Neuropatias Axonales Cronicas Evaluacion 2008+ PDF

The Evaluation of Chronic Axonal
Polyneuropathies
Michelle L. Mauermann, M.D.,1 and Ted M. Burns, M.D.2
ABSTRACT
In this article, we present an easy-to-remember method of evaluating neuropathies. Our proposed method is based on asking four questions about the neuropathy and
the patient: What?, Where?, When?, and What setting? Answering these questions
helps characterize the neuropathy, and this characterization enables the clinician to develop
a focused differential diagnosis and plan. After presenting this approach to evaluating
neuropathy, we discuss many of the most common chronic axonal neuropathies in the
context of this paradigm. Acquired demyelinating neuropathies and inherited neuropathies
are discussed in other articles in this issue of Seminars in Neurology.
KEYWORDS: Peripheral neuropathy, polyneuropathy, axonal neuropathies
eripheral neuropathy has an estimated prevalence of 2 to 3% in the general population and a

prevalence as high as 8% in people older than 55 years.1,2
Evaluation for the cause is important because diagnosis
of an underlying etiology may allow treatment that
prevents progression to disability and poor quality of
life.3 However, the evaluating physician is faced with the
knowledge that there are more than 100 potential
etiologies of polyneuropathy, yet approximately one
third of cases will remain idiopathic despite appropriate
testing.1,3,4 This can contribute to uncertainty about the
level of aggressiveness and the direction of the evaluation. This sometimes leads to a one size fits all strategy,
a strategy that is unfocused, inefficient, and costly, and
that sometimes places the patient at unnecessary risk of a
procedure-related complication (e.g., nerve biopsy, lumbar puncture).
The fundamental steps for evaluating patients
with neuropathy are: (1) collection of clinical data
(history of present illness, detailed family history, examination, etc), (2) determination of what data are relevant
and what are not (to do this well requires, among other
things, an understanding of risk factors for neuropathy),
(3) characterization of the neuropathy, and (4) execution

of a focused workup based on that characterization.5
Step 3, the characterization of the neuropathy, is a
critical, yet often overlooked step that when performed
allows the clinician to engage in an appropriately focused
evaluation. We present our easy-to-remember method
for characterizing neuropathy, based on answering four
clinical questions about the neuropathy and the patient:
What?, Where?, When?, and What setting?
(Fig. 1).5 The usefulness of this characterization is
illustrated throughout this article. Electrodiagnostic
testing can be helpful in providing additional insight
into the characterization of the neuropathy.
@mayo.edu).
Neuromuscular Disorders; Guest Editor, Ted M. Burns, M.D.
Semin Neurol 2008;28:133151. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1062270. ISSN 0271-8235.
Department of Neurology, Mayo Clinic, Rochester, Minnesota;

Department of Neurology, University of Virginia, Charlottesville,
Virginia.
Address for correspondence and reprint requests: Michelle L.
Mauermann, M.D., Department of Neurology, Mayo Clinic, 200 First
Street SW, Rochester, MN 55902 (e-mail: mauermann.michelle
2
WHAT?
The question What? refers to which nerve fiber modalities (motor, sensory, autonomic, or a combination) are
involved. At a minimum, the identification of sensory
nerve involvement allows the clinician to exclude other
neuromuscular diseases not associated with sensory dysfunction, such as myopathies, neuromuscular transmission disorders or disease of the anterior horn cell (e.g.,
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2008
Figure 1 A suggested construct for the approach to neuropathy, using the what, where, when, and what setting approach
to characterize the neuropathy and place the it into a presumed etiologic category. PNSS, positive neuropathic sensory
symptoms; CMT, Charcot-Marie-Tooth; HMSN, hereditary motor and sensory neuropathies; GBS, Guillain-Barre syndrome;
HNPP, hereditary neuropathy with liability to pressure palsies; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; HSN, hereditary sensory neuropathy; MMN, multifocal motor neuropathy.
amyotrophic lateral sclerosis). When sensory symptoms

and signs are present, the characterization of neuropathic
sensory symptoms as being positive or negative acts as
a diagnostic watershed (Fig. 1) because acquired neuropathies are usually accompanied by positive neuropathic
sensory symptoms and inherited neuropathies are usually
not accompanied by positive neuropathic sensory symptoms (although patients with inherited neuropathies display signs of sensory nerve involvement with negative
neuropathic sensory symptoms, such as sensory loss and
sensory ataxia).6 For example, in one cohort of more
than 60 patients with autosomal dominant inherited
Charcot-Marie-Tooth (CMT) disease 1A, only two subjects complained of positive neuropathic sensory symptoms.7 In contrast, 90% of patients with Guillain-Barre
syndrome (GBS), chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP), and alcoholic neuropathy note positive neuropathic sensory symptoms.811 Positive neuropathic sensory symptoms may be painful
(electric shock, burning, freezing, tightness and throbbing) or painless (tingling, swelling, and bunched-up
socks). Patients may also complain of discomfort or
pain to sensory stimuli that are normally not painful
(allodynia) or may report increased sensitivity to painful

stimuli (hyperalgesia). Most patients with neuropathy
have some degree of motor nerve involvement (on
examination or based on electrodiagnostic testing)
that is often overshadowed by their sensory complaints,
although motor nerve or fiber symptoms are infrequently the sole complaint. If the abnormalities are a
combination of motor and sensory involvement, it is
sometimes helpful for the clinician to rank them in
order of symptom predominance (e.g., inflammatory
demyelinating neuropathies often manifest with weakness overshadowing sensory nerve fiber disturbance).
Establishment of autonomic nerve involvement can be
an important clue because the number of processes
that affect both autonomic and somatic nerves is relatively few (Table 1).1,4,12 Autonomic symptoms include
lightheadedness, syncope, diarrhea, constipation, postprandial bloating, early satiety, urinary complaints,
erectile dysfunction, abnormal or absent sweating, and
dry mouth and eyes. Gastrointestinal dysmotility
manifesting as constipation or postprandial bloating is
a particularly common accompaniment of paraneoplastic
neuropathy.1315 Autonomic nervous system involve-
EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
Table 1 Polyneuropathies with Autonomic Nervous

System Involvement155
Acquired Causes
Diabetes mellitus
Amyloidosis
Guillain-Barre syndrome
Pandysautonomia (idiopathic or autoimmune)
Paraneoplastic neuropathy
Sjogrens syndromeassociated neuropathy
Porphyria
Vincristine induced
HIV-related neuropathy
Inherited
Hereditary sensory and autonomic neuropathies (HSAN)
From Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18:718.
ment is also early and prominent in primary systemic

amyloidosis and GBS.1622 When the complaints do not
clearly implicate pathology in the autonomic nervous
system, autonomic testing may sometimes be helpful,
and when performed should be targeted for the functional domain that may be impaired.
WHERE?
Where? refers to the distribution of nerve involvement
in terms of (1) the global distribution throughout the
body and (2) the distribution of involvement along the
nerve(s). It is especially critical to determine whether a
neuropathic process is length-dependent (i.e., distal) or
not (Fig. 1). Length-dependent neuropathies manifest
first in the feet and are symmetrical. Nonlength-dependent neuropathies are not necessarily first evident in
the feet. Whether a neuropathy is symmetrical or not is
another diagnostic watershed (Fig. 1). Symmetrical neuropathies are usually metabolic, toxic, idiopathic, or
inherited, whereas asymmetrical neuropathies are often
immune-mediated or infectious. Some examples of non
length-dependent neuropathies are polyradiculopathies
(e.g., Lyme neuroborreliosis, cytomegalovirus [CMV]
polyradiculitis, sarcoid polyradiculopathy), polyradiculoneuropathies (e.g., GBS, CIDP, diabetic and nondiabetic
radiculoplexus neuropathy), dorsal root polyganglionopathies (e.g., paraneoplastic subacute sensory neuronopathy, immune-mediated sensory ganglionopathy),
plexopathies (often immune-mediated), and mononeuritis multiplex (usually caused by vasculitis). There are, of
course, exceptions, such as the clinical presentation of
recurrent, painless, transient mononeuropathies in hereditary neuropathy (with liability to pressure) palsy
(HNPP)23 and the asymmetrical or unilateral brachial
plexopathy of hereditary neuralgic amyotrophy (which,
although being inherited, likely has an immune-mediated
component in its pathogenesis).24
WHEN?
When? refers to the temporal evolution of the neuropathy. Because of confusion over what is meant by acute,
subacute and chronic, we prefer to describe symptom
onset based on whether the neuropathic symptoms had a
compelling, definite date of onset. Most immune-mediated or infectious (Lyme neuroborreliosis) neuropathies
have a definite date of onset. A less-exact date of onset
suggests a toxic/metabolic, inherited, or idiopathic etiology (Fig. 1). The tempo following symptom onset is also
an important consideration. Symptom onset and tempo
often correlate in a predictable manner, owing in large
part to the underlying mechanism. For example, patients
with GBS present with a definite date of onset followed
by rapid progression of impairment and disability. The
symptom onset date of an inherited neuropathy, however,
usually can only be grossly estimated, and the progression
following symptom onset is almost always gradual.
WHAT SETTING?
What setting? refers to the process of elaborating the
unique clinical circumstance of the patient. This is done
by determining what in the patients past medical history, medication list, social history, family history, and
the review of systems may be germane. An understanding of the significance of these clinical factors requires
knowledge of the risk factors of neuropathy and knowledge of the clinical features of the diseases that are risk
factors for neuropathy. When constructing the patients
clinical setting, the clinician must remember to consider
first the common causes of neuropathy (e.g., diabetes,
alcohol abuse, genetic causes) and search aggressively for
any clinical clues that might suggest these etiologies.
This is perhaps most important when evaluating a
patient for an inherited neuropathy, given that one third
to one half of all neuropathies are likely inherited. At a
minimum, the clinician should ask specifically about
each first-degree relative: Please tell me about your
siblings, and did any sibling have complaints similar to
yours?; Did either parent or any sibling have a problem
with his or her feet or with walking?; Do any of your
siblings or parents have high arches or curled toes? The
patient should be queried also about cousins, aunts, and
uncles. Family members should be examined whenever
possible. By asking specific questions about family and
examining relatives whenever possible, clues are often
uncovered that would have otherwise never been mentioned by the patient, in part because family members
often have alternative explanations for the symptoms
(age, arthritis, etc.). For example, in one of our patients,
a delay in diagnosis of inherited neuropathy occurred
because the mother was queried about symptoms of
neuropathy but not examined at the sons initial visit;
it was only at follow-up that the mother was examined
and subsequently diagnosed with neuropathy, prompting
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further investigation and identification of a specific

