 Patients usually present with com-
plaints of inability to climb stairs and arise from a low chair,
with some degree of numbness and tingling in the distal lower
limbs and occasionally the hands. Physical examination demon-
strates significant weakness in the proximal limb muscles with a
lesser degree of strength reduction in the distal limb muscles.
Sensation to touch and vibration and position sense may be re-
duced, with some minor loss of pain and, rarely, temperature
sensation in the distal limbs. Deep tendon reflexes are reduced
particularly at the ankles.
Histopathology. Muscle biopsies reveals a vacuolar myopa-
thy, whereas sensory nerves demonstrate axonal degeneration.
Pathogenesis. The disruption of the microtubules probably
leads to defective intracellular movement or localization of
lysosomes, which results in the accumulation of autophagic
vacuoles in muscle and nerves.735
1002 — PART IV CLINICAL APPLICATIONS
Electrophysiologic Findings. Nerve conduction studies
reveal low amplitude SNAPs and CMAPs.715,735,1104 The distal
motor and sensory latencies may be normal or slightly pro-
longed. Likewise, conduction velocities are normal or mildly
slow. F-waves can be expected to be significantly prolonged, and
H-reflexes may be prolonged or absent. Needle EMG examina-
tion demonstrates short-duration, low-amplitude MUAPs in the
proximal limb muscles accompanied by positive sharp waves
and fibrillation potentials. In the distal muscles of the upper and
lower limbs, the same type of abnormal membrane instability
can be observed; however, the MUAPs are reduced in number
with longer duration and higher amplitude than normal. This
combined pattern of electrophysiologic alterations is consistent
with a proximal myopathic and distal neurogenic process.
Podophyllin
Clinical Features. Podophyllin resin is a topical agent used
to treat condylomata acuminata. Systemic toxicity has resulted
from topical exposure and oral ingestion.171,225,414,908,1228
Systemic side effects include gastrointestinal paresis, urinary
retention, pancytopenia, and liver and renal dysfunction.
Podophyllin toxicity can also involve the central and peripheral
nervous systems, causing psychosis, altered consciousness, and
peripheral neuropathy. The neuropathy is characterized by
slowly progressive sensory loss, paresthesias, muscle weakness,
and diminished deep tendon reflexes. The distal limbs are af-
fected more than the proximal limbs and the legs more than the
arms, as expected in length-dependent axonopathies. Nausea,
vomiting, ileus, urinary retention, orthostatic hypotension, and
tachycardia may result from involvement of the autonomic ner-
vous system. The neuropathy can progress for a few months
even after the medication is stopped. The neuropathy gradually
improves after discontinuation of the podophyllin, but improve-
ment can take from several months to more than 1 year. Patients
may have residual deficits.
Laboratory Features. CSF protein levels can be elevated.
Pancytopenia, liver function abnormalities and renal insuffi-
ciency also may be noted on routine laboratory work-up.
Histopathology. Nerve biopsies demonstrate axonal degen-
eration.
Pathogenesis. Podophyllin binds to microtubules, like
colchicine, and probably inhibits axoplasmic flow, leading to
axonal degeneration.1039
Electrophysiologic Findings. Sensory nerve conduction
studies reveal absent SNAPs or reduced amplitudes.414 The
distal latencies and conduction velocities of the SNAPs are
normal or only slightly impaired. Motor conduction studies are
less affected, but may demonstrate reduced amplitudes. Distal
latencies and conduction velocities of the CMAPs are relatively
spared. Needle EMG may demonstrate fibrillation potentials
and positive sharp waves in distal limb muscles along with de-
creased recruitment.
Thalidomide
Clinical Features. Thalidomide is a rarely used im-
munomodulating agent because of its profound teratogenic ef-
fects.439,440,756,1067 It is effective in some dermatologic conditions,
such as discoid lupus erythematosus and prurigo nodularis, as
well as graft-versus-host disease and leprosy and multiple
myeloma.1206 One of its major dose-limiting side effects is pe-
ripheral neuropathy, which develops in 10–100 % of patients.
The neuropathy appears to be dose-dependent and occurs after a
total dose of 40–50 gm in most patients. Patients complain of
significant pain, burning, and other uncomfortable paresthesias
in the feet and hands. Some particularly sensitive patients also
experience proximal muscle weakness and atrophy. Loss of sen-
sation is variable, with muscle cramping in the legs.
Unfortunately, even after stopping the drug for 4–6 years, as
many as 50% patients continue to have significant symptoms.
Physical examination demonstrates an erythematous hue to
the palms of the hands as well as increased fragility of the finger
and toenails. Vibration and position sense usually are reduced.
Muscle weakness may be noted in a proximal distribution with
some wasting in severely affected patients. Deep tendon re-
flexes are usually diminished or absent.
Histopathology. Peripheral nerve biopsy reveals axonal de-
generation of the large-diameter myelinated fibers with little ev-
idence of demyelination. A few autopsy studies also have
documented degeneration of dorsal root ganglion cells. Drug
cessation does not lead to a normal fiber profile.
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. The primary abnormality is a
reduction or complete absence of SNAPs.439,440,756,1067 When the
SNAP is present, the conduction velocity remains relatively
well preserved, and SNAP latencies are not significantly af-
fected. The lower limb SNAPs appear to be affected first and
more profoundly than those in the upper limbs, although the
latter follow the lower limb abnormalities rather closely.
Motor nerve conduction studies are expected to reveal normal
distal motor latency, conduction velocity, CMAP amplitude,
and F-waves. A few patients may demonstrate absent F-waves
in the lower limbs. Needle EMG is commonly normal, but a few
patients with particularly profound disease reveal a small degree
of positive sharp waves and fibrillation potentials in the distal
lower limb muscles.
Disulfiram
Clinical Features. Disulfiram (Antabuse) is used in the
treatment of alcoholism. It is metabolized to carbon disulfide,
which is a neurotoxin and can have adverse effects on both the
peripheral and central nervous systems.28,93,126,903,909,995,1015
Patients with peripheral neuropathy can display symptoms re-
flective of axonal loss within 10 days to 18 months of starting
the drug. Sensation is reduced primarily in a stocking distribu-
tion with later development of significant muscle weakness.
Some patients present with bilateral foot drop. Fasciculations
also can be observed. It is important to be aware of these neuro-
toxic effects because the sooner the medication is stopped, the
better the prognosis for return of function.
Histopathology. Sural nerve biopsy demonstrates a loss of
all myelinated fibers with some preference for the large-diame-
ter fibers, although both large and small fibers can be equally
affected.28,93,126,909 Axonal degeneration is the predominant fea-
ture, but segmental demyelination also may be seen. EM reveals
an accumulation of neurofilamentous material within the myeli-
nated and unmyelinated axons, leading to axonal swelling.
Pathogenesis. The neuropathy may be secondary to carbon
disulfide, a metabolite of disufiram.783 A similar axonal neu-
ropathy characterized by accumulation of neurofilaments
occurs with carbon disulfide toxicity.
Electrophysiologic Findings. The electrodiagnostic medi-
cine findings are consistent with the histopathologic findings of
an axonal neuropathy.28,93,909,995,1015 The SNAPs in the lower limb
are usually absent or markedly reduced, whereas those in the
upper limbs are reduced in amplitude. The conduction velocities

are usually mildly reduced, although a few patients with pro-
found disease can have reductions approaching 70% of the
lower limit of normal. H-reflexes are either absent or mildly
prolonged. The CMAPs are either absent or profoundly reduced
in amplitude in the foot muscles. In the upper limbs, the CMAP
amplitudes are usually normal or only borderline reduced.
Motor nerve conduction studies demonstrate a mild prolonga-
tion in the distal motor latencies for the lower limbs with good
preservation in the upper limbs. Conduction velocities are mod-
erately reduced in severely affected patients. Needle EMG com-
monly reveals fibrillation potentials and positive sharp waves in
the distal muscles of the lower limbs with significant reductions
in recruitment. In chronic cases, motor unit remodeling results
in large-amplitude, long-duration MUAPs. All abnormalities
improve to varying degrees, with an occasional return to normal
for the lower limbs, after cessation of the medication.
Dapsone
Clinical Features. Dapsone is used world-wide in the treat-
ment of leprosy and various dermatologic conditions. The most
common side effects are anemia and methemoglobinemia, but
peripheral neuropathy also may occur.7,522,939,1087,1192,1225,1376
Symptoms of a primarily motor neuropathy manifest within 5
days to as late as 5 years after starting the drug. The primary
neurologic manifestation is a progressive weakness that begins
in the small muscles of the hands and feet and progresses to
more proximal muscles over time. The hip girdle muscles may
be preferentially affected in some patients. Roughly 29% of pa-
tients note the progression of weakness first in the hands, 24%
of patients first describe some form of weakness in the feet,
and 41% of patients have initial motor symptoms in both hands
and feet. A few patients have mainly a sensory neuropathy with
minimal motor involvement. Physical examination demon-
strates weakness with accompanying muscle wasting in the
distal upper and lower limbs. Reflexes are usually preserved
but may be diminished in some patients. Objective tests of sen-
sation are relatively normal except for minor alterations in a
few patients.
Histopathology. Biopsy of the motor nerve terminal at the
extensor brevis muscle has demonstrated axonal atrophy and
Wallerian degeneration of the distal motor nerve terminals.1225
Segmental demyelination also is noted. Sural nerve biopsy also
can reveal a loss of myelinated nerve fibers.
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Sensory nerve conduction
studies usually demonstrate normal or slightly reduced ampli-
tudes.7,522,939,1087,1192 Sensory nerve conduction velocities are
normal or only mildly slow. Motor nerve conduction studies
demonstrate that the distal motor latencies are prolonged by
about 10–30% above the upper limit of normal and that conduc-
tion velocity is normal or not less than 80–90% of the lower
limit of normal. The CMAP amplitude is borderline normal or
reduced in the upper limb and considerably reduced or absent in
the lower limb. F-wave latencies can be moderately prolonged
with a number of stimuli resulting in no response. Needle EMG
usually demonstrates high degrees of fibrillation potentials and
positive sharp waves in association with markedly reduced re-
cruitment, particularly in the distal limb muscles. Occasional
fasciculation potentials may be observed. Over time, motor unit
remodeling leads to large-amplitude, long-duration MUAPs.
The nerve conduction studies usually improve to some degree
after medication cessation.
Chapter 23 ACQUIRED NEUROPATHIES — 1003
Nitrofurantoin
Clinical Features. Nitrofurantoin is used in the treatment
of urinary tract infections because of its wide antimicrobial
spectrum and ability to concentrate in the urine rather quickly.
It has been reported to result in the development of an acute
and profound peripheral neuropathy in which patients com-
plain of pain, numbness, tingling, and difficulty in walking as
well as manipulating objects with the hands.376,598,814,1306,1438
These symptoms can occur as early as 9 days after treatment
initiation, and some patients are rendered completely quadri-
paretic. Patients who are elderly or have any degree of renal
dysfunction are particularly sensitive to nitrofurantoin.
Physical examination reveals decrease of all sensory modalities
in the distal regions of the upper and lower limbs. Deep tendon
reflexes are reduced or absent. Cessation of the drug usually re-
sults in recovery, but a complete return to normal may not be
achieved.
Histopathology. Sural nerve biopsy has demonstrated sig-
nificant loss of large myelinated fibers with signs of active Wal-
lerian degeneration. An autopsy study has shown degeneration
of the spinal roots, with more severe effects on dorsal than ven-
tral roots, and chromatolysis of the anterior horn cells.792
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Electrodiagnostic medicine
evaluation documents absent SNAPs or severely attenuated am-
plitude and slightly reduced conduction velocity.598,797,1306,1438
Similarly, in patients with weakness present for some time, the
CMAP may be unobtainable. In patients with reduced CMAPs,
the nerve conduction velocity is reduced by no more than
80–90% of the lower limit of normal. Distal sensory and motor
latencies may be mildly prolonged. Needle EMG examination
typically reveals positive sharp waves and fibrillation potentials
with marked reductions in the number of voluntary MUAPs in
the distal muscles of the upper and lower limbs. In profound
disease, the same findings are noted in the more proximally lo-
cated limb muscles.
Pyridoxine (Vitamin B6) Toxicity
Clinical Features. Pyridoxine is an essential water-soluble
vitamin that acts as a coenzyme for multiple transamination and
decarboxylation reactions within the body.13,14,285,1176 It generally
is considered quite safe with a minimum recommended daily al-
lowance of 2–4 mg in adults. Pyridoxine has become a “fad vit-
amin” in that megadoses (600 mg–3 or 4 gm/day) is supposed
to be beneficial for all types of ailments. Unfortunately, it is not
as harmless as once thought, and people can develop a rather
significant peripheral neuropathy from consuming as little as
116 mg/day. The primary initial symptoms are difficulty in
walking secondary to sensory ataxia. This symptom is espe-
cially problematic during eye closure or at night. Some patients
note that rapid flexion of the neck results in tingling that em-
anates from the neck and radiates down the back and into both
legs (Lhermitte’s sign).
Physical examination reveals impairment in vibratory per-
ception and proprioception, although all sensory modalities can
be reduced. Sensory loss can begin and be more severe in the
upper limbs than in the lower limbs. Fine motor control is im-
paired, particularly in the hands, secondary to sensory loss. Pa-
tients also may exhibit a wide-based gait secondary to sensory
ataxia. Strength is normal, and deep tendon reflexes are re-
duced or absent, particularly at the ankles. Plantar responses
are flexor.
1004 — PART IV CLINICAL APPLICATIONS
Histopathology. In humans, peripheral nerve biopsies reveal
axonal loss of all fiber diameters.1023,1176,1432 Animal studies have
demonstrated that neural damage is located primarily in the
dorsal root ganglion cells with subsequent degeneration of both
peripheral and central sensory processes.730,731
Pathogenesis. The pathogenic basis for the neuropathy is
not known.
Electrophysiologic Findings. Nerve conductions studies
reveal absent or significantly reduced SNAP ampli-
tudes.13,14,1083,1176 The sensory nerve conduction velocities are
minimally reduced when they can be recorded. The CMAP am-
plitudes are normal or borderline small; motor conduction ve-
locities and distal latencies are usually spared or only mildly
abnormal. Needle EMG demonstrates reduced recruitment in
distal muscles with occasional fibrillation potentials and posi-
tive sharp waves in some patients.
