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 neuro-

pathies. Our proposed method is based on asking four questions about the neuropathy and

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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

P eripheral neuropathy has an estimated preva-
lence 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 evalua-
tion. 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, lum-
bar puncture).
The fundamental steps for evaluating patients
with neuropathy are: (1) collection of clinical data
(history of present illness, detailed family history, exami-
nation, 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.
WHAT?
The question ‘‘What?’’ refers to which nerve fiber modal-
ities (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 dys-
function, such as myopathies, neuromuscular transmis-
sion disorders or disease of the anterior horn cell (e.g.,

1
Department of Neurology, Mayo Clinic, Rochester, Minnesota;
2
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
@mayo.edu).
Neuromuscular Disorders; Guest Editor, Ted M. Burns, M.D.
Semin Neurol 2008;28:133–151. 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.
133
134 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008

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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-Barré syndrome;
HNPP, hereditary neuropathy with liability to pressure palsies; CIDP, chronic inflammatory demyelinating polyradiculoneuro-
pathy; 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 neuro-
pathies are usually accompanied by positive neuropathic
sensory symptoms and inherited neuropathies are usually
not accompanied by positive neuropathic sensory symp-
toms (although patients with inherited neuropathies dis-
play 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 sub-
jects complained of positive neuropathic sensory symp-
toms.7 In contrast,
90% of patients with Guillain-Barré
syndrome (GBS), chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP), and alcoholic neuropa-
thy note positive neuropathic sensory symptoms.8–11 Pos-
itive neuropathic sensory symptoms may be painful
(electric shock, burning, freezing, tightness and throb-
bing) 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 infre-
quently 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 weak-
ness 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 relati-
vely few (Table 1).1,4,12 Autonomic symptoms include
lightheadedness, syncope, diarrhea, constipation, post-
prandial 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.13–15 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-Barré syndrome
Pandysautonomia (idiopathic or autoimmune)
Paraneoplastic neuropathy
Sjögren’s syndrome–associated neuropathy
Porphyria
Vincristine induced
HIV-related neuropathy
Inherited
Hereditary sensory and autonomic neuropathies (HSAN)
From Barohn RJ. Approach to peripheral neuropathy and neurono-
pathy. Semin Neurol 1998;18:7–18.
ment is also early and prominent in primary systemic
amyloidosis and GBS.16–22 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 func-
tional 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. Non–length-de-
pendent neuropathies are not necessarily first evident in
the feet. Whether a neuropathy is symmetrical or not is
another diagnostic watershed (Fig. 1). Symmetrical neu-
ropathies 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), polyradiculo-
neuropathies (e.g., GBS, CIDP, diabetic and nondiabetic
radiculoplexus neuropathy), dorsal root polygangliono-
pathies (e.g., paraneoplastic subacute sensory neuronop-
athy, immune-mediated sensory ganglionopathy),
plexopathies (often immune-mediated), and mononeur-
itis multiplex (usually caused by vasculitis). There are, of
course, exceptions, such as the clinical presentation of
recurrent, painless, transient mononeuropathies in he-
reditary 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
135
WHEN?
‘‘When?’’ refers to the temporal evolution of the neuro-
pathy. 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-medi-
ated or infectious (Lyme neuroborreliosis) neuropathies
have a definite date of onset. A less-exact date of onset
suggests a toxic/metabolic, inherited, or idiopathic etiol-
ogy (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
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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 patient’s past medical his-
tory, medication list, social history, family history, and
the review of systems may be germane. An understand-
ing of the significance of these clinical factors requires
knowledge of the risk factors of neuropathy and knowl-
edge of the clinical features of the diseases that are risk
factors for neuropathy. When constructing the patient’s
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 men-
tioned 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 son’s initial visit;
it was only at follow-up that the mother was examined
and subsequently diagnosed with neuropathy, prompting
136 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
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 obvi-
ously also very important considerations for elaborating
the patient’s 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 anti-
HIV treatment exposures (Table 2), but it is still more
common than industrial and environmental neuropa-
thies. 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
Chloroquine
Colchicine
Cardiovascular medications
Amiodarone
Hydralazine
Perhexiline
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;9:160–181.
Once the physician has achieved familiarity with
the patient’s unique clinical setting, he or she must
consider whether the rest of the neuropathy character-
izations (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 co-
morbidity 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 excep-
tions. Some notable exceptions are: distal symmetric
presentation of neuropathies associated with systemic
lupus erythematosus, Sjogren’s syndrome and parapro-
teinemia, positive neuropathic sensory symptoms in fam-
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ilial 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 test-
ing can also characterize the neuropathy as being primar-
ily 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 pre-
dominantly demyelinating. For example, GBS and CIDP
are two relatively common immune-mediated neuro-
pathies that are predominantly demyelinating.8,27–30
CMT1, the most common inherited sensorimotor neuro-
pathy, 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 patient’s course.