inherited neuropathy.25
Second in importance to a detailed family history
in defining the clinical setting may be obtaining a
detailed history of alcohol intake, particularly if the
physician encounters vague responses to questioning
about alcohol intake. In many instances it is illuminating
to probe more into an alcohol consumption history, but
this must be done in a manner that the patient finds to be
nonjudgmental and nonthreatening.
Past medical and medication histories are obviously also very important considerations for elaborating
the patients unique clinical setting. Diabetes mellitus
(DM), end-stage renal disease, vitamin deficiency, HIV,
and paraproteinemia are just some of the disorders that
are risk factors for development of neuropathy. Toxic
neuropathy caused by medication is uncommon other
than in the setting of certain chemotherapeutic or antiHIV treatment exposures (Table 2), but it is still more
common than industrial and environmental neuropathies. Age is another important consideration: young
patients are much more likely to have a genetic-based
neuropathy, elderly patients are much more likely to
have an idiopathic neuropathy, and middle-age patients
are more likely to have acquired neuropathies.
Table 2 Some Medications That May Cause
Neuropathy156
Anti-infectious medications
Chloroquine
Dapsone
Isoniazid
Metronidazole
Nitrofurantoin
Dideoxycytidine and other nucleoside analogs
Chemotherapy and anticancer medications
Cisplatinum
Taxanes (paclitaxel and docetaxel)
Suramin
Thalidomide
Vincristine
Antirheumatic and immunosuppressant medications
Once the physician has achieved familiarity with

the patients unique clinical setting, he or she must
consider whether the rest of the neuropathy characterizations (the what, where, and when?) fit with the
clinical setting, and also must consider other possible
etiologies before implicating a disease or other risk factor
as the cause of the neuropathy. For example, the comorbidity of DM in a patient with neuropathy does not
prove diabetes is causative, as it is posited that 2% of type
1 diabetics and 6% of type 2 diabetics have causes other
than diabetes for their neuropathy.26
While this algorithm (Fig. 1) works for the vast
majority of neuropathy presentations there are exceptions. Some notable exceptions are: distal symmetric
presentation of neuropathies associated with systemic
lupus erythematosus, Sjogrens syndrome and paraproteinemia, positive neuropathic sensory symptoms in familial amyloid neuropathy and CMT with MPZ mutations
and the acute onset of multiple mononeuropathies in
hereditary neuropathy with liability to pressure palsies.
ELECTRODIAGNOSTIC TESTING
The fifth step for characterizing a neuropathy uses
electrodiagnostic testing. Electrodiagnostic testing can
confirm (or rarely refute) the clinical characterization in
terms of what and where, as well as provide another view
of the temporal evolution (when). Electrodiagnostic testing can also characterize the neuropathy as being primarily axonal or demyelinating. The metabolic, toxic, and
idiopathic neuropathies usually manifest with prominent
axonal injury, whereas immune-mediated and inherited
neuropathies may be either predominantly axonal or predominantly demyelinating. For example, GBS and CIDP
are two relatively common immune-mediated neuropathies that are predominantly demyelinating.8,2730
CMT1, the most common inherited sensorimotor neuropathy, is predominantly demyelinating, whereas CMT2
is predominantly axonal.31 Electrodiagnostic testing can
also assess for subclinical involvement and provide baseline
parameters in case future electrodiagnostic testing is
necessary to monitor the patients course.
Chloroquine
Colchicine
Cardiovascular medications
Amiodarone
ETIOLOGIES OF CHRONIC AXONAL

NEUROPATHY
Hydralazine
Perhexiline
Metabolic Etiologies
Propafenone
Psychiatric and sedative medications
Disulfiram
Other medications
Pyridoxine (vitamin B6)
Phenytoin
From Lewis RA. Toxic and deficiency neuropathies. Continuum.
Lifelong Learning in Neurology 2003;9:160181.
CLINICAL PRESENTATION (MOST COMMON)
What? Sensory or sensorimotor; positive neuropathic sensory symptoms.

Where? Distal, symmetrical (i.e., length
dependent).
When? Usually gradual onset but may vary.
Patients may be able to report the month or season of
onset, but it is unusual for a patient to report a more

definite date of onset. Progression is gradual over
months to years.
What setting? No family history of neuropathy,
no foot deformities, onset in adulthood; consider comorbidities (e.g., prior medical history of diabetes) or
risk factors for development of them (e.g., family history
of diabetes).
Diabetes Mellitus
dL ( 11.1 mmol/L) during an oral glucose tolerance

test (OGTT) on two occasions on different days is
necessary to diagnose DM. HgA1c helps to demonstrate
glycemic control over the previous 3 months but should
not be used for diagnosis. Hence, there is little reason for
a neurologist to be checking HbA1c levels unless he or
she is also managing a patients DM. In DPN, the most
common electrodiagnostic test abnormality is reduced
lower extremity sensory nerve action potential amplitudes
(SNAPs). Motor responses can be normal, but often
show mild abnormalities. A purely small-fiber neuropathy will have normal electrodiagnostic test results.37,38
ASSOCIATION WITH NEUROPATHY
Diabetes mellitus is common and it commonly causes

