C H A P T E R
233
Peripheral Neuropathies
William Campbell n Aaron G. Filler
Peripheral neuropathies are conditions that affect peripheral
nerve axons, their myelin sheaths, or both and produce a variety
of signs and symptoms. As with arthritis or anemia, a diagnosis
of peripheral neuropathy is relatively meaningless because
dozens of conditions could be responsible. Greater precision is
required to have any clinical usefulness. Clinical evaluation
attempts to place a peripheral neuropathy into one of several
categories that have pathophysiologic, etiologic, and therapeutic
significance. The process may be generalized, focal, or multifo-
cal; axonal or demyelinating; motor, sensory, or mixed; with or
without autonomic dysfunction; acute or chronic; progressive,
stable, or resolving; and hereditary or acquired. Generalized
peripheral neuropathy is often referred to as polyneuropathy and
focal neuropathy as mononeuropathy. A condition that affects
more than one nerve but not all the nerves is referred to as mul-
tiple mononeuropathy or mononeuropathy multiplex. This
chapter discusses generalized polyneuropathies; focal neuropa-
thies are discussed elsewhere. Table 233-1 lists some of the major
and most common causes of generalized peripheral nerve disease
but is far from exhaustive. A recent major textbook lists more
than 100 causes of peripheral neuropathy.1
The final goal in evaluation for neuropathy is to establish a
precise etiologic diagnosis to guide treatment, if any is available.
Arriving at a final diagnosis can be either simple, as in diabetes
or alcoholism, or exasperatingly difficult. Except in specialized
centers, the exact cause is identified only about half the time, and
many of these patients are diabetics or alcoholics. Thus, a great
deal of time and energy is expended to help only a few patients.
However, effective therapy is frequently available and ranges
from aggressive immunosuppression for inflammatory, demye-
linating neuropathies, to discontinuing use of a medication, to
control of an underlying systemic disease. Even patients for
whom no specific therapy is available can often benefit from
symptomatic treatment.
ANATOMY AND PHYSIOLOGY from acute, evolving over a period of days to weeks, to chronic,
OF PERIPHERAL NERVES
The anatomic site of involvement may range from the nerve cell
body (neuronopathy, e.g., acute ataxic sensory neuronopathy), to
the nerve roots (acute inflammatory demyelinating polyradiculo-
neuropathy [AIDP]), to the nerve proper, to the axon terminals
(twig neuropathy, e.g., hyperparathyroidism). Nerve fibers react
to injury through two primary mechanisms, axonal degeneration
and demyelination. In axonal degeneration the cytoplasm disin-
tegrates. Eventually, the axolemma becomes discontinuous, and
the myelin sheath, but not the Schwann cell, secondarily disinte-
grates. Fragments of axolemma and myelin form linear arrays of
myelin ovoids. Macrophages phagocytose and eventually remove
the debris. Conditions affecting the axon typically begin in the
most terminal axon twigs, and the pathologic changes move
proximally with progression of the disease, a phenomenon known
as dying back. Clinically, signs and symptoms begin in the longest
axons, those innervating the feet and toes, and progressively
involve more proximal areas, a feature known as length depen-
dency. Wallerian degeneration specifically refers to axonal
degeneration distal to a traumatic nerve injury.
2398
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
In demyelinating neuropathies, the primary insult is to the
myelin sheath or the Schwann cell, and varying degrees of inter-
ference with myelin maintenance are produced. In the earliest
stages, the demyelination is paranodal, but with progression, the
rest of the internodal segment becomes involved. Segmental
demyelination refers to the involvement of several internodes
over a segment of nerve. In some conditions the Schwann cells
are involved diffusely and the demyelination is uniform along the
length of the nerve (e.g., Charcot-Marie-Tooth [CMT] disease).
In most acquired myelinopathies, the involvement is multifocal
(e.g., Guillain-Barr syndrome [GBS]). In compression neuropa-
thies, the demyelination is focal and involves only a discrete
segment (e.g., carpal tunnel syndrome).
With severe demyelination, there may be secondary axon loss.
In compression neuropathies, the myelin is more susceptible to
injury and axon loss reflects chronicity and severity. In dysim-
mune inflammatory neuropathies, the axon may be an accidental
victim of the attack, the bystander effect. The secondary axon
loss in myelinopathies and the secondary demyelination in axo-
nopathies add another measure of complexity to the evaluation
of neuropathies. Clinically and electrophysiologically, these sec-
ondary changes may create a mixed picture of axonopathy and
myelinopathy. For example, uremia characteristically produces
an axonopathy with secondary demyelination, and severe GBS, a
primarily demyelinating and inflammatory neuropathy, is often
associated with significant secondary axon loss as a result of the
bystander effect.
With the use of clinical, electrodiagnostic, pathologic, and
laboratory data, neuropathies can be classified according to their
anatomic site of involvement, time course, distribution, pattern
of deficit, type of functional fiber involved, and whether the
process is primarily axonal, primarily demyelinating, or mixed. It
is helpful to classify a neuropathy in as many ways as possible in
the hope of uncovering a characteristic signature. There are two
primary patterns of clinical involvement: generalized, diffuse, or
symmetrical versus focal or multifocal. The time course may vary
evolving over a period of months to years, to very chronic or
lifelong, to relapsing and remitting. Neuropathies may be pre-
dominantly motor (e.g., GBS) or predominantly sensory (e.g.,
amyloidosis). Most neuropathies produce symmetrical distal
involvement, but some may cause primarily proximal weakness
(e.g., porphyria), proximal sensory loss (e.g., Tangier disease), or
acral sensory loss over the coolest parts of the body (e.g., leprosy).
Sensory neuropathies may preferentially affect large fibers (e.g.,
vitamin B12 deficiency) or small fibers (e.g., hereditary sensory
neuropathy). Particular neuropathies may or may not have associ-
ated autonomic dysfunction. As defined by clinical features, by
electrodiagnostic profile as determined by nerve conduction
studies and needle electromyography (EMG), and occasionally
by pathologic examination, a neuropathy may be primarily axonal
(e.g., CMT type 2 [CMT2]), primarily demyelinating (e.g.,
chronic inflammatory demyelinating polyradiculoneuropathy
[CIDP]), mixed but mainly axonal (e.g., chronic renal disease),
or mixed but with significant demyelination (e.g., diabetes).
To establish an etiologic diagnosis, the neuropathy must
be characterized and classified as precisely as possible. To
separate the cause of a particular neuropathy from the protean
 C H A P T E R 233 Peripheral Neuropathies 2399

dominantly motor, multifocal demyelinating neuropathy.

TABLE 233-1 Selected Causes of Peripheral Neuropathy Knowledge of the relevant anatomic, physiologic, and pathologic
concepts helps greatly in this exercise.
INFLAMMATORY DEMYELINATING NEUROPATHY
AIDP (Guillain-Barr syndrome)
CIDP
CLINICAL SIGNS AND SYMPTOMS
INFECTIOUS AND GRANULOMATOUS NEUROPATHY OF PERIPHERAL NEUROPATHY
Leprosy
The cardinal manifestations of peripheral neuropathy are weak-
Sarcoid
ness, alterations in sensation, and changes in reflexes. The pat-
HIV related terns of abnormality are important in the differential diagnosis,
Lyme disease and detailed clinical examination in which the details and specif-
ics are explored is often rewarded. The first step in the differen-
NEUROPATHY ASSOCIATED WITH SYSTEMIC DISEASE
tial diagnosis is determining the pattern of motor and sensory
Diabetes dysfunction. Is the neuropathy predominantly motor or sensory?
Chronic renal disease If weakness has occurred, is it proximal, distal, or diffuse? Is
Alcoholism atrophy present? Are the changes in reflexes dependent on length
Paraproteinemia or are they global? Do the sensory changes demonstrate a predi-
Dysimmune neuropathies lection for large or small fibers? Is there autonomic dysfunction?
Hypothyroidism Are the findings symmetrical?
Vitamin deficiency Generalized, length-dependent peripheral neuropathies are
Paraneoplastic neuropathy typically symmetrical in onset, with numbness beginning initially
in the toes and feet and affecting the lower part of the legs as the
Amyloidosis
neuropathy progresses. The fingers and hands begin to be
Connective tissue disease
affected about the time that lower extremity involvement reaches
Critical illness polyneuropathy the knees. This reflects the length-dependent nature of the
ISCHEMIC NEUROPATHY process because nerve length from the lumbosacral dorsal root
ganglia to the knees is comparable to the length from the cervical
Peripheral vascular disease
dorsal root ganglia to the fingers. The most terminal distribution
Vasculitis
of the intercostal nerves is a strip along the chest and upper part
METABOLIC NEUROPATHY of the abdomen, and in a length-dependent process, sensory loss
Porphyria
can sometimes be found in this region, referred to as a cuirass
distribution. With motor involvement, weakness typically begins
Leukodystrophy
in the toe flexors and extensors, followed by the development of
Lipidosis
footdrop. The foot plantar flexors are so powerful that it is
Bassen-Kornzweig disease seldom possible to find weakness unless the neuropathy is very
Tangier disease severe. In very chronic neuropathies, it is common to see high
Refsums disease arched feet and hammer toes because the greater strength of the
Fabrys disease extrinsic than the intrinsic foot muscles in the lower part of
the leg pulls the toes into this position. Obvious atrophy of the
HEREDITARY NEUROPATHY intrinsic muscles with ridging between the long toe extensor
HMSN type I (hypertrophic form of Charcot-Marie-Tooth disease) tendons is often present. In a length-dependent process the first
HMSN type II (neuronal form of Charcot-Marie-Tooth disease) tendon reflexes to disappear are the ankle jerks; as the disease
HMSN type III (Dejerine-Sottas disease) progresses, knee jerks are lost at about the same time as the upper
Other forms of HMSN extremity reflexes begin to be depressed because of the similar
HSAN type I length of their axons.
HSAN type II In the differential diagnosis, age at onset, pace of evolution,
HSAN type III (Riley-Day syndrome)
presence of associated medical or neurologic conditions, and
medication history are very important. The family history is
Hereditary neuropathy with liability to pressure palsies (tomaculous
crucial but often tricky because many individuals with hereditary
neuropathy) neuropathies do not recognize their own condition. Other family
Giant axonal neuropathy members with odd-looking feet (pes cavus, characteristic of
TOXINS
CMT disease) or feet that are difficult to fit with shoes may be
the only clue to a condition that is rampant but unrecognized in
Pharmaceuticals
a kindred.
Environmental toxins Quantitation of the degree of deficit is useful for longitudinal
follow-up. Sophisticated instrumentation is available for this
AIDP, acute inflammatory demyelinating polyradiculoneuropathy; CIDP,
purpose but is expensive and not in wide use outside academic
chronic inflammatory demyelinating polyradiculoneuropathy; HIV, human
immunodeficiency virus; HMSN, hereditary motor-sensory neuropathy;
centers. Simple bedside testing can provide a great deal of useful
HSAN, hereditary sensory-autonomic neuropathy. information. Strength is most often described according to the
Medical Research Council scale. The power in small hand
muscles can be nicely described with techniques that compare the
patients strength with the examiners.2 Two-point discrimina-
possibilities, an attempt should be made to construct a profile of tion is quantitative and easily performed. Inexpensive handheld
clinical and electrophysiologic characteristics to narrow the dif- esthesiometers can quantitate touch sensibility. Vibratory sensa-
ferential diagnosis. From the long list of causes of neuropathy, tion is a sensitive parameter of peripheral nerve function and can
only a short list of conditions emerges that cause a chronic, pre- be simply quantitated by noting where the patient can perceive
dominantly sensory, large-fiber axonopathy or an acute, pre- the sensation and for how long (e.g., vibration absent at the great

Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
2400 SECTION VIII PERIPHERAL NERVE
toes and metatarsal heads, can perceive a maximally vibrating
128-Hz fork for 5 seconds over the medial malleoli). If the
patient returns and is found to have lost vibration sensibility over
the malleoli, the condition is progressing. If on follow-up vibra-
tion sensation is present for 12 seconds over the malleoli and can
now be perceived for 3 seconds over the metatarsal heads, the
patient is improving. Functional testing is invaluable. The time
required to walk a set distance or get up from the floor, arm and
leg outstretch time, the ability to support the entire body weight
on one tiptoe, and similar functions are objective and
quantifiable.
The onset of neuropathy may be relatively acute or subacute
and evolve over a period of several days to several weeks or be
more chronic and evolve over a period of several months to many
years. There is some unavoidable overlap in the middle, between
what might be called subacute and what might be called chronic.
Some neuropathies have a predilection for certain types and sizes
of fiber. Large-fiber neuropathies affect strength, reflexes, and
proprioception, with relative sparing of pain and temperature
sensation, whereas small-fiber neuropathies primarily affect pain,
temperature, and autonomic function, often with strength and
reflexes being spared. Differential involvement of large versus
small sensory fibers can sometimes be discerned clinically. Stan-
dard nerve conduction studies evaluate the conduction character-
istics of only large, myelinated fibers.
ELECTROPHYSIOLOGY OF PERIPHERAL
NEUROPATHIES
Demyelinating neuropathies and axonopathies generate quite
different electrophysiologic pictures. In brief, primary myeli-
nopathies produce marked slowing of conduction velocity (CV)
with preservation of distal compound muscle action potential
(CMAP) amplitudes, whereas axonopathies produce marked loss
of distal amplitudes with relative preservation of CV. When the
disease process affects only myelin, conduction is impaired
TABLE 233-2 Clinical and Electrodiagnostic Features That Help Distinguish Axonopathy from Myelinopathy
CLINICAL
AXONOPATHY
Insidious onset
Slow progression
Slow recovery
Evidence of length dependency
Loss of ankle jerks with the presence of other reflexes
Stocking distribution sensory loss
Weakness limited to the distal-most muscles
Symmetry
Normal CSF protein
MYELINOPATHY
More rapid onset
More rapid recovery
Mild asymmetry
Global loss of reflexes
Proximal or diffuse weakness
Cranial nerve involvement
Motor > sensory dysfunction
Increased CSF protein
CMAP, compound muscle action potential; CSF, cerebrospinal fluid; CV, conduction velocity; DML, distal motor latency; NAP, nerve action potential;
SNAP, sensory nerve action potential.
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
because of loss of saltatory conduction. If the process is uniform
and diffuse with all myelin being affected, as in a hereditary
myelinopathy, the conduction abnormalities involve all nerves
and all segments of nerves to an approximately equal degree. If
the process is focal, only the involved nerve is affected. If the
process is multifocal, the abnormalities may be widespread but
manifested to different degrees in different nerves and in differ-
ent segments of the same nerve. In either case, with a myelinopa-
thy the axon is intact and there is no loss of trophic influences
on the target motor and sensory organs. Muscle atrophy does not
occur, and denervation potentials, fibrillations, and positive sharp
waves do not appear in the affected muscles.
In contrast, a disease process that primarily affects axons also
causes loss of the axon-mediated trophic influences on target
organs. The muscle becomes atrophic, with a resultant decline in
CMAP amplitude. Axon loss produces a diminution in sensory
or compound nerve action potential amplitude. Involvement of
all the axons in a nerve may render the nerve inexcitable, and no
motor or sensory potentials can be elicited. However, any surviv-
ing axons will conduct at their normal velocity. If a disease
process produces dropout of 50% of the axons in a nerve, the
electrodiagnostic picture would be a 50% () loss of CMAP
amplitude but relatively normal CV. Clinical and electrophysi-
ologic characteristics helpful in distinguishing axonopathy from
myelinopathy are summarized in Table 233-2.
Unfortunately, as is often the case, findings do not always
follow the classic or typical pattern. Some neuropathies are truly
mixed, with electrophysiologic features of both demyelination
and axon loss. In addition, axonopathies can produce some degree
of slowing of CV. Random involvement of axons will inevitably
affect some of the largest and fastest conducting fibers, whose
dropout will then lower the maximum CV. If the largest and
fastest conducting axons are preferentially affected, significant
slowing could occur as a result of an axonopathy. The severity of
an axonopathy is reflected by the degree of muscle fiber atrophy
and its attendant loss of CMAP amplitude. A severe axonopathy
can be expected to involve at least some of the fastest conducting
ELECTRODIAGNOSTIC
Normal or mildly slowed nerve conduction velocities, i.e., do not meet the
criteria for demyelination
Decreased CMAP amplitude
Decreased sensory or compound NAP amplitude
Increased DML/late response latencies proportional to CV slowing
Proximal-to-distal gradient of increasing abnormality on needle examination
Marked conduction velocity slowing, i.e., meets the criteria for demyelination
Normal CMAP amplitude
Spotty or multifocal involvement
Normal sural, abnormal median SNAP
Conduction block or temporal dispersion on proximal stimulation
Prolongation of DML or late-response latencies disproportional to CV slowing
Paucity of denervation on needle examination with no proximal/distal gradient