ETIOLOGIES OF CHRONIC AXONAL
NEUROPATHY
Metabolic Etiologies
CLINICAL PRESENTATION (MOST COMMON)
What? Sensory or sensorimotor; positive neuro-
pathic 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
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
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 co-
morbidities (e.g., prior medical history of diabetes) or
risk factors for development of them (e.g., family history
of diabetes).
Diabetes Mellitus
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 com-
mon cause of neuropathy in developed Western coun-
tries.12 Unlike most etiologies of neuropathy, there are
many different diabetic neuropathies with distinct man-
ifestations, including distal sensory or sensorimotor
polyneuropathy (most common) and diabetic radiculo-
plexus neuropathy.34
Diabetic Polyneuropathy Diabetic polyneuropathy
(DPN) symptoms are often predated by silent dysfunc-
tion 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 neuro-
pathy 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 mel-
litus 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/
137
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 patient’s 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 neuro-
pathy will have normal electrodiagnostic test results.37,38
IMPAIRED GLUCOSE METABOLISM AND NEUROPATHY
The 2003 American Diabetic Association (ADA) guide-
lines defined impaired fasting glucose (IFG) as a plasma
glucose level greater than > 100 and < 126 mg/dL and
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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 metab-
olism is associated with macrovascular disease such as
myocardial infarction, stroke, and peripheral vascular
disease as well as microvascular disease such as retinop-
athy 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 metab-
olism and neuropathy has been suggested by several
retrospective studies.40–43 These studies showed an in-
creased incidence of DM and impaired glucose metab-
olism with CIAP, and this was most commonly
associated with a painful sensory predominant neuro-
pathy.40,41,43,44 Some have suggested the neuropathy of
impaired glucose metabolism more often involves pre-
dominantly 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, insuffi-
cient 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 metabo-
lism may be an earlier, less severe form of diabetic
neuropathy, based on the demonstration of compara-
tively mild abnormality with respect to intraepidermal
nerve fiber density, sural nerve amplitude, sural nerve
138 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
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 re-
ports 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 hyper-
glycemia. However, when these results were adjusted for
age and gender, the difference was not significant for
either the entire cohort or the painful symptoms sub-
group. These authors instead found a significant associ-
ation 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 com-
pared 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 dem-
onstrated 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
ASSOCIATION WITH NEUROPATHY
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.48–52
NEUROPATHY
The neuropathy in uremia is distally predominant, sym-
metrical, and slowly progressive. Symptoms include neg-
ative 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 con-
sidered as causing the neuropathy, such as DM, amyloi-
dosis, 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
ASSOCIATION WITH NEUROPATHY
Thiamine (vitamin B1) deficiency is seen most com-
monly 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 neuro-
pathy (e.g., dry beriberi), Wernicke’s encephalopathy,
and Korsakoff’s syndrome. Symptoms and signs of mild
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to moderate thiamine deficiency are nonspecific. Mod-
erate 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 defi-
ciency, 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 neu-
ropathic sensory symptoms.54 In contrast to alcoholic
neuropathy, thiamine-deficient patients have more
large-fiber (weakness, impairment of deep and super-
ficial 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 specif-
icity, 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 ap-
propriately measured to assess thiamine status. Thiamine
diphosphate in circulating blood is present in erythro-
cytes, but is undetectable in the plasma and serum of
normal controls. High-performance liquid chromatog-
raphy (HPLC) analysis of thiamine diphosphate in
whole blood or erythrocytes is the most sensitive, spe-
cific, and precise method for determining the nutritional
status of thiamine and is a reliable indicator of total body
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
stores.55 Transketolase (TK) assay, once considered the
preferred test to determine thiamine status, is now
considered inferior because of low sensitivity and spe-
cificity. Electrodiagnostic testing shows reduction in
CMAP and SNAP amplitudes with predominant
large-fiber loss.11
Hypothyroid
ASSOCIATION WITH NEUROPATHY
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 de-
creased ankle reflexes; however, only 17% were con-
firmed 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 hypo-
thyroidism should be considered in a patient with
symptoms of hypothyroidism (see previous paragraph).
Screening of hypothyroidism should begin with
measurement of thyrotropin (thyroid-stimulating hor-
mone [TSH]), followed by a free thyroxine (T4) level if
the thyrotropin level is elevated. Electrodiagnostic eval-
uation in hypothyroidism shows evidence for both axo-
nal and demyelinating features.57,58
Cobalamin Deficiency
ASSOCIATION WITH NEUROPATHY
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), gastrec-
tomy, gastric bypass surgery, and nitrous oxide abuse. In
a cohort of patients undergoing evaluation for neuro-
pathy, cobalamin deficiency was found in 8%.60
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-
139
taneously in the hands and feet, is not uncommon in
cobalamin-deficient neuropathy þ /  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
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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 Electro-
diagnostic testing may demonstrate axonal involvement.