neuropathy. The prevalence of diagnosed DM is 5% for
U.S. adults older than 20 years of age and 20% for U.S.
adults older than 60 years.32,33 Neuropathy affects 50%
of insulin-receiving diabetics, making it the most common cause of neuropathy in developed Western countries.12 Unlike most etiologies of neuropathy, there are
many different diabetic neuropathies with distinct manifestations, including distal sensory or sensorimotor
polyneuropathy (most common) and diabetic radiculoplexus neuropathy.34
Diabetic Polyneuropathy Diabetic polyneuropathy
(DPN) symptoms are often predated by silent dysfunction of the nerves with few symptoms,35 but with
progression, positive neuropathic sensory symptoms
and signs predominate with pain, tingling, or burning.
A definite date of onset is atypical and the course is
slowly progressive, symmetrical, and length dependent
(almost exclusively involving distal lower extremities).
The frequency of DPN increases with duration of
diabetes and hyperglycemia.12 The neuropathy coexists
with other noninflammatory microvascular disease such
as retinopathy and nephropathy. In fact, if retinopathy
and nephropathy are absent, other etiologies of neuropathy warrant more consideration. The development of
24-hour microalbuminuria is a significant risk factor for
worsening of nerve function due to diabetes.35
Diabetic Radiculoplexus Neuropathy Diabetes mellitus appears to be a risk factor for the development of
lumbosacral radiculoplexus neuropathy. Lumbosacral
radiculoplexus neuropathy and diabetic lumbosacral
radiculoplexus neuropathy are vasculitic neuropathies,
however, and best classified as immune-mediated
radiculoplexus neuropathies rather than metabolic
neuropathies. Diabetic lumbosacral radiculoplexus
neuropathy appears to affect 1% of type 2 diabetics.36
This will be discussed further in the Immune-Mediated
section.
Fasting plasma glucose 126 mg/dL
( 7.0 mmol/L) or 2-hour postload glucose 200 mg/
IMPAIRED GLUCOSE METABOLISM AND NEUROPATHY
The 2003 American Diabetic Association (ADA) guidelines defined impaired fasting glucose (IFG) as a plasma
glucose level greater than > 100 and < 126 mg/dL and
impaired glucose tolerance (IGT) as a 2-hour glucose
level between 140 and 199 mg/dL after a 75-g oral
glucose load. Both IFG and IGT are indicative of
impaired glucose metabolism. Impaired glucose metabolism is associated with macrovascular disease such as
myocardial infarction, stroke, and peripheral vascular
disease as well as microvascular disease such as retinopathy and nephropathy.39 In addition, impaired glucose
metabolism has recently been suggested as a cause of
chronic idiopathic axonal polyneuropathy (CIAP). Some
feel that it might be representative of an earlier form of
diabetic sensory or sensorimotor neuropathy associated
with prolonged hyperglycemia.
The association between impaired glucose metabolism and neuropathy has been suggested by several
retrospective studies.4043 These studies showed an increased incidence of DM and impaired glucose metabolism with CIAP, and this was most commonly
associated with a painful sensory predominant neuropathy.40,41,43,44 Some have suggested the neuropathy of
impaired glucose metabolism more often involves predominantly small fibers compared with the neuropathy
associated with diabetes and chronic hyperglycemia,
which more commonly involves both small and large
fibers.39,42 However, others have shown associations
with either a sensory (small or large) or sensorimotor
(small and large) neuropathy.43 The reported limitations
of these studies include inclusion of preselected patients
with certain types of neuropathies, referral bias, insufficient exclusion of other causes of neuropathy, and use of
previously published control populations, of which the
reported incidence of impaired glucose metabolism may
not be accurate or representative of the cohort with
disease.45 Sumner and colleagues reported that the
neuropathy associated with impaired glucose metabolism may be an earlier, less severe form of diabetic
neuropathy, based on the demonstration of comparatively mild abnormality with respect to intraepidermal
nerve fiber density, sural nerve amplitude, sural nerve
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velocity, peroneal nerve velocity, and electromyographic

change.42 There was also a trend toward a shorter
duration of symptoms.
In apparent conflict with these retrospective reports is one prospective trial by Hughes and colleagues46
that compared 50 patients with CIAP with 50 control
individuals. The study found 32% of patients and 14% of
controls had impaired glucose tolerance or fasting hyperglycemia. However, when these results were adjusted for
age and gender, the difference was not significant for
either the entire cohort or the painful symptoms subgroup. These authors instead found a significant association with hypertriglyceridemia. These conflicting
results suggest further studies may be needed before
concluding an association.
In evaluation of impaired glucose metabolism,
many authors suggest that the 2-hour OGTT is a more
sensitive measure of abnormal glucose metabolism compared with fasting plasma glucose or HgA1c.41,43,44
Based on the current information, most authors suggest
checking OGTT in all patients with distal axonal sensory
or sensorimotor neuropathy.42 Small studies have demonstrated reduced distal epidermal nerve fiber density in
patients with impaired glucose tolerance, which is less
severe but similar to that found in diabetes.47 Further
studies in large numbers of patients are needed to see if
skin biopsy may be helpful in evaluating these patients.
Uremia
Uremia is the accumulation in the blood of constituents

normally eliminated in the urine that produces toxicity
and occurs in severe kidney disease. Uremic neuropathy
occurs in 10 to 83% of patients with chronic renal failure
who are on dialysis, although today it is less common due
to renal transplant.4852
NEUROPATHY
The neuropathy in uremia is distally predominant, symmetrical, and slowly progressive. Symptoms include negative neuropathic sensory symptoms and positive
neuropathic sensory symptoms such as paresthesias and
burning feet.50,51 Restless legs, cramps, and weakness are
also common. Both small and large-fiber sensory loss and
motor involvement occur.50,51 Other systemic disorders
associated with renal failure must be alternatively considered as causing the neuropathy, such as DM, amyloidosis, or vasculitis.51 Drug-induced neuropathy also
needs to be considered in this population of patients.
The diagnosis should be strongly considered in
patients with end-stage renal failure with a creatinine of
5 mg/dL or higher or creatinine clearance of less than 12
mL/min.50,51 Electrodiagnostic testing may demonstrate
slightly prolonged distal motor latencies, slowed con-
duction velocities, and low or absent compound muscle

action potential (CMAP) and SNAP amplitudes.50
Thiamine Deficiency
Thiamine (vitamin B1) deficiency is seen most commonly in chronic alcohol abuse, recurrent vomiting, total
parenteral nutrition, and following weight reduction
surgery (bariatric surgery).53 Deficiency also can occur
in individuals with chronic gastrointestinal problems or
those who are elderly, on cancer treatment, or those who
are receiving diuretic therapy. Severe deficiency causes
congestive heart failure (wet beriberi), peripheral neuropathy (e.g., dry beriberi), Wernickes encephalopathy,
and Korsakoffs syndrome. Symptoms and signs of mild
to moderate thiamine deficiency are nonspecific. Moderate deficiency can affect intellectual performance and
well-being in the absence of other clinical symptoms.
Thiamine-deficiency neuropathy should be considered
in patients who abuse alcohol or have had bariatric
surgery (e.g., for morbid obesity). Extreme weight loss
following bariatric surgery places patients at risk of
malnutrition, including thiamine deficiency, particularly
if follow-up with a nutritionist is suboptimal. In a large
series of patients who underwent weight reduction
bariatric surgery, 6% developed neuropathy, and in
some of these cases it appeared that nutritional deficiency, including thiamine deficiency, was pathogenic.54
Patients with thiamine deficiency may complain of
fatigue, irritability, and muscle cramps that develop
within days to weeks of nutritional deficiency.53
NEUROPATHY
Neuropathy associated with thiamine deficiency may

present suddenly or gradually with distal, symmetrical,
sensory, or sensorimotor neuropathy with positive neuropathic sensory symptoms.54 In contrast to alcoholic
neuropathy, thiamine-deficient patients have more
large-fiber (weakness, impairment of deep and superficial sensation, less pain) than small-fiber impairment.11
Evaluation for thiamine deficiency should include
measurement of whole blood thiamine. Testing of serum
or plasma thiamine levels has low sensitivity and specificity, in part because only a small fraction of blood
thiamine is contained in serum or plasma. Thiamine
diphosphate, the active form of thiamine, is most appropriately measured to assess thiamine status. Thiamine
diphosphate in circulating blood is present in erythrocytes, but is undetectable in the plasma and serum of
normal controls. High-performance liquid chromatography (HPLC) analysis of thiamine diphosphate in
whole blood or erythrocytes is the most sensitive, specific, and precise method for determining the nutritional
status of thiamine and is a reliable indicator of total body
stores.55 Transketolase (TK) assay, once considered the

preferred test to determine thiamine status, is now
considered inferior because of low sensitivity and specificity. Electrodiagnostic testing shows reduction in
CMAP and SNAP amplitudes with predominant
large-fiber loss.11
Hypothyroid
Hypothyroidism is common with an incidence of 3.5

cases per 1000 women per year and of 0.6 cases per 1000
men per year.56 In one study of newly diagnosed
patients, 42% had clinical symptoms and signs of distal,
symmetrical, sensory-predominant neuropathy with decreased ankle reflexes; however, only 17% were confirmed by electrodiagnostic testing.57 Hypothyroidism
should be considered in patients with fatigue, weakness,
weight gain, cold intolerance, coarse dry hair and skin,
constipation, depression, and abnormal menstrual cycles.
NEUROPATHY
Symptoms of hypothyroid neuropathy include positive

neuropathic sensory symptoms, mainly paresthesias and
pain, and negative neuropathic sensory symptoms.
Weakness is a common complaint but it is less often
evident on examination. Neuropathy caused by hypothyroidism should be considered in a patient with
symptoms of hypothyroidism (see previous paragraph).
Screening of hypothyroidism should begin with
measurement of thyrotropin (thyroid-stimulating hormone [TSH]), followed by a free thyroxine (T4) level if
the thyrotropin level is elevated. Electrodiagnostic evaluation in hypothyroidism shows evidence for both axonal and demyelinating features.57,58
Cobalamin Deficiency
Cobalamin (vitamin B12) deficiency occurs in up to 15%

of people older than 60 years.59 Pernicious anemia is the
most common cause of cobalamin deficiency, with other
causes including dietary avoidance (vegetarians), gastrectomy, gastric bypass surgery, and nitrous oxide abuse. In
a cohort of patients undergoing evaluation for neuropathy, cobalamin deficiency was found in 8%.60
taneously in the hands and feet, is not uncommon in