fibers and will therefore produce more CV slowing than will a
mild axonopathy. For this reason, if the CMAP amplitude is
decreased, more severe conduction slowing must be present
before one can be confident of the existence of demyelination.
Because of these complicating factors, criteria for demyelination
have been developed. Despite the lack of universal consensus, the
use of some criteria set is coming into increasingly wide accep-
tance, but debate continues regarding precise details.
Although CV and CMAP amplitude are the primary param-
eters, other electrodiagnostic variables may be useful as well.
Disproportionate prolongation of distal motor latency or late
response latency, beyond that explicable on the basis of axon loss,
may also indicate demyelination. Axonopathies are length depen-
dent and exhibit a dying-back process that affects the most
distal nerve terminals first and involves more proximal nerve
segments with progression. Disproportionate conduction abnor-
malities in the most distal nerves can thus indicate axonopathy.
A gradient of abnormality on needle examination, with greatest
involvement of the most distal muscles and progressively
less involvement of more proximal muscles, suggests a length-
dependent process.
Another major indicator of demyelination is conduction block
or temporal dispersion. This is a change in amplitude or configu-
ration of the CMAP waveform on stimulation proximal to a given
point. In temporal dispersion, focal demyelination of axons pro-
duces CV slowing that involves some fibers to a greater degree
than other fibers and thereby causes loss of synchrony. The
CMAP conducted through the demyelinated region is dispersed
and spread out, with an increased duration and loss of amplitude.
However, all fibers successfully conduct through the affected
region, so the total area under the CMAP curve remains the same
with both proximal and distal stimulation. In conduction block,
some fibers are so severely demyelinated that they do not conduct
at all. There is not only a diminution in CMAP amplitude but
also a diminution in total area under the curve, thus indicating
that fewer muscle fibers have been successfully depolarized with
proximal stimulation than with distal stimulation.
Clinical weakness seems to correlate with conduction block,
not with CV slowing or temporal dispersion. A great deal has
been made of distinguishing between conduction block and tem-
poral dispersion, but the distinction is of questionable utility
because both these phenomena indicate a focal demyelinating
lesion in the subjacent nerve.3 As a result, the fairly simple crite-
rion of a significant loss of negative spike or peak-to-peak ampli-
tude with proximal stimulation as compared with distal stimulation
may suffice to indicate demyelination, and whether the loss of
amplitude is due to conduction block, temporal dispersion, or a
combination of the two is relatively immaterial.
Demyelination may occur in two major patterns. Disorders
that affect myelin diffusely because of a genetic defect, biochemi-
cal abnormality, or the effect of certain drugs or toxins produce
global, uniform demyelination. There is little variation from
nerve to nerve or from segment to segment of any given nerve.4
In the majority of patients with familial demyelinating neuropa-
thy, distal motor latencies are prolonged in proportion to CV,
median and ulnar forearm CV does not vary by greater than
5m/sec, and there is no evidence of conduction block or temporal
dispersion. Such uniform slowing of conduction suggests a gen-
eralized dysfunction of myelin or Schwann cells.
In acquired demyelinating neuropathies, distal motor latency
and CV vary more randomly, differences between median and
ulnar CV of greater than 5m/sec or even 10m/sec are common,
and conduction block or temporal dispersion may occur. Such a
pattern of conduction abnormality suggests a multifocal attack
on peripheral nerves that may become widespread but does not
truly affect myelin diffusely.
Other laboratory tests are often useful. Macrocytosis on the
hematology profile may be a clue to vitamin B12 deficiency or to
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C H A P T E R 233 Peripheral Neuropathies 2401
alcohol abuse. If alcoholism is strongly suspected, carbohydrate-
deficient transferrin may be useful. It reflects the level of alcohol
intake over the preceding weeks or months in the same way that
glycosylated hemoglobin reflects chronic blood sugar levels. An
elevated carbohydrate-deficient transferrin level may be a clue
to occult alcohol abuse as the cause of a generalized polyne
uropathy.5 Abnormal liver function test results, especially -
glutamyltransferase, may reflect alcohol abuse or a neuropathy
related to underlying hepatitis, especially hepatitis C. Hepatitis
C may cause a neuropathy associated with cryoglobulinemia.
Cryoglobulins are difficult to detect; they are large complex mol-
ecules that may cross-react with rheumatoid factor, so a positive
rheumatoid factor test may be a clue to hepatitis C. Many other
systemic diseases may be manifested as a peripheral neuropathy,
including connective tissue disorders, systemic vasculitis, vitamin
B12 deficiency, Lyme disease, paraproteinemias, porphyria, hypo-
thyroidism, human immunodeficiency virus (HIV) infection,
amyloidosis, sarcoidosis, and occult malignancy.
In GBS and CIDP, cerebrospinal fluid (CSF) protein is often
elevated, and lumbar puncture should be performed whenever
these conditions are in the differential diagnosis. In CIDP, mag-
netic resonance imaging of the lumbosacral spine may reveal
enlarged and inflamed lumbosacral roots. Formal autonomic
testing may help establish whether a neuropathy has a component
of dysautonomia. In recent years, skin biopsy has emerged as a
safe, minimally invasive tool for assessing small epidermal nerve
fibers that are inaccessible for routine neurophysiologic tests.
Biopsy of hairy skin can be used to evaluate unmyelinated and
thinly myelinated fibers, and biopsy of glabrous skin can be used
to examine large myelinated fibers. Standard morphometric tech-
niques have been developed and proven to be reliable and repro-
ducible. Pathologic changes in cutaneous nerves have been found
to occur very early in the course of peripheral neuropathies.
Comparison of the density of the epidermal nerve fiber layer
between a proximal and a distal biopsy site can sometimes docu-
ment the length dependency of a neuropathy, as well as occasion-
ally make the diagnosis in a condition such as amyloidosis.
Peripheral neuropathy is obviously common in patients with
diabetes mellitus. Recently, controversy has arisen regarding the
diagnosis of neuropathy in patients with an abnormal 2-hour
glucose tolerance test but without frank diabetes and the proper
screening test for patients with idiopathic peripheral neuropathy,
especially sensory neuropathy. Undiagnosed impaired fasting
glucose metabolism appears to be associated with neuropathy at
a higher frequency than in the general population when the
2-hour oral glucose tolerance test is used as opposed to a fasting
blood sugar and glycosylated hemoglobin level.6 In a study of 100
consecutive patients with apparently idiopathic peripheral neu-
ropathy, the prevalence of undiagnosed abnormal fasting glucose
metabolism was found to be nearly twofold higher (62%) in
patients with neuropathy than in controls. The 2-hour oral
glucose tolerance test provided a higher diagnostic rate with the
2003 revised American Diabetes Association criteria. There is
increasing evidence that abnormal glucose metabolism, or pre-
diabetes, may be a risk factor for neuropathy and that a 2-hour
oral glucose tolerance test may be more sensitive than fasting
blood sugar and glycosylated hemoglobin in detecting this
condition.
In Tables 233-3 to 233-6, neuropathies are classified into
demyelinating versus axonal and whether the onset is acute/sub-
acute versus subacute/chronic. Other common classifications
include (1) mixed axonopathy/myelinopathy: diabetes, end-stage
renal disease (ESRD), and some cases of acute or chronic inflam-
matory demyelinating neuropathy; (2) primarily motor polyneu-
ropathies: most cases of GBS, CIDP, porphyria, dapsone and lead
intoxication, and CMT disease; (3) large-fiber sensory neuropa-
thies: uremia, diabetes (pseudotabes), paraneoplastic neuropathy,
Sjgrens syndrome, vitamin B12 deficiency, Friedreichs ataxia,
2402 SECTION VIII PERIPHERAL NERVE

TABLE 233-3 Acute/Subacute Myelinopathies TABLE 233-5 Acute/Subacute Axonopathy

UNIFORM DIFFUSE DEMYELINATION PRIMARILY MOTOR
Toxins Acute motor axonal neuropathy (axonal Guillain-Barr syndrome)
Hexacarbons Porphyria
N-Hexane Lead intoxication
Methyl butyl ketone Dapsone
Na+ channel blockers Tick paralysis
Tetrodotoxin Critical illness polyneuropathy
Saxitoxin
PRIMARILY SENSORY
Drugs
Paclitaxel/docetaxel (high dose)
Amiodarone*
Cisplatin
Perhexiline*
Acute sensory neuronopathy
Doxorubicin
Pyridoxine intoxication (high dose)
Cytosine arabinoside*
Ciguatera intoxication
SEGMENTAL, MULTIFOCAL DEMYELINATION Miller-Fisher syndrome
Guillain-Barr syndrome Metronidazole
Acute arsenic intoxication
MIXED
Lymphoma
Critical illness polyneuropathy
Human immunodeficiency virus infection (early)
Diphtheria
Drugs
Amiodarone*
Perhexiline* certain toxins (e.g., pyridoxine, cisplatin, and metronidazole),
Cytosine arabinoside* acute idiopathic sensory neuronopathy, and some cases of CIDP;
(4) small-fiber sensory neuropathies: diabetes mellitus (pseudo-
*Both patterns have been reported. syringomyelia), amyloidosis, hereditary sensory autonomic neu-

Recall that Guillain-Barr syndrome is a syndrome, not a disease, and can ropathies, and leprosy; and (5) neuropathies with major autonomic
occur as part of several conditions. dysfunction: diabetes, alcoholism, amyloidosis, hereditary sensory
autonomic neuropathy type III (Riley-Day syndrome), GBS, por-
phyria, vincristine toxicity, and idiopathic pandysautonomia.

TABLE 233-4 Subacute/Chronic Demyelinating COMMON NEUROPATHIES

Neuropathies The following sections discuss some of the more common or
UNIFORM, DIFFUSE DEMYELINATION interesting neuropathic syndromes. Space limitations do not
HMSN I, III, IV permit discussion of every syndrome. Detailed elaboration is
Metachromatic leukodystrophy
available elsewhere.1,7
Adrenoleukodystrophy
Adrenomyeloneuropathy Diabetic Neuropathy
Krabbes disease Approximately 50% of patients with diabetes have peripheral
Cockaynes syndrome nerve involvement after 25 years of the disease. Most common is
Tangier disease a chronic, generalized, symmetrical polyneuropathy, usually pre-
dominantly sensory but sometimes sensorimotor, with variable
SEGMENTAL, MULTIFOCAL DEMYELINATION autonomic dysfunction and variable, sometimes oppressive pain.
CIDP and variants* The sensory involvement may be predominantly small fiber or
Hypothyroidism predominantly large fiber. There are several types of asymmetric
Leprosy diabetic neuropathy. Ischemia can develop in almost any periph-
Hereditary neuropathy with liability to pressure palsies eral nerve as a result of diabetic small-vessel disease, but the third
Lyme disease cranial nerve and the femoral nerve seem most susceptible. Dia-
HIV infection (early) betic amyotrophy is the most common of the asymmetric neu-
Paraproteinemic neuropathy ropathies and is better described as a radiculoplexopathy.
Symmetrical proximal neuropathies also occur. The different
Cryoglobulinemia
types of diabetic neuropathy are summarized in Table 233-7.
Lymphoma
Several possible mechanisms are possibly operative in the
SLE various diabetic neuropathies. Reversible metabolic changes may
account for some of the conduction abnormalities. Aldose reduc-
*Includes CIDPmonoclonal gammopathy of undetermined significance
(MGUS), POEMS syndrome (polyneuropathy, organomegaly,
tase converts glucose into sorbitol, which accumulates in the
endocrinopathy, M protein, skin changes), multifocal motor neuropathy, nerve, decreases myoinositol levels, and impairs the action of
and antimyelin-associated glycolipid (MAG) neuropathy. the Na/K pump. CV begins to improve within hours of reversing
CIDP, chronic inflammatory demyelinating polyneuropathy; HIV, human the hyperglycemia.8,9 Diabetic microangiopathy and intraneural
immunodeficiency virus; HMSN, hereditary motor-sensory neuropathy; hypoxia probably play a significant role as well. Enzymatic
SLE, systemic lupus erythematosus. reactions between glucose and proteins produce advanced
glycosylation end products, which may contribute to neuropathy

Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
 C H A P T E R 233 Peripheral Neuropathies 2403