Somatosensory-evoked potentials and radiological in-
vestigation may be helpful in demonstrating evidence of
coexisting myelopathy.
TOXIC ETIOLOGIES
What? Sensory or sensorimotor; positive neuro-
pathic sensory symptoms including pain. Autonomic
nerve involvement not uncommon.
Where? Distal, symmetrical (i.e., length depend-
ent), 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 cessa-
tion. Consider comorbidities (e.g., alcoholism) and
therapies of comorbidities.
What setting? No family history of neuropathy,
no foot deformities, onset in adulthood following ex-
posure; consider comorbidities and treatments (e.g.,
chemotherapy) and other risk factors (e.g., accidental
exposures). Systemic symptoms (e.g., weight loss, gas-
trointestinal) are common.
Pharmaceutical, Industrial, and Environmental
Toxins
Several pharmaceutical agents, industrial and envi-
ronmental agents, and substances of abuse may cause
neuropathy, most commonly in the form of a
140 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
length-dependent, sensory, predominant axonal neuro-
pathy.61 However, except for neuropathy caused by
alcohol, toxic neuropathies are probably overinvesti-
gated and overdiagnosed3; in fact, they probably repre-
sent well below 5% of cases of chronic distal,
symmetrical, sensory, or sensorimotor neuropathies.62
Nonetheless, prompt identification of a toxic neuro-
pathy is important because removal of any harmful
agent may lead to improvement or resolution of neuro-
pathy. 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 neuropa-
thies. The neuropathy of heavy metal intoxication is
very rare and is usually accompanied by a combination of
gastrointestinal, hematologic, and central nervous sys-
tems problems. Although heavy metal analysis is rou-
tinely 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 hex-
acarbons.64
Alcohol Abuse
ASSOCIATION WITH NEUROPATHY
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 hospital-
ized 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 poly-
neuropathy 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 sensorimo-
tor (53%).11
With respect to laboratory features, in one series,
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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 inci-
dence of liver dysfunction (81% versus 61%) and elevated
blood sugars (28% versus 5%) occurred in patients with
neuropathy than in those without neuropathy.68 Fre-
quently, alcoholic neuropathy coexists with thiamine-
deficient neuropathy. It is important to assess thiamine
status in all alcoholics with neuropathy and replace thi-
amine 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 neuro-
pathic sensory symptoms, especially pain.
Where? Depends on the infection. HIV neuro-
pathy often presents with a distal, symmetrical distribu-
tion, but others (e.g., Lyme, hepatitis C virus [HCV],
sarcoidosis, leprosy, sporotrichosis69) usually do not.
Lyme and sarcoidosis often present with painful, asym-
metrical polyradiculoneuropathy. HCV associated with
mixed cryoglobulinemia and sporotrichosis may present
with mononeuritis multiplex, asymmetrical distal-pre-
dominant neuropathy or even a distal, symmetrical
polyneuropathy.
When? Definite date of onset is typical, partic-
ularly for Lyme and sarcoidosis.
What setting? No family history of neuropathy,
no foot deformities, onset in adulthood following ex-
posure; 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.
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
Hepatitis C Virus
ASSOCIATION WITH NEUROPATHY
Hepatitis C virus is the most common chronic blood-
borne 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 in-
fection with in situ replication.71 The exact pathophy-
siological role of cryoglobulins in HCV neuropathy is
unclear. Some investigators have posited that intravas-
cular 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 symp-
toms such as burning, prickling, and pain are pro-
minent.74 The neuropathy in HCV with mixed
cryoglobulinemia may present as a distal, asymmetrical
(or less commonly symmetrical), sensory, or sensorimo-
tor polyneuropathy71,73 or as mononeuritis multiplex.71
Patients with HCV neuropathy and mixed cryo-
globulinemia 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 im-
munoblot 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 cryoglo-
bulins usually precipitate quickly, whereas type III cry-
oglobulins can take up to 7 days. The precipitates are then
characterized and typed using immunofixation. The elec-
trodiagnostic study will demonstrate an axonal, sensor-
imotor neuropathy that is often asymmetrical71 or
involves multiple nerves as a mononeuritis multiplex.