cobalamin-deficient neuropathy / myelopathy. Also,
symptom onset may be sudden with a definite date.
Thus, cobalamin-deficiency neuropathy often presents
differently than do other metabolic neuropathies. Pain is
also less likely to occur.60 Myelopathy is frequent in
cobalamin-deficiency, sometimes serving as a clue to
diagnosis, and it may be difficult to determine whether
the sensory symptoms are caused by myelopathy or
neuropathy.
Workup of cobalamin deficiency should include a
serum B12 level. It has been suggested with cobalamin
levels in the low-normal range (but less than 300 pg/mL),
that testing of serum homocysteine and methylmalonic
acid will demonstrate cobalamin deficiency in 5 to 10%;
and in 0.1 to 1% of those with a serum cobalamin level
of greater than 300 pg/mL.60 In cobalamin-deficient
states, homocysteine and/or methylmalonic acid levels
will be elevated. Patients are more likely to have
elevated mean corpuscular volume (MCV), but the
incidence of anemia is probably not higher.60 Electrodiagnostic testing may demonstrate axonal involvement.
Somatosensory-evoked potentials and radiological investigation may be helpful in demonstrating evidence of
coexisting myelopathy.
TOXIC ETIOLOGIES
What? Sensory or sensorimotor; positive neuropathic sensory symptoms including pain. Autonomic
nerve involvement not uncommon.
Where? Distal, symmetrical (i.e., length dependent), or symmetrical but not distal if toxin causes a
sensory neuronopathy (dorsal root polyganglionopathy).
When? Varies, depending on toxin and dose.
Patients with alcoholic neuropathy may be able to report
a month or season of onset but typically not an exact date
of onset. Patients with other toxic neuropathies may
report a definite date of onset if exposure was acute and
taken at a high dose. Progression varies based on toxin
and dose, and usually stabilizes or improves with cessation. Consider comorbidities (e.g., alcoholism) and
therapies of comorbidities.
no foot deformities, onset in adulthood following exposure; consider comorbidities and treatments (e.g.,
chemotherapy) and other risk factors (e.g., accidental
exposures). Systemic symptoms (e.g., weight loss, gastrointestinal) are common.
NEUROPATHY
Although many patients have distal numbness and

paresthesias, similar to other metabolic neuropathies, a
large percentage of patients actually present in a non
length-dependent distribution, perhaps owing in part to
concurrent development of myelopathy. For example,
onset of sensory symptoms, first in the hands or simul-
Pharmaceutical, Industrial, and Environmental

Toxins
Several pharmaceutical agents, industrial and environmental agents, and substances of abuse may cause
neuropathy, most commonly in the form of a
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length-dependent, sensory, predominant axonal neuropathy.61 However, except for neuropathy caused by
alcohol, toxic neuropathies are probably overinvestigated and overdiagnosed3; in fact, they probably represent well below 5% of cases of chronic distal,
symmetrical, sensory, or sensorimotor neuropathies.62
Nonetheless, prompt identification of a toxic neuropathy is important because removal of any harmful
agent may lead to improvement or resolution of neuropathy. The list of potentially offending agents that we
provide in Table 2 is long and includes many common
medications and agents that the population is frequently
exposed to in low doses. The relative risk estimate of the
drug causing neuropathy must be considered in the
context of the overall prevalence of neuropathy in
the general population, the likelihood the neuropathy
has an alternative cause, temporal association of drug
and neuropathy, the degree of impairment, disability
and impaired quality of life, and the salutary effects of
the drug. It is our experience that more often than not
the commonly prescribed drugs are not the cause of a
neuropathy. The most frequent offenders are some of
the chemotherapeutic agents and some of the anti-HIV
drugs. When a drug or toxin is suspected, the exposure
must be verified, the symptoms must be temporally
related to the toxin, and other causes must be ruled
out. Furthermore, some clinical improvement or at least
stabilization should occur following removal of the
offending agent, although this may take months to years
to occur.63 Medication-induced neuropathy is more
common than industrial and environmental neuropathies. The neuropathy of heavy metal intoxication is
very rare and is usually accompanied by a combination of
gastrointestinal, hematologic, and central nervous systems problems. Although heavy metal analysis is routinely obtained for evaluation of neuropathy, it is rarely
ever useful unless there is a strong suspicion for heavy
metal exposure and the neuropathy is acute or subacute.1
Chemicals that can, although rarely, cause neuropathy
at toxic doses include acrylamide, carbamates, carbon
disulfide, ethylene glycol, organophosphates, and hexacarbons.64
Alcohol Abuse
The prevalence of alcohol abuse and dependence is

estimated to be as high as 10 to 20% of the primary
care population.65,66 The prevalence of neuropathy in
alcoholics is uncertain, although one study of hospitalized patients admitting to daily alcohol intake of more
than 100 g for men and 80 g for women (10 oz. of beer,
1 oz of liquor, and 3 to 4 oz of wine each have 10 g of
alcohol) for 2 years or more (mean of 238 120 g for a
period of 22.7 10.2 years) demonstrated that one third
of patients had electrophysiological evidence of polyneuropathy and one fourth had autonomic neuropathy.67
The direct toxic effect of alcohol on peripheral nerves
seems to be the most important etiology.68 Other
investigators prospectively identified neuropathy in
58% of alcoholics, which correlated with the age of the
patient and the duration of alcohol use.68
NEUROPATHY
Alcoholic neuropathy is distal, symmetrical, sensory

predominant, and slowly progressive. There are positive
neuropathic sensory symptoms of pain and/or burning
and loss of superficial sensation, particularly nociception,
on examination.10,11,67 In one study, the neuropathy was
pure sensory (47%) or sensory-predominant sensorimotor (53%).11
With respect to laboratory features, in one series,
47% of alcohol-dependent patients with neuropathy had
macrocytosis compared with 7% of alcohol-dependent
patients without neuropathy.68 Patients often had normal
vitamin B12 levels with absence of clinical or other
laboratory features of malnutrition. Also a higher incidence of liver dysfunction (81% versus 61%) and elevated
blood sugars (28% versus 5%) occurred in patients with
neuropathy than in those without neuropathy.68 Frequently, alcoholic neuropathy coexists with thiaminedeficient neuropathy. It is important to assess thiamine
status in all alcoholics with neuropathy and replace thiamine if patients are found to be thiamine deficient.11
The electrodiagnostic examination demonstrates sensory
or sensorimotor axonal involvement, and nerve biopsy
reveals small, rather than large, myelinated fiber loss with
axonal degeneration, demyelination, and remyelination.11
INFECTIOUS ETIOLOGIES
What? Sensory or sensorimotor; positive neuropathic sensory symptoms, especially pain.
Where? Depends on the infection. HIV neuropathy often presents with a distal, symmetrical distribution, but others (e.g., Lyme, hepatitis C virus [HCV],
sarcoidosis, leprosy, sporotrichosis69) usually do not.
Lyme and sarcoidosis often present with painful, asymmetrical polyradiculoneuropathy. HCV associated with
mixed cryoglobulinemia and sporotrichosis may present
with mononeuritis multiplex, asymmetrical distal-predominant neuropathy or even a distal, symmetrical
polyneuropathy.
When? Definite date of onset is typical, particularly for Lyme and sarcoidosis.
no foot deformities, onset in adulthood following exposure; consider risk factors (e.g., HIV risk factors, tick
bite, previous transfusions, residence in endemic areas,
environmental risks). Systemic symptoms (e.g., weight
loss, rash, fatigue, fevers) are common.
Hepatitis C Virus
Hepatitis C virus is the most common chronic bloodborne viral infection in the United States. The third
National Health and Nutrition Examination Survey
(NHANES) found that 1.8% of Americans have been
infected with HCV, and most are chronically infected.70
Neuropathy in HCV may affect 10% of patients,71,72
and the prevalence increases to up to 30% in those
positive for mixed (type II or type III) cryoglobulins.73
The mechanism of nerve injury may be virus-triggered
nerve microvasculitis rather than direct viral nerve infection with in situ replication.71 The exact pathophysiological role of cryoglobulins in HCV neuropathy is
unclear. Some investigators have posited that intravascular deposits of cryoglobulins lead to interference of the
vasa nervorum microcirculation.73 The finding that not
all HCV patients with neuropathy have detectable serum
cryoglobulins raises the question of whether there are
other mechanisms for nerve injury.72
NEUROPATHY
In HCV neuropathy, positive neuropathic sensory symptoms such as burning, prickling, and pain are prominent.74 The neuropathy in HCV with mixed
cryoglobulinemia may present as a distal, asymmetrical
(or less commonly symmetrical), sensory, or sensorimotor polyneuropathy71,73 or as mononeuritis multiplex.71
Patients with HCV neuropathy and mixed cryoglobulinemia may be otherwise asymptomatic or report
accompanying symptoms such as fatigue, loss of appetite,
nausea, weight loss, fever, weakness, and arthralgias.71,75
Palpable purpura on the ankles, for example, is common
and should be looked for on examination.76
The primary serologic screening assay for HCV
infection is an enzyme immunoassay that is able to
detect antibodies within 4 to 10 weeks after infection,
missing only 0.5 to 1% of cases. Recombinant immunoblot assays are used to confirm the serologic
assay. HCV RNA tests are used to confirm viremia.70
Cryoglobulins are single (type I) or mixed (types II
and III) immunoglobulins (Igs) that precipitate as the
serum is cooled below core body temperature.77 Blood
should be collected in a syringe prewarmed to 378C.78
It should be allowed to clot for 30 minutes and
then be centrifuged at 378C. The plasma and serum
are separated and both incubated for 24 hours at 18C.
The samples are assessed at 24 hours and 7 days
for precipitate78 because type I and type II cryoglobulins usually precipitate quickly, whereas type III cryoglobulins can take up to 7 days. The precipitates are then
characterized and typed using immunofixation. The electrodiagnostic study will demonstrate an axonal, sensorimotor neuropathy that is often asymmetrical71 or
involves multiple nerves as a mononeuritis multiplex.
Pathological findings include multifocal fiber loss with