Isoniazid
Clinical Features. Isoniazid (INH) is used for treatment of tu-
berculosis. One of its most common side effects is peripheral neu-
ropathy.917,975,1177 Typical doses (3–5 mg/kg/day) are associated
with a 2% incidence of neuropathy; neuropathy develops in at
least 17% of patients taking in excess of 6 mg/kg/day.1177 The
neuropathy is more likely in the elderly and malnourished pa-
tients and so-called slow acetylators. It can be prevented by coad-
ministration of pyridoxine, 100 mg/day. The initial symptoms are
numbness and tingling in the distal upper and lower limbs, which
usually occur after 6 months of treatment with smaller doses but
may begin within a few weeks with large doses. If the INH is
stopped early, the symptoms resolve after a few days or weeks.
However, if the medication is continued, the sensory loss spreads
proximally and dysesthesias occur. Furthermore, distal weakness
and aching of the calves may develop. Recovery at this stage can
take months and may be incomplete. Examination reveals loss of
all sensory modalities, distal muscle atrophy and weakness, di-
minished deep tendon reflexes, and occasionally ataxia.
Histopathology. Sural nerve biopsies reveal axonal degen-
eration and loss of both myelinated and unmyelinated nerve
fibers.975 Autopsy studies have demonstrated degeneration of
the dorsal columns.1177
Pathogenesis. INH inhibits pyridoxal phosphokinase result-
ing in pyridoxine deficiency. The neuropathy is thought to be
related directly to INH-induced pyridoxine deficiency. INH is
metabolized by acetylation. People with slow acetylation (an
autosomal recessive trait) maintain a higher serum concentra-
tion of INH and are more susceptible to developing the neuropa-
thy than people with rapid acetylation.1177 Slower acetylation
also can occur with age.
Electrophysiologic Findings. Insufficient data are available.
Ethambutol
Clinical Features. Ethambutol is another antituberculous
medication that can cause a toxic peripheral neuropathy as well
as severe optic neuropathy.933,1177 The neuropathy usually occurs
in patients receiving prolonged doses in excess of 20 mg/kg/day.
Patients describe mild numbness in the hands and feet.
Examination reveals a loss of large fiber modalities and reduced
reflexes distally. Weakness is uncommon. The peripheral neu-
ropathy gradually improves after discontinuation of the medica-
tion, but recovery of the optic neuropathy is more variable.
Histopathology. A decreased number of myelinated nerve
fibers due to axonal degeneration has been noted in human and
animal studies.847
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Nerve conduction studies are
remarkable for diminished amplitudes of the SNAPs with
normal sensory distal latencies and conduction velocities.
Motor conduction studies are usually normal.847
Nucleosides
Clinical Features. The nucleoside analogs zalcitabine
(dideoxycytidine [ddC]), didanosine (dideoxyinosine [ddI]),
stavudine (d4T), lamivudine (3TC), and antiretroviral nucleo-
side reverse transcriptase inhibitor (NRTI) are used in the treat-
ment of HIV infection. One of their major dose-limiting
side-effects is a predominantly sensory, length-dependent, sym-
metric, painful neuropathy.90,106,338,1352 Zalcitabine is the most ex-
tensively studied nucleoside analog. High doses of ddC (> 0.18
mg/kg/day) are associated with a subacute onset of severe burn-
ing and lancinating pains in the feet and hands. The neuropathy
occurs in most patients even at lower doses (0.06 mg/kg/day),
although it is less severe. As many as 34% of patients taking
even lower doses of ddC (0.03 mg/kg/day) develop a toxic neu-
ropathy after 1–51 weeks (mean: 16 weeks) after starting the
medication. Examination reveals hyperpathia, diminished pin-
prick and temperature sensation, and, to a lesser degree, im-
paired touch and vibratory perception. Deep tendon reflexes are
diminished distally. Mild weakness at the ankles and in foot in-
trinsic muscles is seen in a few patients. Of importance, a coast-
ing effect can be demonstrated; patients may continue to worsen
even 2–3 weeks after stopping the medication. Nevertheless, a
reduction of the dose leads to improvement in most patients
after several months (mean time: about 10 weeks).
Histopathology. Detailed histopathologic descriptions in
humans with nucleoside-induced toxic neuropathies are lacking.
Pathogenesis. Nucleoside analogs inhibit reverse transcrip-
tase, impairing HIV replication. They also inhibit mitochondrial
DNA polymerase, which is the suspected pathogenic basis for
the neuropathy. Acetyl-carnitine deficiency may contribute to
the neurotoxicity.
Electrophysiologic Findings. Impaired temperature and vibra-
tory thresholds have been noted on QST.90,106 The QST abnormali-
ties, particularly vibratory perception, precede clinical symptoms
or standard nerve conduction abnormalities. Sensory nerve con-
ductions reveal decreased amplitudes or absent responses.90,338,1352
Distal latencies and conduction velocities of the SNAPs are
normal. Motor conduction studies are usually normal, although un-
obtainable CMAPs have been described.1346 EMG demonstrates
fibrillation potentials and positive sharp waves in distal muscles
along with decreased recruitment of large, polyphasic MUAPs.338
Chloramphenicol
This antibiotic also can cause a distal sensory polyneuropa-
thy and optic neuropathy.643,1083 The neurotoxicity is now rare
but occurred more commonly in the past with prolonged
courses and large doses. The neuropathy is characterized by
numbness and paresthesias in the feet. Hyperpathia and calf ten-
derness can be noted. Sensory examination reveals a mild loss
of all modalities, and deep tendon reflexes are reduced in the
legs. The upper limbs usually are spared. There are no detailed
descriptions of the histologic or electrophysiologic findings.
Phenytoin
Clinical Features. Phenytoin is a commonly used
antiepileptic medication.103,997,1084 Most patients treated with

phenytoin do not complain of symptoms suggestive of periph-
eral nerve compromise. However, rare patients develop symp-
toms and signs of a mild, primarily sensory neuropathy. In
patients who are clinically toxic with elevated blood levels,
overt symptoms of numbness and tingling as well as difficulty
in ambulating may be present. There is usually a loss of touch,
position sense, and vibration as well as diminished or absent
deep tendon reflexes at the ankles. Such patients may demon-
strate a mild degree of weakness in the distal muscles of the
upper and lower limbs. Fortunately, most patients respond well
to lowering the phenytoin levels, with some normalization of
the nerve conduction studies and needle EMG abnormalities.
Phenobarbital can result in a peripheral neuropathy with similar
findings.1212,1275
Histopathology. Sural nerve biopsy may reveal loss of the
large myelinated axons with some accompanying segmental de-
myelination and subsequent evidence of remyelination.1084
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. Electrodiagnostic medicine
findings may reveal alterations suggestive of a mild peripheral
neuropathy, affecting primarily the sensory fibers, in about 20%
of patients taking only phenytoin.780,829,925,1212 In patients with
definite symptoms and signs of a peripheral neuropathy, the
SNAP amplitudes are reduced in both upper and lower limbs
with mildly to moderately reduced conduction velocities. Motor
conduction velocities are low normal or mildly reduced, and the
distal motor latencies are normal or only mildly prolonged. The
CMAP amplitudes in most patients are normal. Similar findings
have been demonstrated in animal studies. Needle EMG in most
patients is normal; however, in persons with significant toxicity,
fibrillation potentials and positive sharp waves are found in the
distal muscles of the upper and lower limbs. Recruitment of
large-amplitude, long-duration, polyphasic MUAPs is reduced.
Lithium
Clinical Features. Lithium can result in central nervous
system toxicity with findings of tremor, dysarthria, confusion,
obtundation, sweating, and seizures, as well as electrocardio-
graphic and electroencephalographic abnormalities. A few pa-
tients have developed significant sensorimotor peripheral
neuropathies after lithium administration.160,952,1317 Usually they
present with central nervous system toxicity. After drug with-
drawal, symptoms related to central nervous system toxicity re-
solve, but patients may demonstrate weakness, loss of sensation
distally, and depressed or absent deep tendon reflexes.
Histopathology. Nerve biopsy demonstrates a loss of large
myelinated fibers with little demyelination.
Pathogenesis. The pathogenic basis of the neuropathy is not
known.
Electrophysiologic Findings. The few reported electrodiag-
nostic medicine studies demonstrated absent SNAP and CMAP
responses in the lower limbs with reduced amplitudes, but rela-
tively normal conduction velocities in the upper limbs. Needle
EMG examination revealed positive sharp waves and fibrilla-
tion potentials as well as complex repetitive discharges. The
numbers of voluntary MUAPs were markedly reduced in the
distal limb muscles.
Eosinophilia-Myalgia Syndrome
Clinical Features. This interesting disorder arose from the
ingestion of contaminated L-tryptophan in the latter part of
the 1980s and early 1990s. 330,567,1131 After identification and
Chapter 23 ACQUIRED NEUROPATHIES — 1005
removal of the contaminant, the disorder has all but disap-
peared. Some patients consuming the offending L-tryptophan
presented with progressive symptoms of fever, skin rash, myal-
gia, arthralgia, peripheral edema, cough, and occasional alope-
cia. About 30% of patients also had symptoms and signs
suggestive of a progressive sensorimotor peripheral neurop-
athy.567,1152,1195,1231,1316 Other patients developed a severe periph-
eral neuropathy simulating Guillain-Barré syndrome567,1231 or
mononeuropathy multiplex.1195 In addition, a number of patients
also had a primary myopathy or combination of myopathy and
peripheral neuropathy. Patients demonstrate a progressive loss
of strength in a proximal, distal, or proximal and distal distribu-
tion with accompanying myalgias. Deep tendon reflexes usually
were depressed in the upper limbs and absent in the lower
limbs. Multimodality stocking-and-glove sensory loss was
worse in the lower limbs.
Laboratory Features. The serum CK level may be normal
or elevated. Autoantibodies are absent and ESR usually is
normal. The absolute eosinophil count is elevated (>1 × 109
cells/L).
Histopathology. Nerve biopsies reveal inflammatory infil-
trate, mainly mononuclear with occasional eosinophils and
often perivascular, in the epineurium, endoneurium, and/or per-
ineurium, accompanied by evidence of vasculopathy and angio-
neogenesis.567,1152,1195,1231,1316 Significant axonal degeneration is
also appreciated.
Pathogenesis. Two trace adulterants have been identified as
the possible toxins: 3-phenylamino alanine (PAA) and 1,1'-eth-
ylidenebis tryptophan (EBT).856 The mechanism by which the
contaminant resulted in the disorder is unknown, but
eosinophilia and eosinophilic infiltrate in tissues suggest some
form of allergic reaction.
Electrophysiologic Findings. Electrodiagnostic medicine eval-
uation reveals reduced or absent SNAPs in the lower limbs with di-
minished-amplitude SNAPs in the upper limbs.567,1152,1195,1231,1316
The distal sensory latencies usually are normal. The CMAPs am-
plitudes may be profoundly reduced or absent in the lower limbs
with mild to moderate amplitude reduction in the upper limbs.
Conduction block is also evident in some cases. Distal motor la-
tency usually is well preserved, but conduction velocities may be
normal or significantly slow, suggesting a major demyelinating
component. F-waves are either present but prolonged and not pre-
sent after each stimulus, or simply absent. Needle EMG demon-
strates positive sharp waves and fibrillation potentials in the distal
limb muscles with reduced MUAP recruitment and increased po-
tential amplitude and duration. Some patients have MUAP parame-
ter alterations consistent with a myopathic process when proximal
girdle muscles are examined (i.e., early recruitment of MUAPs
with reduced durations and amplitudes).
Treatment. Discontinuation of L-trytophan and treatment
with high-dose corticosteroids usually are effective. Some pa-
tients experience relapses after withdrawal of steroids.
INDUSTRIAL AND ENVIRONMENTAL AGENTS
A number of known toxic substances are used in the manu-
facturing process of multiple materials. Once they are identi-
fied, appropriate precautionary measures can be instituted to
protect workers. Unfortunately, multiple people all too often
become impaired before a substance is recognized as hazardous
to human health. Several industrial agents are known to affect
the peripheral nervous system adversely, primarily through the
production of a distal axonopathy.
1006 — PART IV CLINICAL APPLICATIONS
Acrylamide
Clinical Features. Acrylamide, a vinyl monomer, is an im-
portant industrial agent in the form of a white crystalline sub-
stance. The polymerized form of the monomer produces a
substance used as flocculators and in grouting agents. The
monomer is a white powder that can be absorbed through the
skin or inhaled.53,449 A few patients have been reported to
become ill after exposure to water contaminated by acrylamide
grouting of wells.609 After exposure, patients develop contact
dermititis with excessive sweating and peeling of erythematous
skin over the same regions. Shortly thereafter, a distal sensori-
motor polyneuropathy develops.441,609,782 Patients have a loss pri-
marily of large fiber function. Pain and paresthesia are
uncommon. Ataxia, dysarthria, and increasing irritability can be
seen. Chronic low-level exposure may present with mental con-
fusion and hallucinations in addition to weakness, gait difficul-
ties, and occasionally urinary incontinence.
Physical examination reveals distal muscle weakness and
wasting with a loss of vibration in the distal upper and lower
limbs but relatively good preservation of touch, pain, and tem-
perature sensation. Patients may be ataxic and demonstrate a
positive Romberg sign. Deep tendon reflexes are depressed in
the upper limbs and markedly diminished or absent in the lower
limbs. Distal weakness of the hands and feet is noted. A course
tremor may be noted in the hands. After elimination of acry-
lamide exposure, function gradually returns. Patients with low
levels of exposure usually do quite well. However, in patients
exposed to large amounts, significant improvement may require
a year or more, and patients may not recover completely.
Histopathology. A few sural nerve biopsies reveal primarily
axonal degeneration with loss of large myelinated fibers.441
Experimental studies in animals demonstrate that the earliest
histologic abnormality is paranodal accumulation of 10-nm
neurofilaments at the distal ends of the peripheral nerves.1170,1177
Enlargement of the distal axons with subsequent axonal degen-
eration and segmental remyelination can be seen. Unmyelinated
fibers as well as degeneration of the posterior columns, spin-
ocerebellar tracts, optic tracts, mamillary bodies, and the corti-
cospinal tracts also can be found.