TABLE 233-6 Subacute/Chronic Axonopathy TABLE 233-7 Some Forms of Diabetic Neuropathy
PRIMARILY MOTOR GENERALIZED SYMMETRICAL POLYNEUROPATHIES
HMSN II and V Rapidly reversible neuropathies
Paraneoplastic motor neuropathy Hyperglycemic neuropathy
Vincristine Treatment-induced neuropathy
Distal sensory motor autonomic polyneuropathies
PRIMARILY SENSORY
Large-fiber neuropathy (pseudotabetic)
Distal sensory neuropathy in AIDS
Small-fiber neuropathy (pseudosyringomyelic)
Diabetes mellitus
Acute painful neuropathy
Chronic arsenic intoxication
Ataxic neuropathy
Paclitaxel/docetaxel (usually)
Acrodystrophic neuropathy
Cisplatin
Autonomic neuropathy
Pyridoxine intoxication (low dose)
Symmetrical motor neuropathy
Paraneoplastic neuropathy
Proximal symmetrical motor neuropathy
Chronic ataxic neuropathy
Distal motor neuropathy
Sjgrens syndrome
Primary biliary cirrhosis FOCAL AND MULTIFOCAL NEUROPATHIES
Amyloidosis Cranial mononeuropathies
Lyme disease Asymmetric proximal motor neuropathy (diabetic amyotrophy)
Vitamin E deficiency Truncal neuropathy (thoracoabdominal neuropathy)
Tabes dorsalis Compression and entrapment neuropathies
Antisulfatide neuropathy
Friedreichs ataxia
Abetalipoproteinemia
Nonsystemic vasculitic neuropathy in excess of that seen in most myelinopathies.4 It seems increas-
ingly clear that good diabetic control can improve the long-term
MIXED SENSORIMOTOR outlook for patients with most forms of diabetic neuropathy.12
Amyloidosis
Alcoholism
The Neuropathy of Chronic Renal Failure
Vitamin B12 deficiency
Sarcoidosis
The typical neuropathy of ESRD is a distal, symmetrical, sub-
acute, slowly progressive sensorimotor axonopathy. Approxi-
Most toxins
mately 60% to 80% of patients with ESRD have neuropathy at
Most drugs
the onset of dialysis. Although primarily an axonopathy, the neu-
HIV infection ropathy of ESRD may be associated with significant secondary
Diabetes mellitus demyelination, and there may be preferential large-fiber involve-
Chronic arsenic intoxication ment clinically and pathologically.13,14 Although the neuropathy
Lead intoxication may stabilize with dialysis, significant improvement occurs only
Paraneoplastic neuropathy after transplantation. A rapidly progressive neuropathy can occur.
Hypothyroidism Diabetes is a common cause of ESRD, and some patients have
Lyme disease coexistent diabetic and uremic polyneuropathy.
Connective tissue diseases
Vasculitic neuropathy Alcoholic Neuropathy
Multiple myeloma
The pathogenesis of the neuropathy in chronic alcoholics is still
Cryoglobulinemia being debated. Most alcoholics suffer from malnutrition, but no
AIDS specific nutritional deficiencies seem to explain the neuropathy.
Alcohol has direct toxic effects on the central nervous system and
AIDS, acquired immunodeficiency syndrome; HIV, human possibly on the peripheral nervous system. A study of 107 alco-
immunodeficiency virus; HMSN, hereditary motor-sensory neuropathy.
holics showed that 32% had peripheral neuropathy by EMG and
24% had dysautonomia. The neuropathies correlated directly
with the level of alcohol intake and bore no relationship to nutri-
tional status.15 Subsequent literature continues to suggest a direct
neurotoxic effect, perhaps mediated by acetaldehyde.16 Clinically
by damaging the extracellular matrix and enhancing basement and electrodiagnostically, the neuropathy is a nondescript, distal,
membrane thickening and reduplication.10 symmetrical, generalized sensorimotor axonopathy with variable
Some patients, especially those with asymmetric or proximal pain, weakness, and dysautonomia. Sensory dysfunction is more
neuropathy, may have a treatable inflammatory vasculopathy, and prominent than motor; mild weakness is common but severe
some diabetics have a disorder indistinguishable from CIDP.11 weakness is rare.
On electrodiagnostic studies, diabetic generalized sensorimo-
tor polyneuropathy commonly shows evidence of both chronic
axonal degeneration and significant demyelination. The combi- Vitamin B12 Deficiency
nation of axonal degeneration and marked CV slowing is char- Inhibition of the vitamin B12dependent enzyme methionine
acteristic of diabetic neuropathy. The demyelination is beyond synthase creates disturbed methylation reactions leading to
that expected for most axonal neuropathies, and the axon loss is impaired DNA synthesis and a host of attendant complications.

Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
2404 SECTION VIII PERIPHERAL NERVE
Neurologic manifestations include neuropathy, myelopathy, and
dementia. The neuropathy is generally said to be an axonopathy,
but demyelination is prominent pathologically in the central
nervous system, and there is little electropathologic correlative
information regarding the peripheral neuropathy. Clinically, the
neuropathy is predominantly sensory and symmetrical with a
predilection for large fibers. An important clue is evidence of an
associated myelopathy. The combination of absent ankle jerks
and upgoing toes is highly suggestive of vitamin B12 deficiency.
Significant neurologic involvement can occur in the absence of
hematologic abnormalities.
Dysimmune Neuropathies
Dysimmune neuropathies are those in which peripheral nerve
damage results from some aberration of the immune system.
Most involve abnormalities in both cellular and humoral immu-
nity, and the majority are associated with inflammation and
demyelination. The two most common disorders are AIDP (or
GBS) and CIDP.17 A number of other less common disorders
may fall under this rubric, including the demyelinating neuropa-
thies associated with the various paraproteinemias, the syndrome
of multifocal motor neuropathy (MMN), antimyelin-associated
glycoprotein (MAG) neuropathy, antisulfatide neuropathy, and
gait ataxia, late-onset polyheuropathy (GALOP) syndrome.
Acute motor axonal neuropathy (AMAN) is a variant of GBS in
which the immune attack is directed at the axolemma at the nodes
of Ranvier of large motor fibers. Most AMAN cases follow Cam-
pylobacter jejuni infection, in which antibodies directed against
some epitope or epitopes on the organism attack GM1-reactive
epitopes on the nodal axolemma.18
The resemblance of AIDP and CIDP to experimental allergic
neuritis strongly suggests that disordered cellular immunity is
involved in the pathogenesis. In addition, antibody and comple-
ment have been implicated in several syndromes. Impairment of
the blood-nerve barrier (BNB) is another important factor. The
acute and chronic inflammatory demyelinating polyneuropathy
syndromes may well involve a combined land-air attack in
which sensitized cells breach the BNB, thereby paving the way
for antibodies, which then induce demyelination.
A number of antinerve antibodies have been described in asso-
ciation with various syndromes, but their exact pathogenetic role
remains enigmatic. The antibodies described are primarily
directed against the glycolipid and glycoprotein components of
peripheral nerve myelin. Sialic acidbearing glycolipids (ganglio-
sides), including GM1, GD1b, and GQ1b, as well as the asialo form
of GM1, are frequent targets. The majority of patients with CIDP
have autoantibodies against -tubulin. Antibodies to GM1 are
particularly associated with the syndrome of MMN. Antibodies
against MAG and an associated sulfoglucoronyl paragloboside
appear to produce a slightly different syndrome. Whether the
various syndromes are distinct disease entities or variants of CIDP
remains a matter of debate between lumpers and splitters.19
Most of the dysimmune neuropathies are potentially treatable,
but the best treatment may vary with the syndrome. Steroids,
immunosuppressants, plasma exchange, and intravenous immu-
noglobulin (IVIG) have all been used.20
Guillain-Barr Syndrome (Acute Inflammatory
Demyelinating Polyneuropathy)
GBS has an annual incidence in the United States of 1 to 2 per
100,000. In about 60% of cases, some antecedent event has seem-
ingly primed and activated the immune systempreceding infec-
tion (especially cytomegalovirus, Epstein-Barr virus, or C. jejuni
infection), surgery, pregnancy, or immunizations. GBS is a sub-
acutely progressive, largely reversible neuropathy that produces
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
symmetrical weakness and areflexia or hyporeflexia, generally
spares sphincter function, and occasionally results in respiratory
failure. It is primarily a motor disorder and may appear purely
motor. The distribution of weakness is variable, and proximal
weakness is not uncommon. The weakness occasionally descends
rather than ascends. Facial weakness occurs in 50%, and other
cranial nerves are involved now and then. The weakness typically
progresses over a 1- to 3-week period. Respiratory failure requir-
ing ventilator assistance develops in about 25% to 30% of
patients. The initial symptoms are sensory in approximately 70%
of patients and include paresthesia and vague numbness, but
there is typically minimal or no objective sensory loss. Autonomic
dysfunction occurs commonly: hypotension, paroxysmal hyper-
tension, arrhythmias, ileus, or sphincter dysfunction when the
disease is severe. Good recovery occurs in the majority of patients;
about 15% have significant residua, 5% are left with severe dis-
ability, and there is still a 5% mortality rate.
CSF protein is usually normal for the first several days, then
rises, sometimes reaching extraordinary levels, and remains high
for several months. Pleocytosis can develop, but more than 50
cells suggests an alternative diagnosis. Increased cells are espe-
cially common in HIV-associated cases.
The 1976 swine flu/GBS epidemic prompted a set of diagnos-
tic criteria, which were reviewed and updated in 1990.21 Essential
features for the diagnosis include progressive weakness in more
than one limb plus attenuation or loss of reflexes. Features that
strongly support the diagnosis include progression, relative sym-
metry, mild sensory symptoms or signs, cranial nerve involve-
ment, autonomic dysfunction, absence of fever at onset of the
neuropathic symptoms, and eventual recovery. GBS can occa-
sionally deviate from its usual clinical picture, primarily by quirks
in distribution.
The usual differential diagnostic exercise in GBS is to rule out
other processes masquerading as peripheral nerve disease. Pos-
sibilities include acute myelopathy secondary to spinal cord com-
pression or transverse myelitis, acute anterior horn cell disease
caused by poliomyelitis or other viral infections such as West
Nile virus, myopathies (especially in light of the tendency of GBS
to sometimes cause weakness greater proximally, similar to the
pattern commonly seen in myopathies), acute neuromuscular
junction disorder, tick paralysis, poisoning with marine toxins,
other toxins (especially arsenic), and hysterical paralysis.
Electrodiagnosis of Guillain-Barr Syndrome
With the advent of effective treatment, early electrodiagnostic
confirmation of suspected GBS has become more critical.22
There are several problems, primarily related to the nature of the
pathologic process. The inflammation and demyelination are
characteristically spotty, and some nerves may be clearly involved
whereas others escape entirely, so as a general rule, the more
nerve conduction studies performed, the more likely an abnor-
mality will be found. The earliest pathologic changes often
involve the roots and proximal nerves, which are relatively inac-
cessible for routine conduction studies. Late response studies, F
waves and H-reflexes, may therefore detect abnormality when
standard peripheral studies are still normal.
In addition, clinical weakness is related to conduction block
rather than the severity of CV slowing, so there is an imprecise
correlation between the clinical deficit and the electrodiagnostic
abnormalities, especially if the conduction block is proximal.
Patients may be improving clinically at a time when the electro-
diagnostic picture is worsening or may have severe deficits when
the electrical studies are not very impressive. Depending on the
criteria used, most patients demonstrate characteristic electrical
abnormalities at some time in the course of the illness, but 10%
to 20% may have normal studies early in the course when there
is a premium on prompt and accurate diagnosis.