perivascular epineurial inflammation, sometimes suggestive of nerve microvasculitis.71
Lyme Disease
INFECTION AND ASSOCIATION WITH NEUROPATHY
Lyme disease is caused by Borrelia burgdorferi infection

transmitted by the Ixodes tick. Lyme disease occurs in
certain geographic locations (e.g., Northeast and Upper
Midwest in the United States) but not in others. It is
helpful for the evaluating physician to be familiar with
the endemic areas (available online at multiple Web
sites; search, for example, for Lyme endemic areas).
Lyme infection is much more common during spring
through fall. In 2005, 23,000 cases of Lyme disease
were reported in the United States.79 The infection
requires prolonged exposure to the tick (24 to 48 hours),
which allows proliferation of the spirochete and dissemination into the host. In 80% of infected individuals, Lyme disease manifests first with erythema
migrans, a painless and nonpruritic skin lesion that
evolves over days to weeks.80 Patients typically have
flulike symptoms and may have infection of large joints,
heart, meninges, or peripheral nerve. Nervous system
involvement occurs in 10 to 40% of patients with Lyme
disease.81
NEUROPATHY
Approximately 15% of patients develop neurological

complications days to weeks following untreated infection.80 The most typical neuropathic manifestation is
painful polyradiculoneuropathy and lymphocytic meningitis, accompanied by cranial neuropathy in 30 to 50% of
patients.81 The polyradiculopathy or polyradiculoneuropathy is typically sensorimotor, painful, asymmetrical,
and nonlength dependent due to involvement of nerve
roots. Rarely, patients present with what looks like
mononeuritis multiplex.82 Electrodiagnostic testing confirms a polyradiculopathy or polyradiculoneuropathy and
reveals primarily axonal damage.83 Approximately 5% of
untreated patients develop a chronic axonal neuropathy,
occurring a median of 16 months after the initial infection,80,81 with symptoms of relatively symmetrical,
distal paresthesias. The chronic axonal neuropathy may
occur in the setting of encephalopathy or encephalomyelitis.81
Serum IgM for B. burgdorferi infection has a
sensitivity of 32% in acute disease, and IgG has a
sensitivity of 83% in established disease.84 Serologies
may be negative early in the course and should be
repeated if the clinical suspicion is high. Positive serologies should be confirmed by Western blot. Spinal
fluid analysis in acute disease typically shows modest
lymphocytic pleocytosis and mild increase in protein
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2008
concentration.84 Cerebrospinal fluid (CSF) Lyme polymerase chain reaction (PCR) has 40 to 50% sensitivity
and 97% specificity.81
ment or enhancement of affected nerves.93 Electrodiagnostic testing usually reveals an asymmetrical, multifocal
axonal process.93,95
Sarcoidosis
Human Immunodeficiency Virus
Sarcoidosis is a multisystem granulomatous disease. The

causative agent or agents for sarcoidosis are not yet
known, but an infectious etiology is probable. The
diagnosis of sarcoidosis usually requires the presence of
typical clinical and radiological findings, histological
evidence of a noncaseating epithelioid-cell granuloma,
and exclusion of other disorders known to cause granulomatous disease.85 Sarcoidosis affecting the central or
peripheral nervous system (neurosarcoidosis) occurs in
only 5 percent of cases of sarcoidosis.8688 Manifestations of neurosarcoidosis include cranial nerve palsies,
meningeal involvement, central nervous system involvement, myopathy, and peripheral neuropathy. Cases affecting the spinal roots or peripheral nerves are even less
frequent, representing only 1% of total sarcoidosis
cases.8992
Approximately one million people in the United States

were infected with HIV at the end of 2003, and one
quarter of them were unaware of the infection.96
Symptomatic neuropathies occur in 10 to 15% of
HIV-1 infected patients, and the incidence increases
as the CD4 count declines and the immunodeficiency
worsens.97
NEUROPATHY
The neuropathy of sarcoidosis affects sensory and

motor nerve fibers and is almost always accompanied
by positive neuropathic sensory symptoms, especially
pain, which is usually prominent.93 The distribution is
usually asymmetrical and often not length-dependent;
it frequently involves nerve roots. The most common
presentations are polyradiculoneuropathies followed
by polyneuropathy.93 Less common patterns are multiple mononeuropathies, polyradiculopathy, and radiculoplexus neuropathy. A small-fiber neuropathy has
also been reported to commonly occur in sarcoidosis.94 Pain can be a disabling symptom requiring
narcotics. Onset is typically abrupt with a definite
date of onset.92,93 Accompanying cranial neuropathies
and/or thoracic radiculopathies are seen in approximately one third of patients.93 Neuropathy often
occurs in the setting of fatigue, malaise, fever, and
unexplained weight loss in many patients.93 At the
time of the diagnosis of neuropathy, arthralgias, skin,
and eye involvement are also commonly encountered.93
Chest imaging should be performed in all suspected cases, as a suggestive abnormality, such as hilar
adenopathy, is found in the majority of cases of sarcoidosis.93 Serum angiotensin-converting enzyme (ACE) is
elevated in approximately one fourth of patients with
peripheral nerve sarcoidosis. CSF protein concentration
is usually elevated and one third of patients demonstrate
CSF pleocytosis.93,95 Magnetic resonance imaging
(MRI) is sometimes helpful by demonstrating enlarge-
NEUROPATHY
Distal, symmetrical, sensory polyneuropathy, the most

common HIV neuropathy presentation, is present in
35 to 44% of patients with AIDS (e.g., CD4 counts
< 200).97 Distal, symmetrical, sensory polyneuropathy
presents with distal pain, paresthesias, and numbness in a
symmetrical, length-dependent manner. It involves sensory or sensorimotor nerve fibers and is gradually progressive. Thus, HIV neuropathy, in contrast to the other
infectious neuropathies, manifests like a metabolic or
toxic neuropathy. In fact, it is clinically similar to the
toxic neuropathies caused by HIV antiretroviral agents
ddC, ddI, and d4T.98
Polyradiculopathy is a much less common presentation for neuropathy in an HIV-infected patient.
Acute polyradiculopathy (GBS presentation) can occur,
rarely, at the time of seroconversion (CD4 counts
500). Polyradiculopathy can also be seen in moderately
advanced HIV (CD4 counts 200 to 500) as a CIDP. In
both cases, CSF examination typically demonstrates
lymphocytosis of 10 to 50 cells/mm3.99 Co-infection
with other viruses, such as HCV, CMV, and human
T-cell leukemia virus I (HTLV-1), may occur.97,99
Mononeuritis multiplex is another infrequent
presentation of neuropathy that can occur as a complication of HIV (0.1 to 3% of patients). Mononeuritis
multiplex can occur at seroconversion or late stages.97,100
At seroconversion, the neuropathy is self-limited and
either immune or vasculitic in nature.97
In advanced HIV (CD4 counts < 50), coinfection with CMV can cause painful mononeuritis
multiplex, polyradiculoneuropathy, or polyradiculopathy.97,99,101 CSF demonstrates polymorphonuclear
pleocytosis in only 15%, but CMV PCR in CSF is
positive in 90% of cases.99
Diffuse infiltrative lymphocytosis syndrome
(CD4 counts < 260)99 is a rare cause of neuropathy in
HIV. It presents subacutely with a painful, distal, symmetrical or asymmetrical, sensory, or sensorimotor polyneuropathy. The syndrome resembles Sjogrens
syndrome (SS) with CD8 hyperlymphocytosis of salivary

glands, lungs, kidneys, gut, and peripheral nerves.99,102
Electrodiagnostic testing demonstrates axonal damage.
Screening for HIV for patients who present with
a distal, symmetrical polyneuropathy should depend in
part on the patients risk factors and the prevalence of
HIV in the patients community.103 Rapid HIV testing
has a sensitivity of 99 to 100% and specificity of 99 to
100%, depending on the test.104
Leprosy
Leprosy remains the most important infectious neuropathy worldwide with 3 million active cases.105 It is
very prevalent in Southeast Asia, India, Africa, and
Central and South America. Leprosy is transmitted
through nasal droplets and then spreads by hematogenous dissemination to skin and nerves with an incubation period of up to many years.106,107
NEUROPATHY
The three cardinal findings of leprosy neuropathies are