Pathogenesis. The exact pathogenic basis is unknown, but it
is believed that acrylamide impairs fast bidirectional axonal
transport as well as slow antegrade transport.1177
Electrophysiologic Findings. Only a small number of elec-
trodiagnostic medicine examinations have been reported in
humans, and none has included needle EMG.441,609,782 Sensory
nerve conduction velocities are normal or only slightly reduced,
but SNAPs are usually markedly reduced in amplitude. Motor
nerve conduction studies demonstrate well-preserved distal motor
latencies and only an occasional mild reduction in conduction ve-
locities. CMAP amplitudes are at the lower range of normal.
Some degree of temporal dispersion of the CMAPs can be ob-
served in patients exposed to high levels of the substance. These
modest abnormalities are usually observed only in patients suffer-
ing from acute intoxication. In patients chronically exposed to
low levels, nerve conduction studies are relatively normal, despite
clinical symptoms and signs. After elimination of exposure to
acrylamide, electrophysiologic studies return to normal values.
Animal studies have verified a number of the above-noted clini-
cal, histologic, and electrophysiologic findings.1170,1252
Carbon Disulfide
Clinical Features. Carbon disulfide is used in the manufac-
ture of viscose Rayon products and sheets of cellophane.1177,1354
The primary route of entry is through inhalation, but carbon
disulfide can also be absorbed through the skin. Acute exposure
to high levels produces various psychotic disturbances, which
resolve with elimination of exposure. Chronic low-level expo-
sure can result in a peripheral neuropathy.1177,1356 Patients com-
plain of distal numbness and tingling, usually beginning in the
lower limbs and progressing to involve the upper limbs.
Reductions in all sensory modalities can be demonstrated and
accompanied by a diminution in deep tendon reflexes. Distal
muscle atrophy and weakness may be evident.
Histopathology. Detailed descriptions of the histopathology
in humans are lacking. However, experimental studies in ani-
mals have shown accumulation of 10-nm neurofilaments and
axonal swellings, similar to that seen in acrylamide and hexo-
carbon toxicity.1177
Pathogenesis. The exact pathogenic basis for the neuropa-
thy is not known, but theories include (1) a chelating effect on
enzyme function, (2) direct inhibition of various enzymes, and
(3) release of free radicals after cleavage of the carbon-sulfur
bond with secondary axonal damage.1177
Electrophysiologic Findings. Nerve conduction studies
demonstrate a reduction in the SNAP conduction velocities and
may be the only abnormality noted early in the disease.252,1343
The amplitudes of the SNAPs have not been addressed in detail.
Motor conduction studies demonstrate comparatively less pro-
nounced slowing of conduction. The distal motor latencies may
be normal or slightly prolonged. No comments have been made
about the CMAP amplitude during the disease process. Needle
EMG examination may reveal fibrillation potentials and posi-
tive sharp waves in the distal limb muscles, especially in the
lower limbs. After cessation of the toxic exposure, electrophysi-
ologic data may improve in a few patients, but many simply no
longer progress and maintain a new steady state of neural con-
duction slowing.
Ethylene Oxide
Clinical Features. Ethylene oxide is one of the most widely
used industrial substances. It is used for sterilizing heat-sensi-
tive materials, particularly in the health care setting. The pri-
mary manifestations of human exposure are dermatologic
lesions, mucosal membrane irritation, nausea, vomiting, and al-
tered mentation. People exposed to high levels can develop a
severe sensorimotor peripheral neuropathy.269,1184 Patients usu-
ally complain of acral hypesthesia and paresthesias accompa-
nied by difficulty in walking and increased fatigability.
Examination demonstrates a reduction in sensory modalities,
primarily in the distal aspects of the lower limbs, with some ev-
idence of intrinsic foot muscle wasting and a wide-based gait. A
mild reduction in muscle strength can be detected in the intrin-
sic foot and distal lower limb muscles. Heel-to-shin ataxia, slow
and clumsy alternating hand motions, and diminished deep
tendon reflexes are present.
Histopathology. Sensory nerve biopsies reveal the loss of
primarily, but not exclusively, large myelinated fibers.
Pathogenesis. The pathogenic basis of the neuropathy is not
known. Ethylene oxide can act as an alkyating agent and bind
with many organic molecules, including DNA.
Electrophysiologic Findings. Electrodiagnostic medicine
evaluation reveals reduced amplitudes or absence of sensory re-
sponses, especially in the lower limb.418,509,742 Sensory conduc-
tion velocities are diminished but usually not below 80% of the
lower limit of normal. H-reflexes in the lower limbs are com-
monly absent. Motor conduction studies demonstrate reduced

amplitudes or absent CMAP responses. Motor nerve conduction
velocities also are slightly decreased. Needle EMG demon-
strates fibrillation potentials, positive sharp waves, and reduced
recruitment of MUAPs. The MUAPs are increased in duration
and amplitude as well as number of phases.
Organophosphates
Clinical Features. The organophosphorous esters are used
primarily in the production of insecticides, plastics, and petro-
leum products and as toxic nerve agents in biologic warfare.
Multiple instances of accidental and intentional intoxication by
types of organophosphorus compounds have resulted in neuro-
logic complications.583,1196,1197,1233,1373 These compounds inhibit
acetylcholinesterase and result in the accumulation of acetyl-
choline at cholinergic synapses (see Chapter 25). Toxic exposure
to organophosphate esters can result in muscarinic, nicotinic,
and central effects, thus producing the acute clinical symptoms
and signs. The muscarinic effects can cause nausea, vomiting,
abdominal cramping, diarrhea, pulmonary edema, and bradycar-
dia. Central effects can produce anxiety, emotional lability,
ataxia, altered mental status, unconsciousness, and seizures.
Nicotinic actions result in generalized weakness and fascicula-
tions. Acute intervention is directed at maintaining ventilation
and circulation through the administration of atropine to coun-
teract the muscarinic effects. Within 12–96 hours a so-called in-
termediate syndrome may become evident after the onset of
acute muscarinic actions. During this period, proximal muscle
and cranial nerve weakness can develop, along with respiratory
compromise. Supportive care is of primary importance to see the
patient through the several weeks of crisis. Death can result from
respiratory failure and cardiovascular collapse.
Some patients with acute organophosphate toxicity later develop
a distal sensorimotor peripheral neuropathy (organophosphate-in-
duced delayed polyneuropathy [OPIDP]).98,300,583,813,1197,1344,1374
OPIDP evolves several weeks after exposure and maximizes
within several weeks. Patients may note cramping in the calf
muscles followed by burning or tingling in the feet. Weakness is
also an early finding. Symptoms and signs may progress to in-
volve the hands. Weeks after the development of the peripheral
neuropathy, superimposed signs of central nervous system dys-
function with increased tone and hyperreflexia may be seen. In
patients with mild peripheral neuropathy, the prognosis is good.
However, patients with significant peripheral and central ner-
vous system insult generally are left with reduced abilities to
perform activities of daily living.
Histopathology. Autopsy studies of ginger jake-related
OPIDP in Jamaica from 1930 revealed abnormalities suggestive
of a distal axonopathy along with degeneration of the gracile
fasciculus and corticospinal tract.1177 In addition, autopsy of a
patient who died 15 months after intoxication by sarin gas re-
vealed marked loss of both myelinated and unmyelinated nerve
fibers in the sural nerve and a moderate loss of nerve fibers in
the sciatic nerve.583 The posterior columns and dorsal root gan-
glia appeared to be spared.
Pathogenesis. Organophosphates do not cause the toxic neu-
ropathy by inhibiting acetylcholinesterase. Rather, specific
organophosphates cause OPIDP by binding to and inhibiting an
enzyme called neuropathy target esterase (NTE).813 The func-
tion of NTE is not known, but it is present throughout the CNS
and PNS. Inhibition of NTE is not sufficient for the develop-
ment of OPIDP. The organophosphate-NTE complex must age,
whereby a lateral side-chain of NTE is cleaved, before the toxic
neuropathy develops.
Chapter 23 ACQUIRED NEUROPATHIES — 1007
Electrophysiologic Findings. Electrodiagnostic findings in
the acute and subacute stages of the disease are consistent with
neuromuscular dysfunction secondary to compromise of acetyl-
cholinesterase.98,578,1344,1376 Sensory and motor nerve studies are
normal. Of note, however, is the demonstration of repetitive firing
of the CMAPs after a single neural stimulus. A decrement can be
observed in response to low rates of repetitive stimulation and
persists for about 4–11 days. In some patients an interesting
decrement-increment phenomenon can be detected after a mild
exposure or in the recovery phase. At both low (2–5 Hz) and high
(20 Hz) rates of repetitive stimulation, the CMAP amplitudes ini-
tially decrement but then recover, approaching the baseline am-
plitudes. Needle EMG reveals a reduction in voluntary MUAPs.
The electrodiagnostic examination in OPIDP reveals findings
consistent with an axonal sensorimotor polyneuropathy. Sensory
and motor evoked response amplitudes are reduced with only
mild prolongation of the distal latencies. Likewise, the sensory
and motor conduction velocities are usually at the lower limits of
normal or mildly reduced. Needle EMG reveals significant re-
duction in voluntary MUAPs with attempts at muscle contrac-
tion and positive sharp waves and fibrillation potentials at rest.
Hexacarbons (Glue Sniffer’s Neuropathy)
Clinical Features. Both n-hexane and methyl n-butyl ketone
are classified as hexacarbons and are metabolized in the body to
2,5-hexanedione, the substance believed to be responsible for
the toxic neuropathy. Hexacarbons are water-insoluble indus-
trial organic solvents with a high vapor pressure. Accidental ex-
posure in factories and intentional glue sniffing account for
most peripheral neuropathies associated with these compounds.
The clinical manifestations can result from inhaling vapors or
through skin absorption.
A profound subacute sensorimotor polyneuropathy progress-
ing over the course of 4–6 weeks can develop secondary to
hexacarbon toxicity.482,719,1177,1253,1309 Initially, most patients note
numbness and tingling in the feet. A progressive loss of sensa-
tion in the proximal leg may occur, at which time the upper
limbs become numb. Progressive loss of motor function ensues,
with impaired ambulation and decreased fine motor coordination
skills. Sphincter function usually is preserved, as are swallowing
and respiratory functioning. Physical examination is commensu-
rate with the above symptoms. A flaccid weakness is accompa-
nied by loss of deep tendon reflexes and position/vibration sense.
Pain and temperature sensation are only mildly reduced.
Exuberant perspiration may be noted on the soles of the feet.
Histopathology. The nerve biopsy can demonstrate evi-
dence of profound loss of myelinated as well as giant axons
(Fig. 23-10).482,1177,1309 Some degree of demyelination also is
noted, but axonal loss is clearly the dominant finding. There are
no onion-bulb formations or inflammation. EM reveals that the
swollen axons are filled with 10-nm neurofilaments.
Pathogenesis. The exact mechanism by which hexacarbons
cause a toxic neuropathy is not known. It has been speculated that
the neuropathy is due to hexacarbon interactions that lead to co-
valent cross-linking between axonal neurofilaments.1177 Impaired
transportation of cross-linked neurofilaments leads to aggrega-
tion, swelling of the axons, and eventual axonal degeneration.
Electrophysiologic Findings. The electrodiagnostic evalua-
tion demonstrates decreased amplitude of the SNAPs with
normal or only mild slowing of sensory conduction velocities or
prolonged distal latencies.18,197,224,472,576,608,695 Lower limb SNAPs
are preferentially affected, but in profound disease upper limb
SNAP responses also may be markedly reduced or absent. The
1008 — PART IV CLINICAL APPLICATIONS
Figure 23-10. Hexane neuropathy. Sural nerve biopsy reveals
thinly myelinated, markedly swollen axons. (Epoxy-embedded, toluidine
blue stain).
CMAP amplitudes are decreased in the upper and lower limbs.
However, mild cases of neuropathy may be associated with
normal CMAPs. Nerve conduction velocities are usually re-
duced to about 70–80% of the lower limit of normal. In some
patients, a few nerves in both upper and lower limbs may
demonstrate conduction velocities approaching 50% of the
lower limit of normal.695 Needle EMG examination reveals a re-
duced number of MUAPs firing at rapid rates in distal muscles.
These findings usually are accompanied by fibrillation poten-
tials and positive sharp waves. Some patients also have readily
detectable fasciculation potentials.
Vinyl Benzene (Styrene)
Vinyl benzene or styrene is an industrial liquid used in the
manufacture of some plastics and synthetic rubber materials.
Exposed workers can develop a peripheral neuropathy that is
primarily sensory.83 Burning paresthesias begin in the feet and
progress up the legs. Usually strength is preserved and patients
can ambulate without difficulty aside from pain in the feet.
Physical examination demonstrates a reduction in pain and tem-
perature with relatively good preservation of proprioception and
vibration. Deep tendon reflexes are well preserved. Limited
electrophysiologic testing demonstrates a mild reduction in
motor conduction velocities in the lower limbs.
Additional Agents
Other agents reported to result in a preferential axonal senso-
rimotor peripheral neuropathy include dichlorophenoxyacetic
acid and carbon monoxide.470,1241 Such cases are extremely rare,
and only a few patients have been cited in the literature. Briefly
noted electrodiagnostic medicine examinations have described
findings suggestive of a primarily axonal neuropathy with little
in the way of nerve conduction velocity alterations but large
amounts of fibrillation potentials and positive sharp waves asso-
ciated with reduced MUAP recruitment. Further studies are re-
quired to characterize the peripheral neuropathy in greater detail.
HEAVY METAL INTOXICATION
A number of metals, especially those with high atomic
weights (so-called heavy metals), can produce primarily axonal
neuropathies in humans.1420 The severity of the neuropathy is
usually related to the amount of metal that enters the patient’s
system either acutely or chronically. Clinical improvement de-
pends on cessation of exposure and supportive measures.
Unfortunately, a number of the heavy metals can enter various
storage zones in the body, from which they are slowly released,
producing a chronic low-level, continual-dosing phenomenon.
Most patients are exposed to heavy metals as a result of work-
related activities, although a few patients may have attempted
suicide or are the victims of attempted homicide. Multiple organ
systems can be involved in addition to the peripheral nervous
system. The combination of systemic effects and peripheral
nerve dysfunction at times helps to distinguish the type of metal
involved, although laboratory determination of serum and urine
metal levels is the definitive method of diagnosis.