GBS is notoriously variable, both in its clinical manifestations
and in its electrodiagnostic picture. The axonal form of GBS was
first described more than 20 years ago, and AMAN is increasingly
being accepted as a GBS variant. Patients with AMAN have a
higher incidence of associated C. jejuni infection and antibodies
against GM1 ganglioside and a worse long-term prognosis.
In the final analysis, almost any pattern of electrodiagnostic
abnormality, including the absence of any abnormality, could be
consistent with early GBS. The diagnosis should depend on the
total clinical picture, with the electrophysiologic features being
one of the pillars of support.
The electrodiagnostic findings can also provide useful prog-
nostic information.23 The best indicator of prognosis is CMAP
amplitude. Patients with a CMAP amplitude of less than 10% to
20% of the lower limit of normal have a poor prognosis, whereas
those with normal CMAP amplitude have an excellent prognosis.
No significant correlation has been found between long-term
outcome and conduction block or CV. There is disagreement
about whether fibrillation potential intensity has prognostic
implications.
Chronic Inflammatory Demyelinating
Polyradiculoneuropathy and Variants
GBS and CIDP are probably variants of the same disease process
that develop over different time courses. CIDP probably repre-
sents as many as 10% to 20% of all initially undiagnosed neu-
ropathies and is important to recognize because of the likelihood
that it may respond to treatment. Table 233-8 summarizes the
diagnostic criteria for CIDP. To distinguish CIDP from GBS,
the latter is fully developed in 90% of patients by 4 weeks. To
meet criteria for the diagnosis of CIDP, the condition must
evolve over a period of at least 8 weeks. Obtaining pathologic
confirmation of the diagnosis is sometimes difficult, and the need
for nerve biopsy is debatable. If clinical, EMG, and CSF criteria
are met, nerve biopsy serves mostly to exclude other conditions.
Before considering nerve biopsy for diagnosis, however, it should
be considered that CIDP can have a dramatic and unique appear-
ance on magnetic resonance neurography,24 so invasive diagnos-
tic testing may not be justified.
There are several variants of the CIDP syndrome in which a
demyelinating polyneuropathy occurs in association with other
clinical and electrodiagnostic features. CIDP sometimes occurs
in association with a monoclonal gammopathy of undetermined
significance (MGUS). Patients with CIDP-MGUS tend to be
slightly older and have a more chronic course, more sensory
involvement, and more predominantly lower extremity involve-
ment. POEMS syndrome (polyneuropathy, organomegaly, endo-
crinopathy, M protein, skin changes) is essentially CIDP
associated with osteosclerotic myeloma. The clinical picture of
the neuropathy is essentially the same as for CIDP, but patients
have other abnormalities on clinical and laboratory evaluation,
including organomegaly, endocrinopathy (usually diabetes), a
monoclonal paraprotein, and skin changes. A plain film skeletal
survey is usually required to detect the osteosclerotic myeloma
because radioisotope bone scans are negative. The electrodiag-
nostic features of CIDP-MGUS and POEMS syndrome are basi-
cally the same as for CIDP. The neuropathy associated with
antibody to MAG tends to be symmetrical, with predominantly
lower extremity involvement and more striking sensory altera-
tions. Electrophysiologically, anti-MAG neuropathy is primarily
a demyelinating syndrome. A purely sensory variant of CIDP in
which motor involvement may develop late in the course has been
reported.
MMN is a neuropathy that may be a mimicker of amyotrophic
lateral sclerosis (ALS).25 These patients have very chronic,
asymmetric weakness involving the upper more than the lower
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C H A P T E R 233 Peripheral Neuropathies 2405
TABLE 233-8 Clinical and Laboratory Criteria for the
Diagnosis of Chronic Inflammatory
Demyelinating Polyradiculoneuropathy
CLINICAL
Mandatory
Progressive or relapsing dysfunction of a peripheral nerve nature
involving more than one limb and evolving over a period of at
least 2 months
Hyporeflexia or areflexia
Supportive
Large-fiber sensory loss pattern
Exclusionary
Acral mutilation, retinitis pigmentosa, ichthyosis, drug or toxin
exposure, family history suggestive of a genetic neuropathy
Sensory level
Unequivocal sphincter disturbance
PATHOLOGIC
Mandatory
Nerve biopsy showing unequivocal demyelination and
remyelination
Supportive
Nerve biopsy showing nonspecific abnormalities but consistent
with CIDP
Exclusionary
Nerve biopsy to exclude vasculitis, amyloidosis, or other specific
pathology
CEREBROSPINAL FLUID
Mandatory
Cell count <10 if HIV negative, <50 if HIV positive
VDRL negative
Supportive
Elevated protein
CIDP, chronic inflammatory demyelinating polyradiculoneuropathy;
HIV, human immunodeficiency virus; VDRL, Venereal Disease Research
Laboratory.
Modified from American Academy of Neurology AIDS Task Force.
Research criteria for diagnosis of CIDP. Neurology. 1991;41:617-618.
extremities and associated with impressive conduction block on
nerve conduction studies. The authors speculated that the condi-
tion was probably a variant of CIDP, and most current evidence
supports this conclusion.26 The condition may be manifested as
weakness, atrophy, cramps, fasciculations, and preserved reflexes
with minimal sensory complaints or findings, all suggestive of
ALS.27 Further experience has shown that with careful evaluation,
some degree of clinical sensory involvement is the rule rather
than the exception in MMN. Lewis and colleagues had previously
reported a very similar condition and speculated that it was a
variant of CIDP.28 Sensory nerve action potentials tend to be
normal, thus suggesting there may be sensory conduction block
in some segment of nerve not usually tested. There is an associa-
tion between this syndrome and antibodies against GM1 and
other gangliosides. Patients with ALS and other neurologic con-
ditions may also have antiganglioside antibodies, albeit generally
at lower titer than in those with MMN.
It now appears that many patients with MMN respond to
IVIG, which is also of benefit in AIDP and probably in CIDP.
It appears more and more likely that so-called MMN is probably
2406 SECTION VIII PERIPHERAL NERVE
not a separate entity but a variant of CIDP characterized by
asymmetry and prominent conduction block. A condition clini-
cally identical but without conduction block has been reported
and termed multifocal acquired motor axonopathy.29 Many patients,
perhaps most patients, do have sensory complaints and findings.
Some patients have antiganglioside antibodies.
The dysimmune neuropathies are primarily demyelinating
syndromes, with the single exception of antisulfatide neuropathy.
These patients exhibit a painful, predominantly sensory, pre-
dominantly axonal clinical syndrome associated with antibody
reactivity to peripheral nerve sulfatide components and a general-
ized axonopathy electrophysiologically.
Amyloidosis
Amyloidosis develops in a variety of circumstances. It may occur
as a primary process or complicate paraproteinemias or any
chronic systemic disease, especially chronic renal failure and
dialysis. Many cases are familial. The disease causes intercellular
deposition of insoluble, beta-pleated fibrillary protein. Its signs
and symptoms are highly variable, and the disease should be
suspected in patients with unexplained proteinuria, cardiomyopa-
thy, congestive heart failure, hepatosplenomegaly, or cranial neu-
ropathy. Peripheral neuropathy develops in approximately 10%
of cases, and the most severe neuropathies tend to occur in the
familial forms. The mechanism whereby amyloid deposition
causes neuropathy remains obscure, but mechanical compression,
ischemia, and metabolic abnormality have been invoked as expla-
nations. Deposition of amyloid in the transverse carpal ligament
produces carpal tunnel syndrome. When suspected, confirmation
of the diagnosis is often sought by sural nerve biopsy. However,
the utility of sural nerve biopsy for diagnosis has been questioned
by a study in which six of nine biopsy specimens in patients with
amyloid neuropathy demonstrated no amyloid. The diagnosis
was subsequently made by examination of other tissue or the
contralateral sural nerve.30 Even the slightest appearance of
abnormality of the transverse carpal ligament, such as discolor-
ation or thickening, should prompt sending a ligament specimen
for pathologic examination. The diagnosis of amyloidosis has
been made many times in this way.
Hereditary amyloidosis with neuropathy has many forms that
have had colorful designationse.g., Portuguese, van Allen,
Indiana, Finnish, Germanbut are now generally referred to as
familial amyloid polyneuropathy (FAP) types I to IV. Most are
due to mutations in the gene coding for the protein transthyretin
(prealbumin), the primary component of amyloid protein. FAP
type I produces a sensory-dominant neuropathy characterized by
dissociated sensory loss in a small-fiber pattern, autonomic dys-
function, pain, and trophic changes, with amyloid deposition in
the endoneurium of peripheral nerves, dorsal root ganglia, and
sympathetic ganglia. Type II is often manifested as carpal tunnel
syndrome. Type III is associated with a painful, distal axonopa-
thy. Type IV FAP is characterized by progressive cranial neu-
ropathy, corneal dystrophy, and distal sensorimotor neuropathy.
The abnormal amyloid subunit protein in type IV is derived from
a variant molecule of gelsolin, an actin-modulating cytoskeletal
protein.
Nonhereditary amyloidosis is divided into primary and dys-
proteinemic types, which are clinically and electrophysiologically
indistinguishable. The progressive neuropathy is primarily
sensory, small fiber, and accompanied by dysautonomia. Electro-
diagnostically, the neuropathy is a distal, symmetrical sensorimo-
tor axonopathy.
Infection-Related Neuropathies
Aside from HIV-related neuropathies, infection-related neuropa-
thies are rare except in developing countries.31 In fact, the most
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
common cause of peripheral neuropathy in the undeveloped
world is leprosy; in the developed world it is diabetes. The
peripheral nervous system disorders complicating HIV infection
are heterogeneous and highly prevalent. Inflammatory demyelin-
ating neuropathy occurs early in the course of the disease, fre-
quently at the time of seroconversion, and is clinically and
electrophysiologically indistinguishable from AIDP and CIDP.
In the late stages of the disease, usually when the CD4+ T-cell
count is less than 50, the most common neuropathy is a painful,
distal, sensory axonopathy. Less commonly, lymphomatous or
vasculitic neuropathy may develop in HIV-infected patients.
Neuropathies may also occur as a result of antiretroviral therapy,
other drugs, malnutrition, and vitamin B12 deficiency. Herpes-
zoster frequently causes radiculopathy, and cytomegalovirus may
produce a severe polyradiculoneuropathy or diffuse mononeuritis
multiplex.
Lyme disease can produce several different peripheral neuro-
logic complications in up to a third of the patients with late
disease. Vasculitis is probably an important pathophysiologic
mechanism. Most common are a mild, chronic, axonal senso-
rimotor polyradiculoneuropathy and facial nerve palsy.32
Critical Illness Polyneuropathy
Sepsis and multiorgan failure may trigger critical illness poly-
neuropathy, a common cause of severe generalized weakness and
weaning failure in critically ill patients.33 Critical illness poly-
neuropathy may occur in some form in as many as 50% of criti-
cally ill patients who have been in a septic state for more than 2
weeks. The origin is probably multifactorial and related to the
systemic inflammatory response syndrome. The pattern of
weaning failure gradually changes from that of the underlying
disease to one of neuromuscular ventilatory failure. Proximal
muscles, including the facial and paraspinal musculature, are
often involved, but tendon reflexes may be paradoxically pre-
served. Critical illness polyneuropathy is most often a distal sen-
sorimotor axonopathy, but a purely motor form may represent a
variant. Differentiation from early AIDP with minimal electro-
diagnostic abnormalities may be problematic. Recovery is usually
rapid and clinically complete, provided that the patient recovers
from the critical illness, although electrodiagnostic evaluation
may disclose residua.
Paraneoplastic Neuropathies
Neuromuscular complications of cancer can result from direct
effects of the tumor, from side effects of therapy, or from para-
neoplastic syndromes. Through remote effects, tumors can
produce a paraneoplastic subacute sensory axonopathy, a sensory
neuronopathy, or more commonly, a nondescript distal senso-
rimotor axonopathy. Paraproteinemic disorders and lymphomas
may cause a demyelinating neuropathy resembling AIDP or
CIDP. Tumors may also produce vasculitis with an attendant
neuropathy. In most instances, the paraneoplastic effect is immu-
nologically mediated. Anti-Hu antibody (type 1 antineuronal
nuclear autoantibody) is a polyclonal IgG directed against
neurons throughout the central and peripheral systems and asso-
ciated primarily with the subacute sensory neuropathy/neu-
ronopathy syndrome and chiefly with underlying small-cell lung
carcinoma, which is sometimes otherwise silent. The tumor
expresses neuronal antigens or antigenically indistinguishable
epitopes and induces a cross-reaction with various tissues in the
nervous system. An immune response intended to limit the
growth and spread of a neoplasm is then misdirected and causes
autoimmunologically mediated neurologic injury. Anti-Hu anti-
body probably enters the dorsal root ganglion through an incom-
plete BNB to cross-react with dorsal root ganglion neurons and
thereby induce inflammation and cell loss.