anesthetic skin lesions, enlarged peripheral nerves, and
acid-fast bacilli in skin smears or biopsy. The bacilli favor
the cooler areas of the body such as the chin, malar areas of
the face, earlobes, buttocks, knees, and distal extremities,
so sensory testing should be performed on these regions in
suspected cases. The initial symptoms are decreased
thermal sense, followed by loss of pain and pressure
sensations.106 In contrast to most other infectious neuropathies, the neuropathy is painless. There are two main
types: tuberculoid and lepromatous. Tuberculoid leprosy
presents with an asymmetrical, sensory polyneuropathy
with injury confined to nerves adjacent to hypopigmented
skin lesions. Lepromatous leprosy presents as a more
symmetrical, distal neuropathy due to more widespread
involvement of the skin and nerves. Sensory involvement
precedes motor involvement.107 Approximately 10% of
patients may present without skin lesions, often presenting as a mononeuritis multiplex.107
The most widely used serological test is an
antibody to phenolic glycolipid-1 (PGL-1), but it
has a low sensitivity.107 Definitive diagnosis is made
by nerve biopsy with strikingly different findings in the
two forms. Tuberculoid leprosy shows significant destruction of nerve architecture with granulomas extending from the perineurium into the endoneurium.
Bacilli are usually not abundant.107 Lepromatous leprosy shows splitting of the perineurium by edema and
foamy cells, infiltration of the endoneurium and perineurium by foamy cells, and Fite stain showing bacilli
in macrophages and Schwann cells.107 Electrodiagnostic testing demonstrates axonal loss and demyelination.108
IMMUNE-MEDIATED
What? Sensory or sensorimotor; positive neuropathic sensory symptoms, especially pain.
Where? Usually not length dependent. GBS and
CIDP typically present as a polyradiculoneuropathy.
Many other immune-mediated neuropathies present
with an asymmetrical distribution.
When? Definite date of onset is common.
no foot deformities, onset in adulthood; patients may
have symptoms suggestive of more widespread autoimmunity (e.g., sicca complex) or may have a diagnosis
of an autoimmune disease (e.g., Sjogrens or rheumatoid
arthritis). Systemic symptoms (e.g., weight loss, rash,
fatigue, fevers) are common. Many autoimmune diseases
affect women more than men.
Vasculitis
From a clinical standpoint, vasculitis of nerve should be

viewed as being either systemic or nonsystemic. The
systemic vasculitides are commonly divided into primary systemic vasculitis, for which there is no known
cause, and secondary systemic vasculitis, in which case a
virus, drug, or connective tissue disease is responsible
for vessel wall inflammation. The vasculitides are further classified by the kind and size of blood vessels
involved, organ involvement, disease associations,
underlying mechanisms, and, sometimes, autoantibody
profiles.109111 The primary systemic vasculitides most
likely to cause vasculitic neuropathy include polyarteritis nodosa, Wegeners granulomatosis, Churg-Strauss
syndrome, and microscopic polyangiitis.112114 Of
these, microscopic polyangiitis may be the one that
most commonly causes vasculitic neuropathy.111,114
Secondary causes of systemic vasculitis involving peripheral nerves include connective tissue diseases such
as rheumatoid arthritis, systemic lupus erythematosus
(SLE), and SS. Rheumatoid arthritis (RA), for example, may evolve into rheumatoid vasculitis in 5 to 10%
of RA patients, and half of these patients will develop
neuropathy secondary to vasculitis.115 Mixed type II
cryoglobulinemic vasculitis associated with HCV infection is another example of a secondary vasculitis.
Sarcoidosis affecting nerve may also cause angiitis.110,111 Vasculitis that appears confined to the nerve
and muscle has classically been termed nonsystemic
vasculitic neuropathy.116,117 An important distinction
between systemic vasculitic neuropathy and nonsystemic vasculitic neuropathy is that nonsystemic vasculitic
neuropathy is usually not fatal, whereas untreated
systemic vasculitic neuropathy is often fatal. Approximately 10% of cases that initially appear to be nonsystemic vasculitic neuropathy ultimately become
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systemic vasculitis, so early on it may be difficult to

distinguish nonsystemic vasculitic neuropathy from
systemic vasculitic neuropathy.117,118 Many autoimmune, monophasic, or relapsing plexopathiesor,
more accurately, radiculoplexus neuropathiesare
also likely nerve microvasculitides. These include
diabetic lumbosacral radiculoplexus neuropathy (also
known as diabetic amyotrophy, proximal diabetic
neuropathy, and other names), nondiabetic lumbosacral radiculoplexus neuropathy, and immune and inherited brachial plexus neuropathies (also called
neuralgic amyotrophy and hereditary neuralgic amyotrophy).111
NEUROPATHY
Mononeuritis multiplex, the most common presentation of vasculitic neuropathy, is acute to subacute in
presentation and almost always painful. It can begin
in the upper or lower extremities, typically at watershed zones such as the sciatic nerve at the mid-thigh
and nerves in the mid-upper arm.119 Vasculitis less
commonly presents as a painful asymmetrical or
distal, symmetrical, sensorimotor polyneuropathy.110,111 Systemic vasculitis almost always occurs
in patients in the setting of constitutional symptoms
such as weight loss, respiratory symptoms, hematuria,
abdominal pain, rash, myalgias, arthralgias, fever, and
night sweats.110
Laboratory evaluation of suspected cases of vasculitic neuropathy should include a complete blood
count (CBC), metabolic panel (electrolytes, blood
urea nitrogen, creatinine, and glucose), erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP),
antinuclear antibody (ANA), rheumatoid factor (RF),
proteinase 3 (PR3)/cytoplasmic (c)-staining antineutrophilic cytoplasmic autoantibody (ANCA) and myeloperoxidase (MPO)/perinuclear (p)-staining ANCA,
hepatitis B and C panels, and cryoglobulins. Serum
complement determinations are indicated in suspected
mixed cryoglobulinemia or systemic lupus syndromes.
It is also often appropriate to check extractable nuclear
antigen, serum ACE level, serum protein electrophoresis, and HIV. CSF analysis is usually not helpful,
except to aid in the investigation of mimickers, including infectious (e.g., Lyme) or other inflammatory etiologies (e.g., carcinomatous root involvement).111 In
systemic vasculitic neuropathy, serological testing is
abnormal and helps further define the etiology or
syndrome. In nonsystemic vasculitic neuropathy, the
ESR or CRP may be slightly elevated, but other
markers of inflammation or systemic disease are normal.111 Electrodiagnostic testing often demonstrates
acute to subacute sensory and motor axonal injury in a
patchy multifocal pattern. Sensory nerve biopsy (sural
nerve or superficial peroneal nerve) should be performed to establish the diagnosis.120
Diabetic and Nondiabetic Lumbosacral

Radiculoplexus Neuropathies
Diabetic and nondiabetic lumbosacral radiculoplexus
neuropathies are microvasculitides that affect arterioles,
capillaries, and venules. Diabetic lumbosacral radiculoplexus neuropathy occurs more frequently in type II
diabetics with good glycemic control and without
other diabetic complications such as retinopathy or
nephropathy. Coincident weight loss (usually more
than 10 pounds) often occurs.121 The neuropathy often
begins with acute or subacute pain followed by proximal
or distal weakness. The pain is described as sharp or
lancinating, deep aching, burning, or experiencing
contact allodynia. The disorder usually begins with asymmetrical and unilateral onset; however, the majority of
cases become bilateral within 3 months but remain asymmetrical.121 The illness is typically monophasic with
progression lasting weeks to months. Autonomic symptoms are present in approximately one half of patients.121
Cervical radiculoplexus neuropathies can occur in 10 to
15% of patients.121,122 Recovery is slow and incomplete
with patients describing persistent pain and weakness.
CSF examination typically shows a mildly elevated protein concentration.123 Electrodiagnostic testing
demonstrates an asymmetrical, axonal process affecting
the nerves, plexus, and roots, often with more widespread findings than seen on clinical examination.123
Nerve biopsy demonstrates evidence of ischemia with
focal or multifocal fiber loss, focal perineurial degeneration, neovascularization, and injury neuroma. There is
often epineurial perivascular inflammation involving
vessel walls suggestive of microvasculitis.123
Sjogrens Syndrome
Sjogrens syndrome is a systemic autoimmune disease