Lead
Clinical Features. Lead neuropathy is an increasingly rare
cause of peripheral nerve disease because of the realization of
its harmful effects.94,1420 It occasionally can be seen in children
who consume lead-based paints in older buildings and in indus-
trial workers dealing with metals, batteries, or paints containing
lead products. Both organic and inorganic lead substances can
gain access to the human body from environmental sources and
result in central and peripheral nervous system dysfunction. In
children, the most common presentation of lead poisoning is en-
cephalopathy. Patients usually have some abdominal discom-
fort, accompanied by varying degrees of constipation. However,
children and adults can present with symptoms and signs of a
primarily motor peripheral neuropathy.123,408,409,633,1199,1223,1420
A so-called lead line can be seen in some patients. It mani-
fests as a bluish-black coloration of gums near the teeth. With
respect to the neuropathy, patients may note the insidious and
progressive onset of upper limb weakness. There are few or no
sensory complaints, and sensory examination to all modalities
is usually well preserved. The classic sign is noticeable motor
involvement of the radial nerve with a wrist/finger extensor
weakness. When the lower limbs are involved, an asymmetric
foot drop is likely. Deep tendon reflexes are diminished, and
plantar responses are flexor.
Laboratory Features. Laboratory investigation can reveal
an elevated serum coproporphyrin level, basophilic stippling of
erythrocytes, and reduced hemoglobin content, suggesting a mi-
crocytic/hypochromic anemia. A 24-hour urine collection
demonstrates elevated levels of lead excretion, which can be
magnified by the addition of a chelating agent in suspicious
cases.
Histopathology. There is generally a reduction in the
number of large myelinated axons with little, if any, segmental
demyelination.164
Pathogenesis. It is unclear whether the primary target of the
toxic insult is the anterior horn cell or, more distally, the periph-
eral or motor nerve.1420 Nor is the exact pathogenic mechanism by
which lead causes axonal degeneration known. It has been specu-
lated that lead may interfere with mitochondrial function.1420
Electrophysiologic Findings. In motor and sensory nerve
conduction studies, distal latency, amplitude, and velocity have
been reported to be mildly abnormal in studies of relatively
large numbers of patients exposed to various forms of
lead.123,164,183,408,409,1199,1200,1202,1223 When these values are com-
pared with values after treatment, an improvement is noted.36,927
On needle EMG, the most common finding is an increase in the
MUAP amplitude, duration, and number of phases. Alterations

in recruitment usually are not noted until there is moderate loss
of axons. Fibrillation potentials and positive sharp waves can be
seen in the affected muscles.
Treatment. The most important treatment is removing the
source of the exposure. Chelation therapy with calcium disodium
ethylenediamine tetraacetate (EDTA), British anti-Lewisite
(BAL), and pencillamine demonstrates variable efficacy.1420
Mercury
Clinical Features. Intoxication results from exposure to
either organic or inorganic mercurials.656,836,1211,1420 The organic
form is usually found in methyl or ethyl mercury. Perhaps the
most infamous case of organic mercury poisoning resulted from
dumping mercuric chloride into Minimata Bay, where sea life
converted the substance into methyl mercury. The population
dependent on the fish and crustaceans for food developed mer-
cury poisoning. An initial manifestation of organic mercury poi-
soning is paresthesias in the distal regions of the limbs. Over
time, the paresthesias progress proximally, eventually involving
the tongue. Patients may display ataxia, reduced mentation,
visual and hearing loss, and dysarthria.
The inorganic mercury compounds, which are used primarily
for industrial purposes, consist of various mercury salts. The
gastrointestinal system is believed to be the major source of
entry into the human body. Mercury vapors in poorly ventilated
industrial areas also can be a significant health hazard. The
actual mercury metal or fluid at room temperature is reported to
be nonhazardous because it is apparently poorly absorbed from
the gastrointestinal tract. In acute poisonings with mercury
salts, gastrointestinal symptoms predominate, although
nephrotic syndrome may be a major problem. Mercury vapors
exert their toxic effect through their high lipid solubility and
thus result in central nervous system effects such as loss of ap-
petite, mental confusion, weight loss, and fatigue. Some degree
of peripheral neuropathy may be manifest in particularly sensi-
tive patients.
Laboratory Features. Organic mercury intoxication can be
extremely difficult to prove. Little of the metal may be excreted
in the urine because it is highly lipid-soluble and thus remains
in the body. Inorganic mercury, on the other hand, is readily ex-
creted in the urine, and 24-hour urine collection can reveal an
increased concentration.
Histopathology. Histopathologic evaluation of patients ex-
posed at Minimata Bay demonstrated significant degeneration
of the calcarine aspect of the cerebral cortex and cerebellum,
hence accounting for ataxia and visual complaints.1420
Prominent degeneration of axons in the sural nerves and lumbar
dorsal roots was also observed. Segmental demyelination was
absent.
Pathogenesis. It is hypothesized that mercury exerts its toxic
effect on neurons by combining with sulfhidryl groups of enzy-
matic or structural proteins, thereby impairing their proper func-
tion and leading to degeneration of the neurons.1420 The primary
site of pathology appears to be the dorsal root ganglia.
Electrophysiologic Findings. Only a few electrodiagnostic
medicine evaluations have been reported in patients with ongo-
ing mercury exposure.1146 Several investigations have noted a
distinct lack of electrophysiologic abnormalities in patients
with proven mercury exposure; however, these conclusions are
of little value because they were performed 7 months or more
after cessation of exposure.779,1367Electrodiagnostic findings in
patients exposed to organic mercury and mercury vapors may
be abnormal.5,8,614,1205,1224,1305 In patients with low blood levels
Chapter 23 ACQUIRED NEUROPATHIES — 1009
despite clinical symptoms, sensory studies may yield low
normal values for amplitude and conduction velocity. Although
this may be statistically significant when patients are compared
with a control population, the absolute value in individual pa-
tients is within normal limits and, therefore, of little diagnostic
use.
When patients with high serum or urine levels are examined,
a number of abnormalities may be found. The sural and superfi-
cial peroneal nerves may reveal reduced SNAP amplitudes and
normal or slightly reduced (> 80% of lower limit of normal)
conduction velocities. In patients with long-standing exposure,
somatosensory evoked potentials of the median nerve demon-
strate peripheral potentials but no cortical potentials.1305 Motor
conduction velocities are usually normal or borderline slow
with normal CMAP amplitudes. Distal motor latencies are
normal in most patients. F-wave and H-reflex latencies can be
normal or slightly prolonged. The needle EMG examination
may reveal positive sharp waves and fibrillation potentials in
some patients, but there is usually a lack of abnormal sponta-
neous activity. Occasionally, patients exposed to mercury pre-
sent with abnormalities suggestive of motor neuron disease.5
Quantitative motor unit analysis typically demonstrates MUAPs
with increased duration and amplitude, but recruitment is
normal. Such findings in patients with low-level exposure over
years suggests a slow loss of axons with subsequent motor unit
remodeling.
Treatment. Chelating agents such as penicillamine have
been used, but the number of treated cases is too small to allow
comment on efficacy.1420 The mainstay of treatment is removing
the source of exposure.
Thallium
Clinical Features. Thallium is a heavy metal that can exist
as a monovalent or trivalent species.342,1069,1420 Monovalent thal-
lium ions are present in multiple tasteless, and odorless salts
(sulfate, acetate, and carbonate) that are highly soluble in aque-
ous solutions. These solutions are both colorless and highly
toxic. Initially thallium salts were used to treat a variety of con-
ditions, such as tuberculosis, venereal disease, syphilis, and
ringworm. Therapeutic use was abolished after full recognition
of its toxic effects. Subsequently thallium was used primarily as
a rodenticide. Accidental and intentional poisonings resulted in
the banning of thallium for any purpose in the United States in
1965. It is, however, still available worldwide as a rodenticide
and from time to time may be recognized in victims of homi-
cide attempts. The lethal dose of thallium in humans is rather
variable but averages about 1 gram or 8–15 mg/kg body weight.
Death can result in less than 48 hours after a particularly large
dose.
Most patients present initially with complaints of burning
paresthesias of the plantar surfaces of the feet bilaterally as well
as abdominal distress and occasional vomiting.342,1069,1420 The
burning pain in the feet may be severe enough to limit ambula-
tion. Pain and temperature sensation is reduced, and vibratory
perception and proprioception are mildly decreased. Deep
tendon reflexes are reduced distally but generally preserved
proximally. Distal muscle atrophy and weakness gradually
ensue. With severe intoxication, proximal weakness and in-
volvement of the cranial nerves can occur. Some patients re-
quire mechanical ventilation as a result of respiratory muscle
involvement.
In addition to nausea and abdominal pain, retrosternal pain,
thirst, sleep disturbances, and psychotic behavior may be noted.
1010 — PART IV CLINICAL APPLICATIONS
Within the first week, patients may display continued vomiting,
hair root pigmentation, an acne/malar rash, and possible hyper-
reflexia. By the second and third weeks, mild tachycardia and
hypertension are noted as well as hyporeflexia about the ankles
and the beginning of alopecia. The hallmark of thallium poison-
ing is alopecia, but it may not be evident until the third or fourth
week after exposure and can be rather mild in some patients. Of
importance, alopecia is not pathognomonic for thallium intoxi-
cation because exposure to vincristine, chloroprene, and mer-
captopurine also can result in hair loss.
Laboratory Features. Serum and urine levels of thallium
are increased. Routine laboratory testing can reveal anemia,
azotemia, and liver function abnormalities. CSF protein levels
also are elevated.
Histopathology. The primary pathologic reaction of the pe-
ripheral nervous system to thallium intoxication is axonal
loss.185,296,342 Chromatolysis of cranial and spinal motor nuclei
and dorsal spinal ganglia has been demonstrated. Wallerian de-
generation is the prominent feature noted on peripheral nerve
biopsy, with little or no segmental demyelination. There is a
general reduction in nerve fibers of all diameters. Mitochondria
can appear swollen in experimental cultured neuronal tissue.1420
Pathogenesis. It is not known whether the primary insult is
to the neuronal cell body or the axons. The pathogenic basis for
the toxicity is also unknown.
Electrophysiologic Findings. An electrodiagnostic exami-
nation of the patient within the first few days of intoxication re-
veals no significant abnormalities.65,342,796 By 10 days after
thallium exposure, it is possible to note an absence of the medial
and lateral plantar mixed nerve action potentials with preserved
sural nerve SNAPs. This finding is important because the most
distal aspects of the peripheral nervous system are preferentially
affected first. Limiting the sensory examination to the sural
nerve can result in disappointingly normal studies despite pro-
found symptoms.Because patients usually complain of plantar
foot pain, these nerves should be examined. Over the ensuing
weeks, the more proximal lower limb sensory nerves are af-
fected. When present, the SNAP is usually reduced in ampli-
tude, and the distal sensory latencies or conduction velocities
are mildly abnormal. H-reflexes may be present within the first
10 days after exposure but then disappear and may not return
for some time.
Motor conduction studies in the lower limbs can reveal
absent CMAPs in the foot intrinsic muscles. When these re-
sponses are present, the conduction velocity is mildly reduced,
but the CMAP is markedly reduced. Serial studies demonstrate
an initial reduction in amplitude in both upper and lower limb
CMAPs with a gradual increase over the ensuing years. The
distal motor latencies are normal or mildly prolonged.
Needle EMG examination within the first few days of expo-
sure may reveal only a reduced recruitment of motor units.
Within the next 10 days intrinsic foot muscles reveal evidence
of denervation by way of positive sharp waves and fibrillation
potentials. These abnormalities progress to affect the more
proximal muscles in the lower limbs. With time the denervated
muscle fibers are reinnervated, thus reducing the number of ob-
served abnormal spontaneous potentials. Motor unit remodeling
generates MUAPs with elevated amplitudes and durations.
Treatment. With acute intoxication, potassium ferric ferro-
cyanide II may prevent absorption of thallium from the gut.1420
However, it is not clear whether the medication is effective once
thallium has been absorbed. Unfortunately, chelating agents are
not particularly useful. Maintaining adequate diuresis helps to
eliminate thallium from the body without increasing tissue
availability from the serum.1420
Arsenic
Clinical Features. Arsenic is another heavy metal that can
cause a toxic sensorimotor polyneuropathy.221,440,497a,631,928,981,
1420,1447 The neuropathy begins 5–10 days after ingestion of ar-
senic and progresses for several weeks. Most patients with acute
arsenic poisoning complain of abrupt onset of abdominal dis-
comfort, nausea, vomiting, pain, and diarrhea, followed within
several days by a burning sensation in the feet and hands. Soon
thereafter, progressive loss of muscle strength develops distally.
With severe intoxication, weakness progresses to the proximal
muscles and cranial nerves. Some patients may require mechan-
ical ventilation. Diminished deep tendon reflexes are also noted
commensurate with the degree of strength loss. Such symptoms
and signs can be suggestive of AIDP; hence, acute arsenic in-
toxication should be kept in mind when evaluating patients with
an acute onset of sensory and motor loss. Some patients display
slow mentation and confusion, suggesting central nervous
system toxicity. If the ingested dosage is large enough, CNS
symptoms may predominate with rapid progression to death due
to vascular collapse.
Clinical skin changes may be helpful in raising the suspicion
of arsenic intoxication. There can be loss of the superficial epi-
dermal layer several weeks after the initial exposure or with
chronic low levels of ingestion. Variations in skin coloration
create patchy regions with various degrees of increased or de-
creased pigmentation. Mee’s lines, which are transverse lines at
the base of the fingernails and toenails, may become evident by
1 or 2 months. They correlate with arsenic exposure. In patients
with both long fingernails and repeated intoxication, in time one
can observe multiple Mee’s lines on examination. Of note, such
nail abnormalities can be seen in disorders other than arsenic
poisoning (e.g., thallium poisoning).
Laboratory Features. Clearance from blood is rapid; there-
fore, serum concentration of arsenic is not diagnostically help-
ful. Arsenic levels are increased in the urine, hair, or fingernails
of affected patients. As in lead intoxication, basophilic stippling
of erythrocytes occasionally is observed as well as an aplastic
anemia with pancytopenia. Increased CSF protein levels with-
out pleocytosis, as seen in AIDP, also can be demonstrated.