Vasculitic Neuropathies
Polyarteritis nodosa (PAN), Churg-Strauss syndrome, and
hypersensitivity angiitis account for most instances of vasculitic
neuropathy. Other causes include rheumatoid arthritis, systemic
lupus erythematosus, undifferentiated connective tissue disease,
Wegeners granulomatosis, primary Sjgrens syndrome, lym-
phoid granulomatosis, and cryoglobulinemia. Vasculitis may also
complicate cancer, HIV infection, and Lyme disease. Peripheral
neuropathy is often an early and dominant feature of systemic
necrotizing vasculitis and may be the only manifestation of the
underlying process.34 PAN and Churg-Strauss syndrome are
characterized by inflammation of medium and small arteries and
hypersensitivity angiitis by inflammation of capillaries and
venules. A painful multiple mononeuropathy syndrome is the
most common clinical finding, but as more nerves are involved,
the neuropathy may become confluent and appear as a general-
ized but asymmetric polyneuropathy. A distal symmetrical poly-
neuropathy also occurs. Nerve conduction abnormalities are
variable. Electrodiagnostic studies may reveal abnormalities in
patients with no symptoms of neuropathy. Electrical abnormali-
ties of the sural nerve correlate well with the subsequent yield on
biopsy. Some patients have vasculitis isolated to the peripheral
nervous system, or the syndrome of nonsystemic vasculitic neu-
ropathy. The clinical and electrodiagnostic features and pathol-
ogy are similar to PAN, but the peripheral nervous system is
affected in isolation and other systems are spared. It may be an
organ-specific variant of PAN.
Hereditary Neuropathies
There are numerous forms of hereditary neuropathy (Table
233-9). The widely used Dyck classification scheme divides the
hereditary neuropathies into motor-sensory (HMSN) and sen-
sory-autonomic forms (HSAN) and numbers the subtypes. The
HMSN syndromes are now more often referred to as CMT
disease in recognition of the original discovers of the disease.
There are currently seven subtypes of CMT/HMSN disease,
TABLE 233-9 Hereditary Neuropathies
SYNDROME DYCK CLASSIFICATION
CMT1
CMT2
Dejerine-Sottas disease
Refsums disease
Acrodystrophic neuropathy
Morvans disease
Riley-Day syndrome
HNPP
Giant axonal neuropathy
Neuroaxonal dystrophy
Hereditary amyloidosis
Porphyrias
MLD
ALD/AMN
Krabbes disease
Fabrys disease
Bassen-Kornzweig disease
Tangier disease
ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; CMT, Charcot-Marie-Tooth; HMSN, hereditary motor-sensory neuropathy; HNPP, hereditary
neuropathy with liability to pressure palsies; HSAN, hereditary sensory-autonomic neuropathy; MLD, metachromatic leukodystrophy.
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C H A P T E R 233 Peripheral Neuropathies 2407
numbered CMT1 to CMT7 or HMSN I to VII. The many other
forms of hereditary neuropathy are not included in this scheme.
CMT1, also known as HMSN I, peroneal muscular atrophy,
or the hypertrophic form of CMT disease, is a uniform, diffuse
demyelinating neuropathy with marked slowing of nerve CV that
does not vary significantly from nerve to nerve or from segment
to segment, with no evidence of conduction block or temporal
dispersion.35 Nerve CVs are frequently as slow as 50% of normal,
and there is often secondary axon loss. Clinically, CMT1 is a
slowly progressive, symmetrical distal sensorimotor neuropathy
with associated muscle wasting most evident distal to the knee
(stork leg or invertedchampagne bottle deformity) and palpably
enlarged nerves that is frequently accompanied by skeletal defor-
mities such as pes cavus or scoliosis. Sensory dysfunction is less
prominent than motor dysfunction. Nerve pathology demon-
strates demyelination, remyelination, and onion bulb formation.
CMT1 is most often transmitted in autosomal dominant
fashion but may be X-linked. The dominant form is divided into
CMT1A, located on chromosome 17, and CMT1B, located on
chromosome 1. CMT1A is much more common and usually
involves duplication of the region of 17p, which codes for periph-
eral myelin protein (PMP-22). The abnormal genes in the other
forms also involve Schwann cell and myelin proteinsP0 (an
important myelin structural protein) in CMT1B and connexin-32
(which localizes to nodes of Ranvier and Schmidt-Lanterman
incisurae) in CMT1X.36
CMT2, also known as HMSN II, or the neuronal form of
CMT disease, makes up about a third of cases of autosomal
dominant CMT. It is associated with selective degeneration of
lower motoneurons and dorsal root ganglion cells. There is con-
siderable overlap between CMT1 and CMT2. The clinical
picture is identical except for the presence of nerve hypertrophy
in CMT1. CMT2 may be autosomal dominant or recessive, and
there are numerous subtypes because of different genetic abnor-
malities, currently designated CMT2A through CMT2L. Elec-
trophysiologically, conduction slowing is less severe and may
even be absent. Distal sensory potentials are abnormal in about
half the cases.
SYNONYMS
HMSN I Hypertrophic form of CMT
HMSN II Neuronal form of CMT
HMSN III Infantile hypertrophic neuropathy
HMSN IV Phytanic acid storage disease
HSAN I Multiple
HSAN II Multiple
HSAN III Familial dysautonomia
Tomaculous neuropathy
Seitelbergers disease
Numerous types
Globoid cell leukodystrophy
Angiokeratoma corporis diffusum
Abetalipoproteinemia
Analphalipoproteinemia
2408 SECTION VIII PERIPHERAL NERVE
Hereditary neuropathy with liability to pressure palsies
(HNPP) is the genetic mirror image of CMT1A.37 In CMT1A,
the PMP-22 gene on chromosome 17 is duplicated (70% of cases)
or sustains a point mutation, whereas the same region shows large
deletions in HNPP. Clinically, patients with HNPP are initially
seen in the second or third decade with a mononeuropathy,
multiple mononeuropathy, or brachial plexopathy, often precipi-
tated by trivial trauma. Conduction studies may show a mild
underlying neuropathy, but the prominent abnormality is a focal
or multifocal picture of demyelinating lesions at common pres-
sure sites. Nerve biopsy shows characteristic focal hypermyelin-
ation involving many internodes that causes segments of thickened
myelin resembling links of sausage (tomaculi), hence its original
name of tomaculous neuropathy.
The rare HSANs are divided into three groups according to
the degree of involvement of electrophysiologic modalities and
the age at onset. All are primarily sensory axonopathies by EMG.
HSAN I is dominantly inherited and features small-fiber sensory
loss and painless foot ulcers, with onset in the second decade.
HSAN II develops in infancy and results in anesthesia and muti-
lation of the extremities. HSAN III (Riley-Day syndrome, famil-
ial dysautonomia) causes small-fiber sensory loss with prominent
autonomic dysfunction.
Toxic Neuropathies
Although an important consideration in the differential diagnosis
of generalized peripheral nerve disease, toxic neuropathies are
either rare conditions or fairly obvious, as in chemotherapy
patients. Potential toxins include heavy metals, environmental
toxins, and pharmaceutical agents. There are numerous potential
offenders, and this discussion must of necessity focus on only a
few agents.
Intoxication with several heavy metals may cause neuropathy,
but the agents of greatest practical importance are lead and
arsenic. There is a correlation between cumulative exposure to
lead and electrophysiologic abnormalities. Classically, lead pro-
duces a predominantly motor neuropathy with a predilection for
the radial nerve and is manifested as wristdrop. Demyelination is
impressive experimentally, but human lead neuropathy is an axo-
nopathy.7 The neuropathy of arsenic intoxication is usually a
sensory more than motor axonopathy, but in acute cases the
electrodiagnostic picture may resemble GBS.
Hexacarbon neuropathies are due to exposure to either n-
hexane or methyl butyl ketone (MBK); the neurotoxic effect from
both agents is primarily mediated by their common metabolite
2,5-hexanedione. Peripheral neuropathy may develop in workers
exposed to only a few parts per million of MBK.38 These agents
produce giant axonal swellings that contain accumulations of
neurofilaments resembling those in hereditary giant axonal neu-
ropathy. Exposure may occur occupationally or recreationally
(glue sniffing, huffers neuropathy). The neuropathy is primarily
a distal sensorimotor axonopathy with secondary demyelination,
and severity correlates with duration of exposure. Worsening
may continue after cessation of exposure (coasting), but the long-
term prognosis is good.
Chemotherapy-Related Neuropathies
The majority of toxic neuropathies are iatrogenic and related to
drugs used to treat a variety of conditions ranging from cancer
and acquired immunodeficiency syndrome to gout. Unfortu-
nately, the antimitotic effects of several important chemothera-
peutic agents are accompanied by incidental damage to the
peripheral nervous system. The taxoid class of agents, paclitaxel
and docetaxel, bind to tubulin and promote microtubule polym-
erization, which leads to the accumulation of bundles of disor-
dered microtubules that interrupt normal mitotic operations and
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
possibly interfere with axonal transport. In one study, docetaxel
produced a sensorimotor peripheral neuropathy in 11% of the
patients exposed.39 The vinca alkaloids, vincristine and vinblas-
tine, in contrast, induce microtubule disassembly, which impairs
neurotubule function and axonal transport. The neuropathy of
vincristine is a sensorimotor axonopathy with variable dysauto-
nomia. Cisplatin is a heavy metal complex that cross-links DNA
in a manner similar to alkylating agents. The neuropathies of
both cisplatin and paclitaxel/docetaxel are predominantly sensory
and dose dependent.39,40 The cisplatin neuropathy is primarily
large fiber with loss of proprioception and sensory ataxia. Che-
motherapy may unmask a previously unrecognized neuropathy.41
A long-standing quest to find agents that can at least partially
negate the neurotoxic side effects of chemotherapeutic agents has
been unproductive.
Other Drug-Related Neuropathies
Among the numerous medications that may cause neuropathy,
colchicine and pyridoxine merit particular mention because of
the prevalence of their use. Like some chemotherapeutic agents,
colchicine interferes with microtubule growth and impairs
microtubule-dependent functions; it may cause a generalized sen-
sorimotor axonopathy, frequently associated with a myopathy.
Pyridoxine, commonly used for such conditions as premenstrual
syndrome and carpal tunnel syndrome, has significant neurotoxic
potential, primarily involving dorsal root ganglion neurons. It is
also frequently prescribed, in potentially toxic doses, for the
empirical treatment of neuropathies that are seldom if ever due
to pyridoxine deficiency. Initial reports described a profound,
often permanent ataxic neuropathy with massive doses. Lower
doses, in the 100- to 200-mg/day range, taken over a long period
can also produce neuropathy. In one study, a high serum vitamin
B6 level was present in 172 women, 60% of whom had neurologi-
cal symptoms, which disappeared when B6 was withdrawn. The
mean dose of vitamin B6 in the 103 women with neurological
symptoms was 117 92mg, and the average duration of ingestion
was 2.9 1.9 years. The symptoms included paraesthesia, hyper-
esthesia, bone pain, muscle weakness, numbness, and fascicula-
tions. Intoxication from acute high-dose pyridoxine can leave a
severe residual sensory ataxia, but patients taking a lower dose of
vitamin B6 had complete recovery within 6 months of stopping
B6.42 Vitamin B6 tablets containing 500 to 1000mg are available
over the counter. The daily requirement is in the range of 2mg/
day. Physicians should be aware of the neurotoxic effects of pyri-
doxine before prescribing it for trivial conditions and in situations
in which it is extremely unlikely to have a true therapeutic benefit.
Most pharmaceuticals cause a chronic, generalized sensorimo-
tor axonopathy. Notable exceptions are the sensory neuropathy/
neuronopathy secondary to pyridoxine, cisplatin, and the taxoids
and the motor neuropathy of dapsone. Amiodarone, perhexiline,
and cytosine arabinoside may cause a myopathy in conjunction
with a neuropathy.7
Mononeuropathy Multiplex
A mononeuropathy affects only one peripheral or cranial nerve,
and the most common cause is trauma, most often resulting from
compression or entrapment. The term mononeuropathy multiplex,
or multiple mononeuropathy, refers to a condition that produces
two or more nontraumatic mononeuropathies. A patient with
more than one mononeuropathy at common entrapment sites
(e.g., bilateral carpal tunnel syndrome) probably has multiple
compression syndromes rather than mononeuropathy multiplex
in the true sense of the term. Occasionally, features suggesting
both generalized polyneuropathy and mononeuropathy multiplex
may be present simultaneously. Late in the course of mononeu-
ropathy multiplex, when many nerves have become involved, the
 C H A P T E R 233 Peripheral Neuropathies 2409