that primarily affects middle-age women.124 The diagnosis of SS is best established by using criteria proposed
by the Diagnostic Committee of Health and Welfare of
Japan and by the American-European community.125,126
Criteria for diagnosis include sicca symptoms (i.e., dry
eyes and dry mouth), objective evidence of keratoconjunctivitis, evidence of chronic lymphocytic sialoadenitis,
and the presence of either anti-SS-A or anti-SS-B
antibodies. Rash, arthralgias, and Raynauds symptoms
are common.127,128 Neuropathy is reported to occur in
10 to 30% of patients with SS.129,130
NEUROPATHY
Considerable confusion and disagreement exist about

the classification SS-associated immune-mediated neuropathies, in part because different case series use different clinical criteria for study inclusion. Furthermore,
presence of sicca complex does not always imply
glandular inflammation (e.g., parotid), as sometimes

dry eyes and mouth may be a manifestation of concurrent autonomic ganglionopathy (e.g., inflammation
damaging the otic ganglion) or a side effect of a
medication rather than of glandular inflammation. It
has recently been proposed that these neuropathies
instead be classified as immune-sensory and autonomic
neuropathies with or without sicca.131
The neuropathy of SS is secondary to vasculitis in
some cases and secondary to mononuclear cell infiltration without vasculitis (e.g., ganglionitis) in other cases.
There also may be other mechanisms of neuropathy; for
example, the etiology of the small-fiber neuropathy seen
in some cases of SS may be different. Several patterns of
neuropathy are seen in association with SS: sensory
ataxic neuropathy, painful sensory neuropathy without
ataxia, multiple mononeuropathies, multiple cranial
neuropathies, trigeminal sensory neuropathy, autonomic
neuropathy with anhidrosis, and radiculoneuropathy.128
Abnormal pupils and orthostatic hypotension are common accompaniments to many of these neuropathies.
Sensory ataxic neuropathy typically presents with asymmetrical paresthesias and ataxia, and gradually becomes
more widespread.124,132 Painful sensory neuropathy
without ataxia may present insidiously with asymmetrical, painful positive neuropathic sensory symptoms that
gradually progress in a length-dependent manner.128,133
Laboratory testing of suspected cases should include ESR, ANA, anti-SS-A and anti-SS-B antibodies,
and RF testing. ANA titer is elevated (> 1:160) in one
third to one half of patients in some series (e.g., elevated
in 8 of 19 lip biopsy-positive patients compared with 5 of
19 lip biopsy-negative patients.)127 Anti-SS-A or antiSS-B antibodies have also been reported to be present in
approximately one third to one half of SS patients with
neuropathy.124 In another study, antiSS-A or SS-B
antibodies were detected in 30% of lip biopsy-positive
patients and in only 6% of lip biopsy-negative patients.127 For all SS patients (with or without neuropathy), antibodies to SS-B (seen in 50 to 70% of patients
with SS) are more sensitive than anti-SS-A antibodies.124 Evidence of salivary gland dysfunction can
be obtained by measuring salivary flow rates or by
imaging salivary glands with radiographic contrast
agents or technetium scanning. Biopsy of the minor
salivary glands provides a means of assessing the extent
and nature of infiltration by lymphocytes and plasma
cells, and glandular destruction.124 The Schirmer test
can assess for lacrimal gland dysfunction. The specific
electrodiagnostic test findings depend on the form of
neuropathy. For example, sensory ataxic neuropathy
demonstrates features of axonal sensory neuropathy
and/or ganglionopathy with absent or low amplitude
SNAPs.128 In these patients, MRI may show T2weighted hyperintensity in the posterior columns.128
Nerve biopsy may demonstrate loss of large myelinated
fibers with increased axonal degeneration.128 The electrodiagnostic test results for patients with painful
sensory neuropathy without ataxia is in keeping with
a predominantly small-fiber neuropathy (e.g., normal
results).128
Systemic Lupus Erythematosus

The incidence of SLE is 124 cases per 100,000 people

and affects women much more than men.134 It is more
prevalent among Asians, African Americans, and Native
Americans in the United States. SLE is associated with
variable combinations of fever, rash, alopecia, arthritis,
pleuritis, pericarditis, nephritis, anemia, leukopenia,
thrombocytopenia, and nervous system disease. Neuropathy is reported in 5 to 27% of patients with SLE.135
NEUROPATHY
As is the case with the neuropathies associated with SS,

several types of neuropathies are associated with SLE.
Most often neuropathy in SLE is a mild, modestly
progressive, length-dependent, sensory, or sensorimotor
neuropathy. Sensory symptoms include distal tingling,
numbness, and dysesthesias. Less commonly, patients
have a pure small-fiber sensory neuropathy.136 In less
than 5% of patients with SLE and neuropathy, the
pattern is a mononeuritis multiplex, likely secondary to
vasculitis.137
In patients with neuropathy possibly secondary to
SLE, laboratory testing should include ANA and anti
double-stranded (ds)DNA testing. In SLE, ANA sensitivity is 99% and specificity is 80%; anti-dsDNA has a
sensitivity of 70% and specificity of 95%; and anti-Smith
(Sm) has 25% sensitivity and 99% specificity.134
PARAPROTEINEMIAS
What? Sensorimotor; often with positive neuropathic sensory symptoms.
Where? Variable, but often length dependent.
When? May be gradual onset.
no foot deformities, onset in adulthood; patients may
have systemic symptoms (e.g., weight loss, fatigue) if
paraproteinemia is malignant.
Monoclonal Gammopathy of Undetermined

Significance
Monoclonal gammopathy of undetermined significance
(MGUS) occurs in 5% of persons older than age
50 years.138 The criteria for MGUS have been defined
previously in the literature.139,140 The monoclonal M
protein can be of IgM, IgG, or IgA heavy chain. IgG is
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the most common class of paraprotein associated with

MGUS in the general population; however, IgM with a
kappa light chain is seen most frequently in patients with
neuropathy.141,142
When encountering a patient with a neuropathy associated with a paraprotein, such as MGUS, the clinician
must try to determine whether the neuropathy is idiopathic or due to another cause, and thus its association
with the paraprotein is simply a chance association, or
whether the neuropathy is secondary to the process
causing the paraprotein. Neuropathies associated with
paraproteinemias include distal acquired demyelinating
symmetrical with M-protein (DADS-M) neuropathy
(also known as a CIDP variant), neuropathy associated
with primary systemic amyloidosis, neuropathy of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), neuropathy
associated with Waldenstroms macroglobulinemia, neuropathy associated with multiple myeloma, and neuropathy associated with Castlemans syndrome. The
history and electrodiagnostic testing are particularly
helpful in sorting this out: accompanying systemic
symptoms raise concern for primary systemic amyloidosis, POEMS, or malignancy; autonomic symptoms and
signs are common in primary systemic amyloidosis;
electrodiagnostic testing features of primary demyelination are commonly seen in neuropathies of DADS-M,
POEMS, Waldenstroms macroglobulinemia and
Castlemans syndrome, whereas the neuropathy is
usually axonal when associated with primary systemic
amyloidosis. The demyelinating neuropathies associated with a paraprotein are not discussed further in this
article. Please refer to David Sapersteins article,
Chronic Acquired Demyelinating Polyneuropathies,
in this issue of Seminars of Neurology for an excellent
discussion of DADS-M and many other chronic
acquired demyelinating neuropathies.
Primary Systemic Amyloidosis

Primary systemic amyloidosis is a disorder characterized
by deposition of insoluble, monoclonal Ig light chain
fragments in various tissues.21 Ninety percent of cases
have an M protein in either the serum or the urine, and
most are IgG lambda or the light chain alone.141 Primary
systemic amyloidosis presents more commonly in men
after age 40 years. Patients usually present with prominent systemic symptoms such as fatigue, weight loss,
and edema.20 Often there is multiorgan involvement,
with the heart, liver, and kidney being most commonly
affected.21 The frequency of neuropathy is between 15
and 20%.21 The most common symptoms are paresthesias, muscle weakness, and numbness in the distal lower
extremities.21 Burning or painful paresthesias can be
present. Autonomic involvement occurs in the majority

of patients and can be extreme.
The workup for a monoclonal gammopathy
should begin with serum protein electrophoresis
(SPEP) with high-resolution agarose gel.143 Immunofixation should be performed when a sharp peak or
band is found to differentiate a monoclonal from
polyclonal increase in Igs, and for detecting a small
M-protein in the presence of normal background Igs.
If an M-protein or serum light chain is found, a
24-hour urine collection with electrophoresis and
immunofixation should be performed.143,144 In those
without detectable monoclonal proteins, bone marrow
examination usually detects a clonal population of
plasma cells.145 Mild anemia occurs in 50% of patients.21 Electrodiagnostic testing demonstrates a symmetrical, axonal sensorimotor neuropathy. Diagnosis
depends on the demonstration of amyloid deposits in
bone marrow aspirate (positive in 50% of patients),
abdominal fat aspirate (70%), rectal biopsy (80%), or
nerve biopsy (80%).146 Nerve pathological findings
show a marked decrease in myelinated fiber density
with axonal degeneration and endoneurial/epineurial
perivascular amyloid deposition.21
PARANEOPLASTIC SYNDROMES
What? Variable. May be sensory (e.g., sensory
neuronopathy), sensorimotor or, rarely, predominantly
motor. Concomitant autonomic neuropathy (e.g., gastrointestinal dysmotility) is common. Positive neuropathic sensory symptoms are typical.
Where? Usually not length dependent, often
asymmetrical.
When? Definite date of onset with rapid progression; usually leading to severe impairments.
no foot deformities, onset usually in adulthood; smoking
history; patients may have systemic symptoms (e.g.,
weight loss, fatigue).
Association with Neuropathy