Histopathology. Peripheral nerve biopsies in patients with
arsenic poisoning demonstrate an increase in interstitial fibrosis
as well as increased endoneurial cells. A reduction in total num-
bers of large- and small-diameter myelinated fibers results from
axonal degeneration. Segmental demyelination is rare, but occa-
sional onion-bulb formations are evident. Autopsy studies have
revealed a loss of anterior horn cells.
Pathogenesis. The pathogenic basis of arsenic toxicity is not
known. It is believed that arsenic reacts with sulfhydryl groups
of enzymatic and structural proteins in the neurons. In particu-
lar, arsenic may inhibit the pyruvate dehydrogenase com-
plex.1420 The resulting impairment of cellular metabolism may
lead to neuronal degeneration.
Electrophysiologic Findings. The traditional electrophysio-
logic abnormalities are consistent with a primarily axonal sen-
sorimotor polyneuropathy.221,410,497a,631,928,981,984,1420 Specifically,
sensory studies commonly reveal complete absence of the
SNAPs, especially in the lower limb. The upper limb SNAPs are
also absent or markedly reduced in amplitude. Not uncom-
monly, the CMAPs may be absent, particularly in the lower
limb. When obtainable, motor nerve conduction studies are

mildly to moderately reduced (i.e., 80–90% of the lower limit of
normal). Distal motor latencies are not especially affected.
Maximum abnormalities in motor nerve conduction studies
occur approximately 3–5 weeks after exposure. Return to normal
requires several years, and in some patients normal neural con-
duction may not be restored. Needle EMG examination reveals
positive sharp waves and fibrillation potentials with reduced
numbers of motor units in the distal muscles, progressing proxi-
mally in patients exposed to significant amounts of arsenic. The
important point about the studies defining the above abnormali-
ties is that they were performed somewhat late in the disease.
Of interest are a number of reports documenting arsenic in-
toxication of significant degree after single or limited doses
with electrophysiologic studies performed soon after or before
diagnosis.320,328,463,781,1411 Such patients customarily are exposed
to a single large dose and present clinically with AIDP. The
electrophysiologic studies demonstrate absent or markedly re-
duced sensory responses. Motor conduction studies may reveal
evidence suggestive of conduction block and prolongation of F-
wave latencies. Serial studies demonstrate progressive deterio-
ration of the CMAP amplitudes to distal stimulation, associated
with progressive conduction block and reductions in the con-
duction velocities. Initially, needle EMG examination reveals an
increase in insertional activity and reduced MUAP recruitment,
but by 2–3 weeks marked fibrillation potentials and positive
sharp waves are found with reduced number of MUAPs. Early
in the disease, membrane instability may be noted only in the
paraspinal muscles, which always should be examined.
Treatment. Chelation therapy with BAL has yielded incon-
sistent results in small retrospective studies. Nevertheless, the
beneficial effect of BAL, if any, is not dramatic; therefore, its
use is not recommended.1420
Gold
Clinical Features. Gold therapy (e.g., sodium aurothioma-
late) is sometimes used to treat rheumatoid arthritis. Some pa-
tients treated with gold salts develop a sensorimotor peripheral
neuropathy several months after drug initiation.1420 Most pa-
tients complain first of paresthesias in the distal aspects of the
lower and sometimes upper limbs. These sensations usually
progress over the ensuing weeks with accompanying weakness
primarily, but not exclusively in the distal muscles of the lower
limbs. Not uncommonly, a systemic reaction (e.g., rash and pru-
ritus) to gold is also noted. Examination reveals diminution of
deep tendon reflexes with plantarflexor responses and reduc-
tions in all sensory modalities in the distal lower limbs and oc-
casionally upper limbs. A few patients display spontaneous and
vermicular movements of some limb muscles (i.e., myokymia).
Patients with connective tissue diseases who do not take gold
therapy also can develop peripheral neuropathies. Stopping the
gold usually results in remission of most if not all symptoms
over the course of several weeks. This does not occur if connec-
tive tissue disease is the primary cause of the peripheral nerve
symptoms. It is wise to stop gold therapy in patients with pe-
ripheral nerve symptoms to evaluate the respective roles of gold
and connective tissue disease.
Histopathology. The few studies that have been performed
in humans found a number of peripheral nerve alterations, indi-
cating both axonal degeneration and segmental demyelination
of varying degrees.
Pathogenesis. The pathogenic basis for the neuropathy is
not known. It may be related to an immunologic reaction trig-
gered by gold therapy.1420
Chapter 23 ACQUIRED NEUROPATHIES — 1011
Electrophysiologic Findings. Electrodiagnostic medicine
findings are somewhat variable, depending on the degree of pe-
ripheral neuropathy at the time of examination.659,900,1379 Mild
cases may demonstrate few abnormalities. For example, a slight
prolongation in the SNAPs or mild reduction in amplitudes and
conduction velocities may be noted. Motor studies and needle
EMG are normal.
On the other hand, patients with significant neuropathy may
show complete absence of SNAPs in the lower limbs with sig-
nificant reductions in amplitude of upper limb SNAPs. The
distal sensory latencies may be mildly to moderately pro-
longed with slowing of conduction velocities into the abnor-
mal range (usually not exceeding 70% of the lower limit of
normal). The CMAPs are well preserved in most patients, but
the motor conduction velocity can be mildly reduced in addi-
tion to a slight prolongation in the distal motor latency. Needle
EMG examination demonstrates reduced recruitment with oc-
casional positive sharp waves and fibrillation potentials in the
distal muscles of the lower limb. Myokymia may be noted in
both upper and lower limb muscles in some patients, with or
without accompanying positive sharp waves and fibrillation
potentials.
Treatment. Treatment consists of stopping the gold therapy.
BAL has been tried in a few patients, but its efficacy is unclear.1420
NEUROPATHIES RELATED TO NUTRI-
TIONAL DEFICIENCIES
THIAMINE (VITAMIN B1)
Clinical Features. Thiamine deficiency is rare except in
people who consume alcohol as their major source of nutrition.
This section, however, focuses on patients with a primary thi-
amine deficiency unrelated to excessive alcohol ingestion.
Symptoms due to insufficient dietary intake of thiamine are
known as beriberi and may present in two forms: dry and wet.
The difference is simply the presence (wet beriberi) or absence
(dry beriberi) of congestive heart failure and lower limb edema.
Both forms are associated with neurologic symptoms. Beriberi
primarily results from a diet high in processed foods without
appropriate vitamin supplements. Prisoners of war and people
consuming milled rice, from which the outer coating is re-
moved, are at risk for developing beriberi.
Patients usually present with complaints of numbness and
tingling or burning in the soles of the feet.288,599,1279 Within sev-
eral days, weakness may be noted in the distal muscles of the
lower limbs, accompanied by similar sensory symptoms in the
fingertips. Physical examination may reveal lower limb edema
with cardiac enlargement and an apical systolic cardiac murmur
(wet beriberi). Sinus tachycardia is present, and cardiac conduc-
tion blocks may be identified. Deep tendon reflexes are absent
at the ankles and occasionally at the knees, with depressed
upper limb reflexes. A mild to moderate reduction in all sensory
modalities is noted in a stocking distribution, with some patients
displaying similar sensory findings in the hands. Calf tender-
ness may be noted in some patients.
Histopathology. Sural nerve biopsies reveal significant
axonal loss primarily of large myelinated fibers with little seg-
mental demyelination. Chromatolysis of the anterior horn cells
and dorsal root ganglia cells, along with axonal degeneration
and secondary demyelination of the posterior columns, has been
noted on autopsies.
1012 — PART IV CLINICAL APPLICATIONS
Pathogenesis. The pathogenic basis for neuropathy in pa-
tients with thiamine deficiency is not known. Thiamine is a
coenzyme required for oxidative decarboxylation of ketoacids
and transketolation in the pentose phosphate shunt. Impaired
energy metabolism due to thiamine deficiency may result in im-
pairment of axonal transport and other high energy-dependent
intracellular processes.
Electrophysiologic Findings. The electrodiagnostic evalua-
tion demonstrates findings consistent with the histopathologic
loss of large myelinated axons. Sensory nerve conduction stud-
ies document that the distal sensory latencies and conduction
velocities are normal or only mildly impaired, whereas the
SNAP amplitudes are either absent or significantly reduced.599
The CMAP is normal or slightly reduced in the upper limbs and
reduced or absent in the lower limbs. Distal motor latencies are
at the upper limits of normal or slightly prolonged. Motor con-
duction velocities are normal or reduced to not less than
75–80% of the lower limit of normal. Needle EMG demon-
strates positive sharp waves and fibrillation potentials, mainly in
the distal lower limbs. Occasionally, abnormal spontaneous ac-
tivity is noted in the hand intrinsic muscles. A few patients may
demonstrate complex repetitive discharges and fasciculation po-
tentials. The MUAPs display increased durations, large ampli-
tudes, and decreased recruitment.
Treatment. Thiamine (50 mg) is injected intramuscularly
daily for 2 weeks, followed by 5 mg/day orally. Administration
of thiamine improves the symptoms and signs of beriberi.
PYRIDOXINE (VITAMIN B6)
Pyridoxine is not only neurotoxic in large dosages (see
above) but may be associated with a sensorimotor polyneuropa-
thy in patients with deficiencies. Pryridoxine deficiency has
been associated with isoniazid and hydralazine treatment.
COBALAMIN (VITAMIN B12)
Clinical Features. Patients can present with hematologic
(megaloblastic anemia), gastrointestinal, and neurologic mani-
festations of vitamin B12 deficiency. Neurologic symptoms
result from both peripheral and central nervous system
insult.416,417,534,571,641,664,720,733,804,861 Either the central or peripheral
nervous system may be perferentially affected, and a number of
patients have combined peripheral and central nervous system
dysfunction. In patients with a primarily central nervous system
disorder, altered mentation combined with primarily posterior
column and occasionally pyramidal fiber insult (subacute com-
bined degeneration) can result. Such patients not only have de-
creased cognitive abilities but also display gait ataxia with
primarily lower limb weakness in association with extensor
plantar responses, hyperreflexia, and a positive Romberg sign.
On the other hand, a preferential alteration of the peripheral ner-
vous system manifests with complaints of numbness and tin-
gling. Examination demonstrates decreased or absent deep
tendon reflexes in the lower and occasionally upper limbs,
flexor plantar responses, reduced vibration, and some diminu-
tion in pain and temperature sensation in the distal aspects of
the limbs as well as muscle wasting and weakness in the distal
lower limb muscles. A combination of central and peripheral
neural insults is essentially a peripheral neuropathy superim-
posed on a central nervous system insult. Patients complain of
the distal limb paresthesias with significant difficulty in ambu-
lating, particularly in the dark. Muscle wasting in the foot intrinsic
muscles is observed as well as reduced lower limb reflexes. In
the upper limbs, normal deep tendon reflexes or hyperreflexia
can be found in addition to upper limb hypertonicity accompa-
nied by lower limb extensor plantar responses.
Laboratory Features. Serum cobalamine levels are de-
creased or in the low range of normal. In patients with B12 levels
in the low normal range and symptoms and signs suggestive of
cobalamine deficiency, it is important to assess serum or urine
levels of methylmalonic acid and homocysteine. These metabo-
lites are increased in patients with cobalamine deficiency and
can precede abnormalities in serum B12 concentrations. A com-
plete blood count and smear can reveal megaloblastic anemia.
Of importance, the neurologic complications of cobalamine de-
ficiency can be evident before the hematologic abnormalities
are appreciated. Patients with an autoimmune basis for B12 defi-
ciency may demonstrate autoantibodies directed against gastric
parietal cells.
Histopathology. Histopathologic examination reveals de-
generation of the posterior columns in patients with central ner-
vous system disorders, whereas axonal degeneration with
secondary segmental demyelination is noted in peripheral nerve
dysfunction.
Pathogenesis. The cobalamin molecule is a heme-like com-
pound that is water-soluble but lipid-insoluble. It is found in
meat, fish, and dairy products; fruits, vegetables, and grains do
not contain this vitamin.1021 The molecule is far too large to dif-
fuse readily across the intestinal mucosa; therefore, it requires a
transport molecule known as intrinsic factor, which is synthe-
sized by the gastric parietal cells. Vitamin B12-deficient states
thus result from dietary deficiency (strict vegetarian diet: lac-
tovegetarian), lack of intrinsic factor (pernicious anemia with
autoimmune destruction of parietal cells or gastrectomy), mal-
absorption syndromes (sprue or lower ileum resection), genetic
defects in methionine synthetase, and bacteria (blind-loop syn-
drome) or parasites (Diphyllobothrium latum [fish tapeworm])
that consume the vitamin before it is absorbed. Cobalamin is
necessary for demethylation of methyltetrahydrofolate. Tetra-
hydrofolate, in turn, is important in the production of folate
coenzymes, which are required for DNA synthesis. The patho-
genic mechanism for the neuropathy associated with cobalamin
deficiency is not known. The neuropathy may result from im-
pairment in DNA synthesis or some other biochemical defect.
Electrophysiologic Findings. The electrodiagnostic evalua-
tion reveals abnormalities consistent with a sensory or sensori-
motor axonopathy in patients with peripheral neuropathy.416,417,
534,571,641,664,720,733,804,861 The SNAP amplitudes are reduced or
absent, whereas the distal sensory latencies and conduction ve-
locities are essentially normal or only mildly abnormal. Motor
conduction studies may be normal or demonstrate low-ampli-
tude CMAPs. The motor conduction velocities and distal motor
latencies are usually normal. However, F-waves and H-reflexes
may be prolonged in latency, and there may be an increase in F-
wave chronodispersion. Somatosensory evoked potentials of
both upper and lower limb nerves demonstrate findings consis-
tent with prolongation of central conduction time in patients with
central nervous system dysfunction.571 Magnetic stimulation also
may demonstrate slow central motor conduction.571 Needle EMG
reveals fibrillation potentials and positive sharp waves in the
distal lower limb muscles with significant reductions in motor
unit recruitment. The administration of cobalamin usually re-
verses, at least in part, most electrophysiologic abnormalities.
Treatment. Cobalamin deficiency is treated with intramus-
cular injections of vitamin B12.