infarctions.43,44 In underdeveloped countries, leprosy is an impor-

TABLE 233-10 Some Causes of Mononeuropathy tant consideration. Some causes of mononeuropathy multiplex
Multiplex are listed in Table 233-10.
VASCULITIS
Churg-Strauss syndrome suggested readings
Polyarteritis nodosa Albers JW. Clinical neurophysiology of generalized polyneuropathy. J Clin Neuro-
Wegeners granulomatosis physiol. 1993;10:149-166.
Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-
Nonsystemic vasculitic neuropathy Barr syndrome. Ann Neurol. 1990;27(suppl):S21-S24.
Czaplinski A, Steck AJ. Immune mediated neuropathiesan update on therapeutic
CONNECTIVE TISSUE DISORDERS strategies. J Neurol. 2004;251:127-137.
Systemic lupus erythematosus Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome.
Acta Neurol. Scand. 1987;76:8-11.
Rheumatoid arthritis Donofrio PD, Albers JW. AAEM minimonograph #34: polyneuropathy: classifica-
Sjgrens syndrome tion by nerve conduction studies and electromyography. Muscle Nerve. 1990;
Cryoglobulinemia 13:889-903.
Filler AG, Maravilla KR, Tsuruda JS. MR neurography and muscle MR imaging
Hypereosinophilic syndrome for image diagnosis of disorders affecting the peripheral nerves and musculature.
Neurol Clin. 2004;22:643-682.
INFECTION Hawke SH, Davies L, Pamphlett R, et al. Vasculitic neuropathy. A clinical and
Leprosy pathological study. Brain. 1991;114:2175-2190.
Hock B, Schwarz M, Domke I, et al. Validity of carbohydrate-deficient transferrin
Human immunodeficiency virus, especially with cytomegalovirus (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular
infection erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in
patients with alcohol dependence and liver disorders of non-alcoholic and alco-
Lyme disease
holic origin. Addiction. 2005;100:1477-1486.
Malaria Hoffman-Snyder C, Smith BE, Ross MA, et al. Value of the oral glucose tolerance
Infective endocarditis test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol.
2006;63:1075-1079.
PARANEOPLASTIC Katz JS, Barohn RJ, Kojan S, et al. Axonal multifocal motor neuropathy without
conduction block or other features of demyelination. Neurology. 2002;58:
Lymphoma, angiotropic large cell 615-620.
Leukemia Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol. 2006;19:481-486.
Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial
Other
and acquired demyelinative neuropathies. Neurology. 1982;32:592-596.
Sarcoid LoMonaco M, Milone M, Batocchi AP, et al. Cisplatin neuropathy: clinical course
Burns and neurophysiological findings. J Neurol. 1992;239:199-204.
Miller RG, Gutmann L, Lewis RA, et al. Acquired versus familial demyelinative
Neurofibromatosis type 2 neuropathies in children. Muscle Nerve. 1985;8:205-210.
Focal perineuritis New PZ, Jackson CE, Rinaldi D, et al. Peripheral neuropathy secondary to
docetaxel (Taxotere). Neurology. 1996;46:108-111.
Olney RK. AAEM minimonograph #38: neuropathies in connective tissue disease.
Muscle Nerve. 1992;15:531-542.
Simmons Z, Blaivas M, Aguilera AJ, et al. Low diagnostic yield of sural nerve biopsy
pattern may begin to resemble a generalized polyneuropathy. in patients with peripheral neuropathy and primary amyloidosis. J Neurol Sci.
1993;120:60-63.
Subtle asymmetry on clinical or electrodiagnostic testing is an van den Berg-Vos RM, Franssen H, Wokke JH, et al. Multifocal motor neuropathy:
important clue to the possibility of such a confluent or summated long-term clinical and electrophysiological assessment of intravenous immuno-
mononeuropathy multiplex syndrome. Any generalized neuropa- globulin maintenance treatment. Brain. 2002;125:1875-1886.
thy may render nerves more susceptible to injury and produce Vandenberghe A, Latour P, Chauplannaz G, et al. Molecular diagnosis of Charcot-
Marie-Tooth 1A disease and hereditary neuropathy with liability to pressure
focal accentuation of the diffuse process as a result of vulnerable palsies by quantifying CMT1A-REP sequences: consequences of recombinations
nerve syndrome. For instance, a patient with a mild generalized at variant sites on chromosomes 17p11.2-12. Clin Chem. 1996;42:1021-1025.
neuropathy caused by diabetes may be initially evaluated for Weinberg DH. AAEM case report 4: Guillain-Barre syndrome. American Associa-
carpal tunnel syndrome, and the underlying polyneuropathy only tion of Electrodiagnostic Medicine. Muscle Nerve. 1999;22:271-281.
becomes apparent with electrodiagnostic testing of apparently
unaffected nerves.
Generally, the primary diagnostic concern in a patient with Full references can be found on Expert Consult @ www.expertconsult.com
mononeuropathy multiplex is vasculitis causing multiple nerve

Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.

references
1. Dyck JB, Thomas PK. Peripheral Neuropathy. Philadelphia: WB Saunders; 2005.
2. Wolf JK. Segmental Neurology: a Guide to the Examination and Interpretation of
Sensory and Motor Function. Baltimore: University Park Press; 1981.
3. Cornblath DR, Sumner AJ, Daube J, et al. Conduction block in clinical practice.
Muscle Nerve. 1991;14:869-871.
4. Miller RG, Gutmann L, Lewis RA, et al. Acquired versus familial demyelinative
neuropathies in children. Muscle Nerve. 1985;8:205-210.
5. Hock B, Schwarz M, Domke I, et al. Validity of carbohydrate-deficient transfer-
rin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular
erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in
patients with alcohol dependence and liver disorders of non-alcoholic and
alcoholic origin. Addiction. 2005;100:1477-1486.
6. Hoffman-Snyder C, Smith BE, Ross MA, et al. Value of the oral glucose toler-
ance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch
Neurol. 2006;63:1075-1079.
7. Donofrio PD, Albers JW. AAEM minimonograph #34: polyneuropathy: clas-
sification by nerve conduction studies and electromyography. Muscle Nerve.
1990;13:889-903.
8. Albers JW. Clinical neurophysiology of generalized polyneuropathy. J Clin
Neurophysiol. 1993;10:149-166.
9. Schaumburg HH, Berger AR, Thomas PK. Other systemically related disor-
ders. In: Schaumberg HH, Berger AR, Thomas PK, eds. Disorders of Peripheral
Nerves. 2nd ed. Philadelphia: FA Davis; 1992:151-163.
10. Anthony DC, Vogel FS. Peripheral nervous system. In: Damjanov I, Linder J,
eds. Andersons Pathology. 10th ed. St. Louis: CV Mosby; 1996:2799-2831.
11. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies
in patients with diabetes mellitus. Arch Neurol. 1995;52:1053-1061.
12. The effect of intensive diabetes therapy on the development and progression
of neuropathy. The Diabetes Control and Complications Trial Research
Group. Ann Intern Med. 1995;122:561-568.
13. Angus-Leppan H, Burke D. The function of large and small nerve fibers in
renal failure. Muscle Nerve. 1992;15:288-294.
14. Ropper AH. Accelerated neuropathy of renal failure. Arch Neurol.
1993;50:536-539.
15. Monforte R, Estruch R, Valls-Sole J, et al. Autonomic and peripheral neuropa-
thies in patients with chronic alcoholism. A dose-related toxic effect of alcohol.
Arch Neurol. 1995;52:45-51.
16. Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol. 2006;19:
481-486.
17. van der Meche FGA, van Doorn PA. Guillain-Barr syndrome and chronic
inflammatory demyelinating polyneuropathy: immune mechanisms and update
on current therapies. Ann Neurol. 1995;37:S14-S31.
18. Hafer-Macko C, Hsieh S-T, Li CY, et al. Acute motor axonal neuropathy: an
antibody-mediated attack on axolemma. Ann Neurol. 1996;40:635-644.
19. Czaplinski A, Steck AJ. Immune mediated neuropathiesan update on thera-
peutic strategies. J Neurol. 2004;251:127-137.
20. Finsterer J. Treatment of immune-mediated, dysimmune neuropathies. Acta
Neurol Scand. 2005;112:115-125.
21. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guil-
lain-Barr syndrome. Ann Neurol. 1990;27(suppl):S21-S24.
22. Meulstee J, van der Meche FG. Electrodiagnostic criteria for polyneuropathy
and demyelination: application in 135 patients with Guillain-Barr syndrome.
Downloaded from ClinicalKey.com at Homerton University Hospital NHS Foundation Trust -JC July 27, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
C H A P T E R 233 Peripheral Neuropathies 2409.e1
Dutch Guillain-Barr Study Group. J Neurol Neurosurg Psychiatry. 1995;
59:482-486.
23. Weinberg DH. AAEM case report 4: Guillain-Barr syndrome. American Asso-
ciation of Electrodiagnostic Medicine. Muscle Nerve. 1999;22:271-281.
24. Filler AG, Maravilla KR, Tsuruda JS. MR neurography and muscle MR
imaging for image diagnosis of disorders affecting the peripheral nerves and
musculature. Neurol Clin. 2004;22:643-682.
25. Manganelli F, Pisciotta C, Iodice R, et al. Nine-year case history of monofocal
motor neuropathy. Muscle Nerve. 2008;38:927-929.
26. van den Berg-Vos RM, Franssen H, Wokke JH, et al. Multifocal motor neu-
ropathy: long-term clinical and electrophysiological assessment of intravenous
immunoglobulin maintenance treatment. Brain. 2002;125:1875-1886.
27. Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerad-
ing as motor neuron disease. Muscle Nerve. 1988;11:103-107.
28. Lewis RA, Sumner AJ, Brown MJ, et al. Multifocal demyelinating neuropathy
with persistent conduction block. Neurology. 1982;32:958-964.
29. Katz JS, Barohn RJ, Kojan S, et al. Axonal multifocal motor neuropathy without
conduction block or other features of demyelination. Neurology. 2002;58:
615-620.
30. Simmons Z, Blaivas M, Aguilera AJ, et al. Low diagnostic yield of sural nerve
biopsy in patients with peripheral neuropathy and primary amyloidosis. J Neurol
Sci. 1993;120:60-63.
31. de Freitas MR. Infectious neuropathy. Curr Opin Neurol. 2007;20:548-552.
32. Logigian EL, Steere AC. Clinical and electrophysiologic findings in chronic
neuropathy of Lyme disease. Neurology. 1992;42:303-311.
33. Hund EF, Fogel W, Krieger D, et al. Critical illness polyneuropathy: clinical
findings and outcomes of a frequent cause of neuromuscular weaning failure.
Crit Care Med. 1996;24:1328-1333.
34. Said G. Vasculitic neuropathy. Baillieres Clin Neurol. 1995;4:489-503.
35. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic
familial and acquired demyelinative neuropathies. Neurology. 1982;32:
592-596.
36. Ionasescu VV. Charcot-Marie-Tooth neuropathies: from clinical description to
molecular genetics. Muscle Nerve. 1995;18:267-275.
37. Vandenberghe A, Latour P, Chauplannaz G, et al. Molecular diagnosis of
Charcot-Marie-Tooth 1A disease and hereditary neuropathy with liability to
pressure palsies by quantifying CMT1A-REP sequences: consequences of
recombinations at variant sites on chromosomes 17p11.2-12. Clin Chem.
1996;42:1021-1025.
38. Bos PM, de Mik G, Bragt PC. Critical review of the toxicity of methyl n-butyl
ketone: risk from occupational exposure. Am J Ind Med. 1991;20:175-194.
39. New PZ, Jackson CE, Rinaldi D, et al. Peripheral neuropathy secondary to
docetaxel (Taxotere). Neurology. 1996;46:108-111.
40. LoMonaco M, Milone M, Batocchi AP, et al. Cisplatin neuropathy: clinical
course and neurophysiological findings. J Neurol. 1992;239:199-204.
41. Graf WD, Chance PF, Lensch MW, et al. Severe vincristine neuropathy in
Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77:1356-1362.
42. Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syn-
drome. Acta Neurol Scand. 1987;76:8-11.
43. Hawke SH, Davies L, Pamphlett R, et al. Vasculitic neuropathy. A clinical and
pathological study. Brain. 1991;114:2175-2190.
44. Olney RK. AAEM minimonograph #38: neuropathies in connective tissue
disease. Muscle Nerve. 1992;15:531-542.