Paraneoplastic syndromes are a rare complication of
malignancy. More than half of patients with a paraneoplastic syndrome present with neurologic symptoms.13,14,147,148 Paraneoplastic syndromes are found
more commonly in women in the sixth decade149 but
can occur at any age. Positive smoking history (with lung
cancer) is found in 97 to 99% of patients with antineuronal nuclear antigen-1 (ANNA-1 [anti-Hu] antibody) syndromes148; a smoking history is likely as
common in the other antibody syndromes. The cancer
is usually small-cell lung cancer (SCLC). As many of
these patients are found to have limited disease burden,
they often do not have systemic evidence of malignancy
such as weight loss, fever, or night sweats. Neuropathy

may be the most common presentation, especially in
those with ANNA-1 antibody.148 Other presentations
include cerebellar syndrome, limbic encephalitis, brainstem dysfunction, and dysautonomia.13,148,150 Most
often, the effect on the nervous system is multifocal.13
The neurological symptoms usually precede the tumor
detection.14,148
Neuropathy
The paraneoplastic neuropathy may present as a sensory
ganglionopathy or sensory-predominant neuropathy,
sometimes associated with autonomic neuropathy. Subacute onset with rapid progression is typical.13,148 Sensory symptoms such as paresthesias, dysesthesias, and
pain predominate, whereas motor involvement is typically mild and may only be found on electrodiagnostic
evaluation.14,147 There may be prominent upper extremity involvement and pseudoathetosis.13,14 Autonomic
involvement is found in up to one fourth of patients,
most commonly orthostatic hypotension and gastroparesis, although many other dysautonomic symptoms may
manifest.1315 Most patients develop severe disease with
significant disability.150
Laboratory evaluation should be directed toward
paraneoplastic antibodies, of which there are many.
These antibodies usually do not predict the neurological
syndrome but rather predict the malignancy, and the
coexistence of antibodies can also be used to predict the
underlying malignancy.151 The sensitivity and specificity
of the ANNA-1 antibody is thought to be 80% and
98%, respectively.15 The sensitivity and specificity of the
other antibodies have not yet been established. Electrodiagnostic testing often shows axonal sensory or sensorimotor neuropathy or sensory ganglionopathy.14 Any
workup should also include investigation for a malignancy.13,14,148,150 With a paraneoplastic syndrome associated with SCLC, the tumor is limited to the
mediastinum in 90% of patients.13,148 The workup
should begin with chest radiograph. If this is negative,
the clinician should proceed to computed tomography
(CT), MRI, or positron emission tomography (PET)
imaging.148,149,152,153 In the other antibody syndromes,
the workup should be directed toward the recognized
associated malignancies.
INHERITED NEUROPATHIES
What? Sensory or sensorimotor; often only negative neuropathic sensory symptoms (particularly so for
CMT1A, the most common inherited neuropathy).
Where? Distal, symmetrical (i.e., length dependent).
When? Insidious onset without definite date.
Very slowly progressive.
What setting? Family history of neuropathy, foot

deformities, onset at any age but often the first through
third decades. Absence of systemic symptoms or acquired risk factors for neuropathy. Note that a negative
family history does not preclude the possibility of a
neuropathy caused by a genetic mutation because
de novo mutations occur frequently and also because
incomplete penetrance of inherited mutations can occur;
thus, disease may not necessarily manifest in affected
relatives.
Charcot-Marie-Tooth and Other Inherited

Neuropathies
Neuropathy caused by a genetic mutation probably
represents about one third to one half of the neuropathies seen in neurology practice.6 CMT disease (a.k.a.
hereditary motor and sensory neuropathy [HMSN]) is a
genetically heterogeneous group of disorders with a
similar clinical phenotype that affects 1 in 2500 individuals.23 The mode of inheritance of CMT is usually
autosomal-dominant. Autosomal-dominant CMT can
roughly be divided into CMT1, the demyelinating form
of CMT, and CMT2, the axonal form of CMT.31
CMT, especially CMT1, the most common inherited
neuropathy, usually begins insidiously during the first or
second decade and progresses gradually. Patients typically have high arches or hammer toes, distal weakness
and atrophy (especially the peroneal muscles), and abnormalities of gait and difficulty running.31 Positive
neuropathic sensory symptoms, for example neuropathic
pain or paresthesias, are uncommon in inherited neuropathies, particularly CMT1A. For example, in one
cohort of 61 subjects with CMT1A, only 2 complained
of positive neuropathic sensory symptoms, yet sensory
loss was evident on examination in 43.7 There is a wide
variability in clinical expression, even within the same
kinship, which can make it difficult to assess the inheritance pattern. De novo mutations are also common.
Thus, a family history of CMT may be absent or not
evident in many patients with neuropathy caused by a
genetic mutation. CMT disease is classified both according to whether the primary pathology is demyelinating
or axonal and by the mode of inheritance. The inherited
neuropathies are further discussed in an excellent article
in this issue of Seminars in Neurology, titled, CharcotMarie-Tooth Neuropathies: Diagnosis and Management, by Agnes Jani-Acsadi, Karen Krajewski, and
Michael Shy.
Other less common inherited neuropathies include the hereditary sensory and autonomic neuropathies (HSAN), neuropathies associated with inborn
errors of metabolism, and mitochondrial neuropathies.
In the HSAN and mitochondrial neuropathies, onset
of neuropathy is almost always insidious with very
slow progression. Neuropathy is symmetrical and
147
148
2008
presents in a distal-predominant distribution. For

the neuropathies associated with inborn errors of
metabolism, onset of neuropathy may be more subacute.154
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The Evaluation of Chronic Axonal

eripheral neuropathy has an estimated prevalence of 2 to 3% in the general population and a

(3) characterization of the neuropathy, and (4) execution

Department of Neurology, Mayo Clinic, Rochester, Minnesota;

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

amyotrophic lateral sclerosis). When sensory symptoms

(allodynia) or may report increased sensitivity to painful

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

Table 1 Polyneuropathies with Autonomic Nervous

ment is also early and prominent in primary systemic

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

further investigation and identification of a specific

Once the physician has achieved familiarity with

ETIOLOGIES OF CHRONIC AXONAL

CLINICAL PRESENTATION (MOST COMMON)

What? Sensory or sensorimotor; positive neuropathic sensory symptoms.

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

onset, but it is unusual for a patient to report a more

dL ( 11.1 mmol/L) during an oral glucose tolerance

ASSOCIATION WITH NEUROPATHY

Diabetes mellitus is common and it commonly causes

IMPAIRED GLUCOSE METABOLISM AND NEUROPATHY

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

velocity, peroneal nerve velocity, and electromyographic

Uremia is the accumulation in the blood of constituents

duction velocities, and low or absent compound muscle

Neuropathy associated with thiamine deficiency may

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

stores.55 Transketolase (TK) assay, once considered the

Hypothyroidism is common with an incidence of 3.5

Symptoms of hypothyroid neuropathy include positive

Cobalamin (vitamin B12) deficiency occurs in up to 15%

taneously in the hands and feet, is not uncommon in

Although many patients have distal numbness and

Pharmaceutical, Industrial, and Environmental

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

The prevalence of alcohol abuse and dependence is

Alcoholic neuropathy is distal, symmetrical, sensory

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

Pathological findings include multifocal fiber loss with

Lyme disease is caused by Borrelia burgdorferi infection

Approximately 15% of patients develop neurological

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

Human Immunodeficiency Virus

ASSOCIATION WITH NEUROPATHY

ASSOCIATION WITH NEUROPATHY

Sarcoidosis is a multisystem granulomatous disease. The

Approximately one million people in the United States

The neuropathy of sarcoidosis affects sensory and

Distal, symmetrical, sensory polyneuropathy, the most

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

syndrome (SS) with CD8 hyperlymphocytosis of salivary

The three cardinal findings of leprosy neuropathies are

From a clinical standpoint, vasculitis of nerve should be

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

systemic vasculitis, so early on it may be difficult to

Diabetic and Nondiabetic Lumbosacral

Sjogrens syndrome is a systemic autoimmune disease

Considerable confusion and disagreement exist about

EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS

glandular inflammation (e.g., parotid), as sometimes

Systemic Lupus Erythematosus

The incidence of SLE is 124 cases per 100,000 people