Vitamin B12 Deficiency Secondary
to Nitrous Oxide Inhalation
Nitrous oxide has been abused because of its ability to cause
a euphoric state. Nitrous oxide can inactivate methylcobal-
amine, giving rise to clinical and laboratory features described
above with vitamin B12 deficiency. Several patients have devel-
oped neuropathy and subacute combined degeneration related
to nitrous oxide inhalation.577,771,1153,1358 Physical examination re-
veals reduced sensation to touch and vibration with relatively
good preservation of pain, temperature, and proprioception
throughout. Deep tendon reflexes are diminished at the ankles,
but are normal in other body regions. Sural nerve biopsy can
reveal a reduction in the total number of myelinated fibers and
evidence consistent with axonal loss. Electrodiagnostic studies
demonstrate occasional low-amplitude SNAP responses with
normal latencies and conduction velocities. H-reflexes are typi-
cally absent in the lower limbs. Similarly, the CMAPs for both
upper and lower limb nerves are well preserved for distal motor
latency with a minor reduction in conduction velocity. The am-
plitude may be borderline low. F-waves are usually prolonged
in the upper limb and absent in the lower limbs. Needle EMG of
the distal muscles may be normal or reveal a reduced number of
MUAPs. Some patients have positive sharp waves and fibrilla-
tion potentials.
FOLIC ACID
Clinical Features. Neurologic disorders are similar to those
encountered with vitamin B12 deficiency (see above).129,379,404,1229
Subacute combined degeneration, a sensorimotor peripheral
neuropathy, or both can be present in patients with folic acid de-
ficiency. Patients with a peripheral neuropathy usually complain
of numbness and tingling in the hands and feet with difficulty in
ambulating. Distal muscle atrophy usually is observed on phys-
ical examination, as is the absence or significant reduction in
deep tendon reflexes. A reduction to vibration, touch, and pain
and temperature sensation is present in the lower limbs. It is
necessary to measure both serum folic acid and vitamin B12
levels to define a pure folic acid deficiency.
Histopathology. No histopathologic analysis has been done in
the limited number of patients reported with folic acid deficiency.
Pathogenesis. Folic acid is found in fruit and vegetables;
liver has particularly high concentrations.1229 Dietary sources of
folic acid contain primarily the conjugated compound, but opti-
mal absorption requires deconjugation through specific en-
zymes at a pH of 5.0. Humans absorb folic acid primarily in the
proximal jejunum, but only after the deconjugated form is
bound to a specific carrier molecule. Folic acid is required in
DNA synthesis. The first signs of deficiency are megaloblastic
erythrocyte alterations. Pure folic acid deficiencies are ex-
tremely rare but may occur in elderly people on poor diets, alco-
holics, young people consuming only snack foods, and patients
with partial gastrectomies, duodenojejunal resections, celiac
disease, or disorders of the jejunal mucosa.129,379,404,1229 A
number of drugs (phenytoin, phenobarbitol, sulfasalazine,
colchicine) also interfere with optimal utilization of folic acid.
Electrophysiologic Findings. Electrodiagnostic evaluations
have been sparse in the few reported patients. The sensory and
motor nerve conduction velocities are usually normal or mildly
reduced, whereas SNAP and CMAP amplitudes may be slightly
diminished. Distal motor and sensory latencies are margin-
ally affected. Needle EMG examinations are normal in most
patients, but reduced recruitment associated with fibrillation
Chapter 23 ACQUIRED NEUROPATHIES — 1013
potentials, positive sharp waves, and occasional fasciculation
potentials may be observed.
Treatment. Administration of folic acid usually results in
good clinical recovery.
VITAMIN E
Clinical Features. Vitamin E or alpha-tocopherol is a lipid-
soluble antioxidant vitamin considered essential for humans. It is
present in minute amounts in the lipid bilayer constituting the cell
membrane. There is a close relationship between the metabolism
of lipids and that of vitamin E. Three major conditions are associ-
ated with vitamin E deficiency: (1) deficient fat absorption (e.g.,
cystic fibrosis, chronic cholestasis, short-bowel syndrome, and
intestinal lymphangiectasia); (2) deficient fat transport (abetal-
ipoproteinemia, hypobetalipoproteinemia, normotriglyeridemic
abetalipoproteinemia, and chylomicron retention disease), and
(3) a genetically based abnormality of vitamin E metabo-
lism.511,549,550,616a Any of the preceding disorders can result in vita-
min E deficiency with neurologic consequences.
Patients usually note progressive difficulty in ambulating, es-
pecially in the dark, secondary to lack of control of the legs and
trouble with “sensing” there position in space. Ability to per-
form fine-motor activities with the hands may be markedly re-
duced . Even with gross movement the upper limbs are
described as “not going where the patient desires them to go.”
Some patients report difficulty in arising from a low chair or
placing objects overhead. Some patients note a loss of sensation
in the feet. Progressive loss of speech control also may be noted.
Physical examination reveals an unsteady gait with an inabil-
ity to walk in tandem as well as a positive Romberg test.
Marked upper and lower limb ataxia is noted; truncal ataxia is
prominent in some patients. A marked reduction or absence of
deep tendon reflexes is a prominent finding, as is loss of posi-
tion and vibration in the lower and upper limbs. Manual muscle
testing is difficult because of the loss of proprioception makes it
difficult for some patients to control their musculature ade-
quately. Preferential proximal muscle weakness in some pa-
tients suggests a superimposed myopathic process. Ocular
examination reveals ophthalmoplegia and retinopathy in pa-
tients with significant disease.
Histopathology. Peripheral nerve biopsy reveals loss of the
large-diameter myelinated fibers, demonstrating that the dorsal
root ganglion cell bodies are a major focus of neural loss.
Relative sparing of the small-fiber population is noted.
Occasional vacuoles in the myelin sheath and break-up of the
Schmidt-Lanterman incisures are found. Segmental demyelina-
tion is not a feature of vitamin E deficiency. Autopsy has
demonstrated profound loss of fibers in the dorsal columns and
reductions in the cells of the gracile and cuneate nuclei.
Pathogenesis. The pathogenic basis for vitamin E deficiency
is not known. Vitamin E has antioxidant properties and may
serve to modulate glutamate excitotoxicity. The dorsal root gan-
glia and the posterior column nuclei have the lowest concentra-
tions in the nervous system and therefore may be particularly
sensitive to diminishing concentrations of vitamin E and its pos-
sible neuroprotective effects.
Electrophysiologic Findings. The most consistent finding
in vitamin E deficiencies is reduced amplitudes or absent
SNAPs.149,511,549,550,616a,1171 The sensory nerve conduction veloci-
ties are normal or only borderline reduced. Somatosensory
evoked potentials demonstrate normal peripheral nerve poten-
tials, and marked slowing and attenuation of central responses
1014 — PART IV CLINICAL APPLICATIONS
document slowing of central conduction with loss of posterior
column fibers.
Motor conduction studies are normal with no alterations in
conduction velocity, distal motor latency, or CMAP amplitude
in either upper or lower limbs. Needle EMG is also typically
normal. A few patients may demonstrate rare fibrillation poten-
tials in distal muscles with some MUAP parameter alterations,
suggesting a neurogenic type of motor unit remodeling. A rare
patient may demonstrate an abundance of short-duration, low-
amplitude, polyphasic MUAPs with early recruitment, implying
the presence of a superimposed myopathic process.
Treatment. Early recognition is imperative because treat-
ment can arrest and sometimes reverse the neurologic symp-
toms. 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 injec-
tions in doses of 100 mg/week.
POSTGASTRECTOMY SYNDROMES
Patients who undergo gastrectomies for various medical
reasons or gastric restriction operations for morbid obesity can
have a sensorimotor peripheral neuropathy or central nervous
system dysfunction similar to that found in pernicious
anemia.1,63,405,1416 The peripheral nerve manifestations may pre-
sent in an acute fashion, resembling AIDP, or, more com-
monly, as a distal sensorimotor peripheral neuropathy. The
disorder is usually a result of vitamin B12 malabsorption;
hence the neurogenic disorder is understandable. The few re-
ported 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 con-
duction velocities. Needle EMG may only reveal reduced re-
cruitment, and a few patients may have electrical myotonia.
Abnormal membrane instability in the form of fibrillation po-
tentials and positive sharp waves is apparently not particularly
common.
HYPOPHOSPHATEMIA
Patients undergoing hyperalimentation can develop hy-
pophosphatemia if insufficient phosphate is included.95,1396,1433
A rare complication of this electrolyte imbalance is the devel-
opment of a subacute and severe sensorimotor peripheral neu-
ropathy that at times presents clinically as AIDP. Patients
complain of paresthesias that begin in the feet and progress to
the upper limbs and remainder of the body. Difficulty in am-
bulating secondary to weakness and poor appreciation of and
inability to control the limbs in space develops over the course
of hours to days. Weakness, ataxia, depressed deep tendon re-
flexes, and reduced perception of all sensory modalities are
noted on physical examination. Weakness also may involve the
respiratory muscles, requiring assisted ventilation. Elec-
trodiagnostic evaluation reveals an absence of SNAPs. Motor
conduction studies reveal slowed lower limb conduction ve-
locities. The lower limb CMAPs are reduced in amplitude and
temporally dispersed. F-waves can be difficult to elicit or com-
pletely absent. Needle EMG examination shows reduced
MUAP recruitment with fibrillation potentials and positive
sharp waves in the distal limb muscles. Correction of the hy-
pophosphatemia results in clinical and electrophysiologic im-
provement.
JAMAICAN NEUROPATHY
Clinical Features. Jamaican neuropathy occurs in two
forms: (1) ataxic neuropathy or tropical ataxic neuropathy and
(2) spastic or tropical spastic paraparesis.71,1008,1113,1114 The spas-
tic form of the disease may be more common and involves pri-
marily the pyramidal tracts at or about the lumbosacral region.
Slow progression of leg weakness, numbness, dysesthesias,
back pain, impotence, and urinary incontinence usually are
noted. Examination reveals spastic paraparesis with hyper-
reflexia in the lower limbs and extensor plantar responses.
Patients ambulate with a scissors gait. In Jamaica, as opposed to
other parts of the world, retrobulbar neuritis and deafness are
rather common. The ataxic form of the disease is characterized
by the onset of burning feet, with profound loss of posterior
column modalities and fewer alterations in pain and tempera-
ture sensation. Lower limb absence of deep tendon reflexes is
the rule, but strength is well preserved.
Histopathology. Sural nerve biopsies reveal axonal loss of
both myelinated and unmyelinated fibers. The sensory ganglia
also are involved, with both peripheral and central degeneration
of sensory nerve fibers.
Pathogenesis. The exact cause is unknown but may be asso-
ciated with some form of toxin or malnutrition. Some cases of
tropical spastic paraparesis probably are caused by human T-
cell lymphotropic virus type I (HTLV-1; see above).100
Electrophysiologic Findings. There is only one electrodiag-
nostic medicine report of a patient with the ataxic form of
Jamaican neuropathy.71 The upper and lower limb SNAP re-
sponses were reduced in amplitude with mild prolongation of
the distal sensory latencies. Lower limb CMAP amplitudes
were reduced, whereas those in the upper limb were preserved.
The distal motor latencies and conduction velocities demon-
strated no significant abnormalities. Upper and lower limb F-
wave minimal latencies were normal. Needle EMG was
consistent with chronic axonal loss in that reduced numbers of
MUAPs had prolonged durations and increased amplitudes.
ALCOHOLIC NEUROPATHY
Clinical Features. People who have consumed alcohol for
many years, especially to the exclusion of adequate nutritional
intake, can develop a generalized sensorimotor primarily axonal
peripheral neuropathy.6,84,104,178,,180,853,1204,1208,1413 Some patients pre-
sent with acute or subacute onset of paresthesias, numbness, are-
flexia, and weakness, which can resemble GBS.1035,1276,1426 Cranial
nerves are spared, but autonomic dysfunction is common.
Nutritional deficiency with prominent weight loss 2–3 months
before onset of the acute neuropathy is common. Unlike GBS,
CSF protein in alcohol-related acute axonal polyneuropathy is
usually normal or only slightly elevated. Much more common in
alcoholics is insidious onset of a slowly progressive sensorimotor
polyneuropathy. Patients present mainly with numbness, pares-
thesia, and burning pain. Weakness, if evident, is mild.
In acute and chronic forms of alcohol-related polyneuropathy,
examination demonstrates reduction to all sensory modalities in a
glove-and-stocking distribution; findings are worse in the lower
than in the upper limbs. Deep tendon reflexes at the ankles are
usually absent, whereas those at the knee and upper limbs are di-
minished. Distal lower limb weakness is common, but distal upper
limb weakness and occasionally proximal lower limb weakness
can be demonstrated. An occasional patient presents with symp-
toms and signs suggestive of myopathy as opposed to neuropathy.

Histopathology. Reductions in the total number of large-
and small-caliber myelinated fibers maintain the bimodal fiber
distribution.84,1378,1426 Wallerian degeneration is the primary ab-
normality, with small degrees of secondary segmental demyeli-
nation. In the acute form of peripheral neuropathy, significant
degrees of axonal degeneration can be observed, whereas the
more slowly progressive form results in only a few degenerated
axons despite documentation of an overall loss of fibers.
Pathogenesis. The exact cause of peripheral nerve insult in
alcoholism is unknown, but it may be related in part to nutri-
tional deficiency (e.g., B vitamin group, folate) or a direct toxic
effect of alcohol on peripheral nerves. A dose-dependent toxic
effect of alcohol on sensorimotor and autonomic nerves was
noted in a case-controlled study.918
Electrophysiologic Findings. Electrodiagnostic evaluation
reveals a sensory or sensorimotor polyneuropathy.6,84,104,178,
180,272,853,1204,1378,1413,1426 Evaluation of the sensory fibers demon-
strates that the lower limb sensory nerves are altered early in the
disease even before the development of overt symptoms of pe-
ripheral neuropathy. For example, the sural nerve conduction ve-
locity is mildly to moderately reduced, as is the SNAP
amplitude. Over time, the conduction velocity worsens mildly,
but the SNAP amplitude eventually may become unobtainable.
As the condition progresses, the H-reflex latencies can become
prolonged until they also disappear. With marked reduction in
the lower limb sensory responses, the upper limb sensory re-
sponses 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. Brainstem and visual evoked potentials may
be abnormal in alcoholic patients, suggesting that the central
portions of the cranial nerves also are affected.198,199
Motor conduction studies in the lower and upper limbs follow
a pattern similar to that of the sensory nerves. The peroneal and
tibial nerve conductions demonstrate a mild to moderate reduc-
tion in velocities as well as a mild prolongation of the distal
motor latencies. Of importance is the progressive reduction in
CMAP amplitudes. The F-waves are only mildly prolonged in
latency but become harder to obtain as the corresponding CMAP
amplitudes decline. Motor conduction studies in the upper limb
usually are less affected early in the disease, but in chronic alco-
holics, upper limb nerves may be markedly abnormal. The rela-
tive refractory period can be used to detect early abnormalities in
patients without clinical evidence of peripheral neuropathy.16
Needle EMG of the distal lower limb muscles characteristi-
cally reveals positive sharp waves and fibrillation potentials. A
reduced number of MUAPs is detected with increased durations
and numbers of polyphasic MUAPs. Similar findings are noted
in time when the upper limb muscles are investigated. Single-
fiber EMG shows an increase in fiber density accompanied by
increased jitter and blocking.1292 All of these findings are con-
sistent with a primarily axonal neuropathy accompanied by
motor unit remodeling.
Treatment. Abstaining from alcohol and consuming an op-
timal diet can improve the peripheral neuropathy.582,1426
CHRONIC IDIOPATHIC SENSORY OR
SENSORIMOTOR POLYNEUROPATHY
Clinical Features. Chronic acquired sensory or sensory
motor polyneuropathies occur in approximately 3% of middle-
aged to older adults. Despite extensive evaluation, the cause of
10–35% of all polyneuropathies cannot be determined. Such
Chapter 23 ACQUIRED NEUROPATHIES — 1015
cases are categorized as chronic idiopathic polyneuropa-
thy.387,474,594,851,873,968,1045,1070,1428,1429 The diagnosis of chronic idio-
pathic polyneuropathy is one of exclusion. Laboratory tests for
fasting blood glucose, ANA, ESR, SPEP, vitamin B12, thyroid,
liver, and renal functions should be normal.
Most patients present with sensory symptoms between the
ages of 45 and 70 years. Patients may complain of numbness,
tingling, or pain (e.g., sharp stabbing paresthesias, burning, or
deep aching sensation) in the feet. In fact, discomfort or pain is
quite common (65–80% of patients).445,486,968,970 In a large series
of 93 patients with idiopathic sensory polyneuropathy, the pre-
senting symptoms were numbness and tingling with pain in
63%, numbness or tingling without pain in 24%, and pain alone
in 10%.1429 These sensory symptoms begin in the toes, slowly
progress up the legs, and eventually reach the distal upper
limbs. In about 50% of patients, sensory symptoms are confined
to the lower limbs.968,970,1429 The average time to involvement of
the upper limbs is about 5 years.968
Physical examination reveals a stocking-glove pattern of sen-
sory loss. Vibratory perception is the sensory modality most
commonly impaired (80–100% of patients).968,970,1045,1429 Pro-
prioception is impaired in only 20–30% of patients, and fewer
than 25% have a positive Romberg sign. Pinprick is reduced in
75–85% of patients, whereas light touch is impaired in 54–92%.
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.969,970,1429 Less than 20% of patients
have hand intrinsic weakness. However, the mild weakness is
not clinically significant and is not the primary symptom or sign
of the neuropathy in which sensory abnormalities predominate.
Deep tendon reflexes are usually absent at the ankle and dimin-
ished at the knees and upper limbs.968,970,1429 Approximately
15–25% of patients have generalized areflexia.
Classified in the category of idiopathic sensory or sensorimo-
tor polyneuropathies are patients who appear to have pure
small-fiber sensory neuropathies.474,594,1045,1429 Such patients
have normal sensory nerve conduction studies, and nerve biop-
sies demonstrate a relatively normal density of large myelinated
nerve fibers. Approximately 80% of patients complain of burn-
ing pain in the feet. Sharp, lancinating pain, numbness, or pares-
thesias occur in 40–60% of patients. The hands often become
affected over time. Symptoms restricted to the upper limbs, cra-
nial nerve involvement, and superimposed autonomic neuropa-
thy are exceptional.474,594 Reduced pinprick or temperature
sensation is noted in almost all patients, and vibratory percep-
tion is reduced in over 50% of patients. Fewer than 14% of pa-
tients have a reduction in proprioception. Motor examination is
normal in patients with small-fiber sensory neuropathies. Deep
tendon reflexes are usually normal; fewer than 10% of patients
have reduced reflexes at the ankles. Symptoms and signs of au-
tonomic impairment (e.g., dry eyes or mouth, facial flushing,
reduced or increased sweating, impotence, incontinence, consti-
pation, diarrhea) are seen in the majority of patients with painful
sensory neuropathies.972a
Laboratory Features. Although patients have normal fast-
ing blood glucose and hemaglobin A1C levels, oral glucose tol-
erance tests are abnormal in approximately one-third of
patients.1224a,1271a About 5–10% of patients with chronic idio-
pathic sensory or sensorimotor polyneuropathy have a mono-
clonal protein.723,970 The overall incidence of monoclonal
proteins in older populations is approximately 5%.746 Therefore,
the relationship between monoclonal proteins and pathogenesis
of the neuropathies is unclear. A strong pathogenic relationship
1016 — PART IV CLINICAL APPLICATIONS
has been demonstrated only in patients with demyelinating sen-
sorimotor polyneuropathies and IgM monoclonal proteins,
most of whom have anti-MAG antibodies. Most patients with
chronic idiopathic sensory or sensorimotor polyneuropathy
have axonal neuropathies histologically and electrophysiologi-
cally (see below).
PCR amplification of the variable T-cell receptor γ-chain gene
reveals the frequent occurrence of dominant T-cell clones of un-
known significance.455 Some authors have reported that as many
as 30% of patients with chronic idiopathic sensory neuropathy
demonstrate antisulfatide antibodies.948,1051 However, other large
studies, even by the original group of investigators, have failed to
show increased titers of antisulfatide antibodies.968,811,1045,1427,1429
Panels screening for various antiganglioside and other anti-
nerve antibodies (e.g., anti-GM1, anti-Hu antibodies) have no
role in screening patients with chronic idiopathic sensory neu-
ropathy.703,1045,1427–1429 CSF examination is usually normal and
thus unwarranted.
Histopathology. Sural nerve biopsies confirm the axonal
nature of chronic idiopathic sensory polyneuropathies. Axonal
degeneration and regeneration with secondary demyelination
are often evident on biopsy.873,968,970,1045,1429 Loss of large- and
small-diameter myelinated fibers and small unmyelinated fibers
can be seen on quantitative morphometry. Demyelination is not
a prominent feature. Scattered T-cells may be seen on nerve
biopsy although neither significant inflammation of the nerves
nor vasculitis is present. The findings on nerve biopsy are rather
nonspecific and not helpful in finding the cause of the neuropa-
thy. Thus, we do not routinely perform nerve biopsies on pa-
tients with chronic idiopathic sensory polyneuropathies. We
consider biopsy in patients with autonomic signs or monoclonal
gammopathies to assess for amyloidosis and in patients with un-
derlying diseases at risk for vasculitis (e.g., connective tissue
disorders, hepatitis B or C).
As expected, patients with small-fiber neuropathies display a
selective loss of small myelinated nerves and unmyelinated nerve
fibers.474,574,1045 However, even with quantitative analysis, nerve
biopsies are normal. The measurement of intraepidermal nerve
fiber density on skin biopsies appears to be more sensitive in iden-
tifying patients with small-fiber neuropathies than sural nerve
biopsies, nerve conduction studies, or quantitative sensory testing
(QST).574,593,596,859,1045 After a punch biopsy of the skin in the distal
lower limb (foot, calf, or thigh), immunologic staining (e.g., pro-
tein gene product 9.5 or PGP 9.5) can be used to measure density
of small intraepidermal fibers. Antibodies directed against vasoac-
tive intestinal polypeptide, substance P, and calcitonin gene-re-
lated proteins can be used to measure the density of sudomotor
axons innervating sweat glands, piloerector nerves to hair folli-
cles, and nerves to small arterioles. Intraepidermal nerve fibers
arise entirely from the dorsal root ganglia and are believed to rep-
resent the terminals of C and Aδ nociceptors. The density of these
nerve fibers is reduced in patients with small-fiber neuropathies, in
which nerve conduction studies, QST, and routine nerve biopsies
are often normal. In more than one-third of patients with painful
sensory neuropathies, intraepidermal nerve fiber density on skin
biopsies represent the only objective abnormality even after exten-
sive evaluation.1045
Pathogenesis. The pathogenesis probably is multifactorial.
With advances in molecular genetics, some cases probably will
be determined to be genetic; others may have a degenerative or
immunologic basis. Recent studies suggest that glucose intoler-
ance alone without frank diabetes may be the cause of neuropa-
thy in as many as one-third of patients.407a,1224a,1271a.
Electrophysiologic Findings. Sensory nerve conduction stud-
ies demonstrate either absent or reduced amplitudes, particularly
of the sural SNAPs.387,594,851,968,970,1045,1070,1428,1429 Sensory nerve con-
duction velocities, when obtainable, are normal or only mildly
slow, whereas distal sensory latencies are normal or slightly pro-
longed. QST demonstrates abnormal thermal and vibratory per-
ception in as many as 85% of patients.1045,1429 In addition,
autonomic testing (e.g., QSART) is abnormal in some patients.
Despite the fact that sensory symptoms are much more promi-
nent and weakness, if present, is mild, motor nerve conduction
studies are often abnormal. In the large series of patients with id-
iopathic sensory polyneuropathy reported by Wolfe and col-
leagues, 60% had motor conduction abnormalities.1429 The most
common motor findings are reduced peroneal and posterior tibial
CMAP amplitudes. Distal latencies and conduction velocities of
the peroneal and posterior tibial CMAPs are normal or only
slightly impaired. Abnormalities of median and ulnar CMAPs
are much less common. Occasionally both tibial and peroneal
nerve responses to the foot intrinsic muscles are absent.
The needle EMG examination is consistent with an axonal
neuropathy. Positive sharp waves, fibrillation potentials, and re-
duced recruitment usually are detected in the foot intrinsic and
distal lower limb muscles. In profound disease, similar but less
severe findings are noted in the upper limbs. MUAP changes of
long-duration and increased-amplitude potentials also can be
detected. These findings are consistent with a long-standing pe-
ripheral neuropathy, causing axonal loss with compensatory
motor unit remodeling through collateral sprouting.
In patients with pure small fiber neuropathies, motor and sensory
nerve conduction studies as well as needle EMG are, by definition,
normal.474,574,594,1045 However, QST may reveal abnormal thermal
and vibratory perception.594,972a,1045,1429 Furthermore, autonomic test-
ing demonstrates abnormalities in some patients.972a,1045,1260
Treatment. No treatment slows the progression or reverses
the “numbness” or lack of sensation. The disturbing neuropathic
pain often can be eased with various medications.445,1428,1429 Our
approach to treating the painful paresthesias and burning sensa-
tion is similar to the treatment of neuropathic pain, regardless of
its cause (e.g., painful sensory neuropathies related to diabetes
mellitus, HIV infection, herpes zoster infection) (Table 23-9).
Antiepileptic medications (e.g., gabapentin, carbamazepine,
phenytoin) and antidepressant medications (e.g., amitriptyline,
nortriptyline, desipramine) are most commonly used. The non-
narcotic analgesic, tramadol, also may be tried.
ILLUSTRATIVE CASES
CASE 1:ACUTE ONSET OF LIMB WEAKNESS
Reason for Referral. Acute onset of weakness and sensory
complaints.
History. A 40-year-old male physician is seen in the hospi-
tal with a 4-week complaint of diminished sensation and mild
weakness. Approximately 3 weeks before this examination he
noted the onset of numbness and tingling in the left and right
toes, followed in 2 days by prominent numbness and tingling in
the hands. These sensations slowly progressed proximally along
both upper and lower limbs over the next 2 weeks to involve all
4 limbs and the trunk. During this same period, progression of
reduction in muscle strength was noted throughout, but the
weakness in the proximal limb muscles was slightly greater
than in the distal ones. He also had difficulty in climbing stairs,
 Chapter 23 ACQUIRED NEUROPATHIES — 1017

not because of weakness, but because of a decreased ability to measured baseline to peak. Sensory latencies are measured to
sense where his limbs were. He also noted that he could no peak and motor latencies to initial negative onset.
longer walk with a narrow base gait or perform a heel-to-toe gait. Needle Electromyography. A needle EMG investigation is
Running was rather difficult, again not because of overt weak- performed on the right upper and lower limb, using a disposable
ness, but secondary to coordination of the legs. Approximately 5 monopolar needle.
days before hospital admission, he noted loss of the nasolabial Muscle Rest Activity Recruitment
fold bilaterally, worse on the right than on the left. Over the Supraspinatus Silent Normal
course of the next several days it became increasingly difficult to Deltoid Silent Normal
close his eyes, purse the lips, or retain fluids in the mouth. The Biceps brachii Silent Normal
patient denies any history of illness over the past 3 months, but Triceps Silent Normal
approximately 6 weeks before the onset of symptoms, he had re- Pronator teres Silent Normal
ceived the second dose of a hepatitis immunization. Extensor carpi radialis Silent Normal
Physical Examination. During physical examination 3 Extensor digitorum Silent Normal
weeks after the onset of abnormal sensations and weakness, the communis
patient is alert and oriented. Deep tendon reflexes are absent Abductor pollicis brevis Silent Normal
throughout, and the patient states that previously they were easy First dorsal interosseous Silent Normal
to obtain and symmetric. A reduction in position and vibration Abductor digiti quinti Silent Normal
sensation is noted in the toes only. Pinprick and temperature are Paraspinal C4–T1 Silent Normal
reduced in the distal regions of the upper and lower limbs bilat- Tensor fascia lata Silent Normal
erally. Manual muscle testing demonstrates a reduction in neck Gluteus maximus Silent Normal
flexor and extensor strength. The proximal upper and lower Vastus medialis Silent Normal
limb muscles are approximately 4/5 and the distal muscles are Tibialis anterior Silent Normal
4+/5. Shoulder shrugging is approximately 4/5 bilaterally. Of Gastrocnemius Silent Normal
note, the patient states that the reduction in strength is signifi- Abductor hallucis Silent Normal
cant since he participated noncompetitively in weight-lifting ac- Comment. The morphology of motor unit action potentials
tivities. An obvious bilateral facial palsy is noted with an appeared normal.
inability to bury the eyelids or hold air in the mouth on com-
pressing the cheeks. The patient cannot tandem walk and ambu- Summary of Findings
lates with a mildly wide-based gait. A reduction in sensation in 1. The nerve conduction velocities in the lower limb are
the cutaneous distribution of the trigeminal nerve is observed as mildly slowed.
well as a diminished degree of sensation in the oral cavity. 2. All F-waves are abnormally prolonged and reduced in
Extraocular muscle movements are intact. His blood pressure, number compared with the number of stimuli delivered.
normally 108/70 mmHg, is 160/90 mmHg and is verified at the 3. Sensory and motor evoked response amplitudes are at the
elevated level by the patient in the resting state. His resting heart lower spectrum of normal for this patient.
rate is approximately 90 beats/minute compared with a previous 4. Distal motor latencies are prolonged for lower limb nerves
level of 60 beats/minute. Cerebrospinal fluid analysis revealed and the median nerve.
an elevated protein level and no cells. By the time of the exami- 5. Needle EMG examination reveals no abnormalities in any
nation the patient has received two doses of intravenous im- of the muscles tested.
munoglobulin (IVIG).
Nerve Conduction Studies. Nerve conduction studies are Electrodiagnostic Medicine Impression
performed in the right upper and lower limbs. The mid-palm 1. The patient demonstrates electrophysiologic evidence of
temperature is 32.5°C on the right and 31.5°C posterior to the a mild degree, suggesting a widespread demyelinating neural
right lateral malleolus. process. The markedly abnormal F-waves suggest that a sig-
DSL S Amp DML M Amp NCV nificant degree of the pathology is located proximally and not
Nerve (ms) (µV) (ms) (mV) (m/s) F-wave amenable to routine nerve conduction testing. The combina-
R median 4.1 15.7 4.6 7.8 55.0 38.2 tion of nerve conduction abnormalities and cerebrospinal/clin-
R median 1.9 25.5 ical findings suggests that the patient may have a slightly
(7.0 cm) atypical presentation of acute inflammatory demyelinating
R ulnar 3.9 10.1 3.8 5.9 57.0 34.2 polyradiculoneuropathy.
R peroneal 4.1 8.8 10.4 4.9 39.0 59.2
R tibial 11.5 5.1 37.0 58.7 Comment
R sural 4.4 10.1 The patient has comparatively less pronounced motor weak-
R facial 5.4 3.1 ness than objective sensory loss. In general, the history and
Note. No evidence suggests conduction block in any of the physical findings suggest a mild to moderate degree of periph-
motor nerves studies in comparing CMAP duration and proxi- eral nervous system dysfunction. The distinct lack of mentation
mal vs. distal amplitudes. The F-wave latencies are reported as difficulties excludes an overt central nervous system disorder. A
the shortest in a series of 15. Supramaximal stimulation alone combination of elevated CSF protein with no cells and physical
produced approximately one-half as many responses as stimuli findings suggesting a peripheral nerve disorder progressing over
delivered. several weeks is certainly suspicious of AIDP. Reduced num-
DSL, distal sensory latency; S Amp, sensory amplitude; DML, bers and prolongation of F-waves with essentially normal limb
distal motor latency; M Amp, motor amplitude; NCV, nerve conduction velocities are somewhat confirmatory of a preferen-
conduction velocity; ms, milliseconds; µV, microvolts; mV, mil- tially proximal peripheral nerve disorder. Mildly abnormal
livolts; m/s, meter/second. Motor and sensory amplitudes are distal motor latencies, normal nerve conduction velocities in the
1018 — PART IV CLINICAL APPLICATIONS

upper limbs, and borderline abnormalities in the lower limbs her. Cranial nerves are intact. Deep tendon reflexes are absent at the
document a mild slowing of nerve conduction in both upper and ankle and knee with diminished reflexes for the biceps and triceps.
lower limbs. Needle EMG abnormalities are absent and support Plantar responses are neutral. The jaw jerk is present but diminished.
the lack of significant axonal loss or conduction block. The Manual muscle testing demonstrates 3+/5 for the toe extensors/flex-
electrophysiologic findings are rather nonspecific but certainly ors and ankle dorsiflexors/plantarflexors. Knee flexors and exten-
compatible with the clinical impression of AIDP. sors are 4–/5, as are the hip flexors and extensors. The upper limb
Although conduction block was not demonstrated by this pa- demonstrates a 3+/5 grade of strength for the hand intrinsic muscles
tient, it is important to document its presence by careful recording with a 4–/5 strength for the remainder of the upper limb muscula-
the CMAP amplitude subsequent to multiple stimulation sites ture. Sensation is decreased to all modalities in a typical glove-and-
along the course of different nerves. A dramatic reduction in am- stocking distribution. Mild hepatomegaly is noted on abdominal
plitude not accompanied by an abnormal increase in CMAP dura- examination, and the skin demonstrate numerous spider angiomata.
tion certainly suggests neural blockade. Localizing the CMAP to Nerve Conduction Studies. Nerve conduction studies are
a short segment is further substantiation of the focal nature of the performed in the right upper and lower limbs. The mid-palm
lesion and helps to confirm the impression of conduction block. temperature is 33.5°C on the right and 32.5°C posterior to the
In the upper limb, the axilla-to-elbow and forearm-to-wrist seg- right lateral malleolus.
ments can be readily assessed for conduction block. In examining DSL S Amp DML M Amp NCV
the lower limb, it is rather difficult, although not impossible, to Nerve (ms) (µV) (ms) (mV) (m/s) F-wave
examine the portions of the peroneal and tibial nerves that tra- R median 4.4 4.0 5.2 3.8 44.0 35.2
verse the thigh by stimulating the sciatic nerve just inferior to the R median 2.9 5.5
gluteal fold. Multiple sensory nerves should be examined because (7.0 cm)
the patient may have preferential involvement of upper limb sen- R ulnar 4.2 3.1 4.6 2.9 47.0 34.2
sory nerves with relative sparing of nerves in the lower limb, par- R peroneal Absent Absent
ticularly during the early stage of the disease. Needle EMG is of R tibial 6.9 0.5 36.0
minimal help in formulating a diagnosis in the above patient; R sural Absent
however, the absence of membrane instability is certainly ex- L sural Absent
pected, given the lack of muscle wasting, minimal strength reduc- L peroneal Absent
tion, and good preservation of CMAP amplitudes to distal L tibial 6.6 0.6 35.0
stimulation. In some patients with profound disease, it is possible DSL, distal sensory latency; S Amp, sensory amplitude;
to detect positive sharp waves and fibrillation potentials, which DML, distal motor latency; M Amp, motor amplitude; NCV,
define the presence of axonal loss. nerve conduction velocity; ms, milliseconds; µV, microvolts;
The preservation of CMAP amplitudes, lack of significant con- mV, millivolts; m/s, meter/second. Motor and sensory ampli-
duction block distal to the forearm, and absent abnormal sponta- tudes are measured baseline to peak. Sensory latencies are mea-
neous activity suggest a good clinical prognosis with eventual sured to peak and motor latencies to initial negative onset.
motor return. Indeed, the patient recovered relatively close to his Needle Electromyography. A needle EMG investigation is
previous level of functioning over the ensuing 8 months. performed on the right upper and lower limb, using a disposable
monopolar needle.
CASE 2: PROGRESSIVE LOWER LIMB Muscle Rest Activity Recruitment
NUMBNESS AND WEAKNESS Supraspinatus Silent Normal
Deltoid Silent Normal
Reason for Referral. Progressive lower limb numbness and Biceps brachii Silent Normal
weakness. Triceps Silent Normal
History. A 45-year-old, cachectic-appearing woman is re- Pronator teres 1+ Fibs/PSW Normal
ferred for an electrodiagnostic medicine evaluation of progres- Extensor carpi radialis Silent Normal
sive lower limb numbness and weakness. Approximately 8 Extensor digitorum 1+ Fibs/PSW Normal
months ago the patient noted the development of numbness and communis
tingling in the plantar surfaces of both feet and a mild degree of Abductor pollicis brevis 2 Fibs/PSW Reduced
“a burning sensation” in the same distribution. Over the past 8 First dorsal interosseous 2+Fibs/PSW Reduced
months the burning has intensified, making ambulation increas- Abductor digiti minimi 2+ Fibs/PSW Reduced
ingly difficult. Over the same period the patient noted an exten- Paraspinal C4–T1 Silent Normal
sion of the numbness and tingling to the lower limb just distal to Abductor pollicis brevis* 2+Fibs/PSW Reduced
the knee region. About 1 month ago similar symptoms began in First dorsal interosseous* 2+ Fibs/PSW Reduced
the fingertips and now involves both hands. The patient also Tensor fascia lata Silent Normal
states that walking is becoming difficult because of more fre- Gluteus maximus Silent Normal
quent tripping on pavement. She admits to drinking about a fifth Vastus medialis 1+ Fibs/PSW Normal
of whatever hard liquor she can obtain per day for the past sev- Tibialis anterior 2+ Fibs/PSW Reduced
eral years and is rather vague about the exact time frame. There Gastrocnemius 2+ Fibs/PSW Reduced
is some suggestion of at least a 25-pound weight loss over the Abductor hallucis 3+ Fibs/PSW Markedly
past year. The patient admits to smoking approximately 2–3 reduced
packs of cigarettes per day for the past 15–20 years. Paraspinals L1–S1 Silent Normal
Physical Examination. The patient appears older than her Tibialis anterior* 2+ Fibs/PSW Reduced
stated age and is quite thin, presently weighing 100 pounds. Previ- Gastrocnemius* 2+ Fibs/PSW Reduced
ous medical records indicate a weight of 140 pounds 18 months ago. Abductor hallucis* 3+ Fibs/PSW Markedly
She is alert and cooperative with a definite odor of alcohol about * Also performed on the left side.

Summary of Findings
1. The nerve conduction studies in the lower limbs are
absent, whereas those in the upper limb reveal reduced motor
and sensory amplitudes with mild prolongation of distal laten-
cies and reductions in conduction velocity.
2. All F-waves that can be obtained are mildly prolonged.
3. Needle EMG examination demonstrates a loss of MUAPs
in the distal upper and lower limb muscles with a concomitant
documentation of positive sharp waves and fibrillation poten-
tials in the same muscular distribution.
Electrodiagnostic Medicine Impression
The patient demonstrates electrophysiologic evidence consis-
tent with a generalized sensorimotor peripheral neuropathy re-
sulting in primarily loss of axons, as demonstrated by reduced
or absent sensory and motor responses with only mild reduc-
tions in conduction velocity. The needle EMG examination re-
veals a reduced number of motor units with denervation in the
distal upper and lower limb musculature. These findings are
compatible with the history of reduced nutrition and increased
alcohol intake. A thorough medical evaluation should be pur-
sued to investigate the possibility of a coexistent occult process.
Comment
The patient provides a history compatible with significant al-
cohol intake for a prolonged period, coupled with reduced nutri-
tional intake. A prolonged history of smoking also is noted. A
complaint of progressive numbness, tingling, and burning be-
ginning in the feet and progressing not only proximally in the
lower limbs but also in the hands, accompanied by weakness, is
certainly suspicious for a generalized sensorimotor peripheral
neuropathy. The physical examination is compatible with the
history: a glove-and-stocking distribution of sensory loss is ob-
jectively found as well as absent or reduced deep tendon re-
flexes and distal muscle weakness. The clinical impression of a
generalized sensorimotor peripheral neuropathy is appropriate.
An electrodiagnostic medicine evaluation reveals a number of
confirmatory electrophysiologic findings. Both motor and sensory
responses are absent in the lower limbs, and distal motor latency and
conduction velocity are relatively preserved in a single nerve, given
the CMAP amplitude. These findings suggest profound axonal loss.
In the upper limbs, the distal motor latencies are mildly prolonged
and the conduction velocities reduced, but the major abnormality is
a reduction in all CMAP amplitudes. The reduced CMAPs are out
of proportion to the neural conduction parameters, again supporting
the impression of preferential axonal loss as the major disease
process. Reduced MUAPs, accompanied by positive sharp waves
and fibrillation potentials in the distal regions of the limbs, with the
lower limbs more affected than the upper limbs, are compatible with
the impression of a distal axonal generalized polyneuropathy affect-
ing both motor and sensory fibers. Despite the obvious clinical his-
tory and physical examination as well as the electrodiagnostic
findings, all of which support a diagnosis of an alcohol-induced gen-
eralized sensorimotor axonal polyneuropathy, a number of meta-
bolic (nutritional, diabetes mellitus) and occult disorders (carcinoma
of the lung) should be pursued to some degree, given the patient’s
poor nutrition, weight loss, and smoking history.
CONCLUSION
Because of the vast number of acquired peripheral neu-
ropathies, evaluation and accurate diagnosis can be challenging
Chapter 23 ACQUIRED NEUROPATHIES — 1019
for the clinician. The clinical history and examination are the
most important aspects of evaluating patients with neuropathy.
However, electrodiagnostic techniques are extremely valuable
in helping to define the underlying pathophysiologic process
(e.g., axonal or demyelinating), its distribution (e.g., multifocal
or generalized), and the functional subtypes of the nerves in-
volved (e.g., motor, autonomic, large-fiber sensory, small-fiber
sensory). Clinical and electrophysiolgic features of a demyeli-
nating polyneuropathy or multifocal/multiple mononeu-
ropathies are extremely important findings because these types
of acquired peripheral neuropathies are often treatable. Based
on clinical and electrodiagnostic studies, the appropriate labora-
tory work-up should be ordered, eliminating the costly and inef-
ficient “shotgun” approach to evaluating patients with
neuropathy. Again, the authors emphasize that electrodiagnostic
medicine specialists must be knowledgeable about the underly-
ing pathophysiology and treatment of the different types of ac-
quired peripheral neuropathy.299,482
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