141
Pathological findings include multifocal fiber loss with
perivascular epineurial inflammation, sometimes sugges-
tive 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
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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 dis-
semination into the host. In
80% of infected individ-
uals, 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 infec-
tion.80 The most typical neuropathic manifestation is
painful polyradiculoneuropathy and lymphocytic menin-
gitis, accompanied by cranial neuropathy in 30 to 50% of
patients.81 The polyradiculopathy or polyradiculoneur-
opathy is typically sensorimotor, painful, asymmetrical,
and non–length dependent due to involvement of nerve
roots. Rarely, patients present with what looks like
mononeuritis multiplex.82 Electrodiagnostic testing con-
firms 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 in-
fection,80,81 with symptoms of relatively symmetrical,
distal paresthesias. The chronic axonal neuropathy may
occur in the setting of encephalopathy or encephalomye-
litis.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 serol-
ogies should be confirmed by Western blot. Spinal
fluid analysis in acute disease typically shows modest
lymphocytic pleocytosis and mild increase in protein
142 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
concentration.84 Cerebrospinal fluid (CSF) Lyme poly-
merase chain reaction (PCR) has 40 to 50% sensitivity
and 97% specificity.81
Sarcoidosis
ASSOCIATION WITH NEUROPATHY
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 gran-
ulomatous disease.85 Sarcoidosis affecting the central or
peripheral nervous system (neurosarcoidosis) occurs in
only
5 percent of cases of sarcoidosis.86–88 Manifes-
tations of neurosarcoidosis include cranial nerve palsies,
meningeal involvement, central nervous system involve-
ment, myopathy, and peripheral neuropathy. Cases af-
fecting the spinal roots or peripheral nerves are even less
frequent, representing only
1% of total sarcoidosis
cases.89–92
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 mul-
tiple mononeuropathies, polyradiculopathy, and radi-
culoplexus neuropathy. A small-fiber neuropathy has
also been reported to commonly occur in sarcoido-
sis.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 approxi-
mately 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 encoun-
tered.93
Chest imaging should be performed in all sus-
pected cases, as a suggestive abnormality, such as hilar
adenopathy, is found in the majority of cases of sarcoi-
dosis.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-
ment or enhancement of affected nerves.93 Electrodiag-
nostic testing usually reveals an asymmetrical, multifocal
axonal process.93,95
Human Immunodeficiency Virus
ASSOCIATION WITH NEUROPATHY
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
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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 sen-
sory or sensorimotor nerve fibers and is gradually pro-
gressive. 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 pre-
sentation 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 compli-
cation 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), co-
infection with CMV can cause painful mononeuritis
multiplex, polyradiculoneuropathy, or polyradiculop-
athy.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, sym-
metrical or asymmetrical, sensory, or sensorimotor poly-
neuropathy. The syndrome resembles Sjögren’s
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
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 patient’s risk factors and the prevalence of
HIV in the patient’s community.103 Rapid HIV testing
has a sensitivity of 99 to 100% and specificity of 99 to
100%, depending on the test.104
Leprosy
ASSOCIATION WITH NEUROPATHY
Leprosy remains the most important infectious neuro-
pathy 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 hematoge-
nous dissemination to skin and nerves with an incuba-
tion 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 neuro-
pathies, 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 present-
ing 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 de-
struction of nerve architecture with granulomas ex-
tending from the perineurium into the endoneurium.
Bacilli are usually not abundant.107 Lepromatous lep-
rosy shows splitting of the perineurium by edema and
foamy cells, infiltration of the endoneurium and peri-
neurium by foamy cells, and Fite stain showing bacilli
in macrophages and Schwann cells.107 Electrodiagnos-
tic testing demonstrates axonal loss and demyelina-
tion.108
143
IMMUNE-MEDIATED
What? Sensory or sensorimotor; positive neuro-
pathic 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.
What setting? No family history of neuropathy,
no foot deformities, onset in adulthood; patients may
have symptoms suggestive of more widespread auto-
immunity (e.g., sicca complex) or may have a diagnosis
of an autoimmune disease (e.g., Sjögren’s or rheumatoid
arthritis). Systemic symptoms (e.g., weight loss, rash,
fatigue, fevers) are common. Many autoimmune diseases
affect women more than men.
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Vasculitis
ASSOCIATION WITH NEUROPATHY
From a clinical standpoint, vasculitis of nerve should be
viewed as being either systemic or nonsystemic. The
systemic vasculitides are commonly divided into pri-
mary 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 fur-
ther classified by the kind and size of blood vessels
involved, organ involvement, disease associations,
underlying mechanisms, and, sometimes, autoantibody
profiles.109–111 The primary systemic vasculitides most
likely to cause vasculitic neuropathy include polyarter-
itis nodosa, Wegener’s granulomatosis, Churg-Strauss
syndrome, and microscopic polyangiitis.112–114 Of
these, microscopic polyangiitis may be the one that
most commonly causes vasculitic neuropathy.111,114
Secondary causes of systemic vasculitis involving pe-
ripheral nerves include connective tissue diseases such
as rheumatoid arthritis, systemic lupus erythematosus
(SLE), and SS. Rheumatoid arthritis (RA), for exam-
ple, 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 in-
fection is another example of a secondary vasculitis.
Sarcoidosis affecting nerve may also cause angii-
tis.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 nonsyste-
mic vasculitic neuropathy is that nonsystemic vasculitic
neuropathy is usually not fatal, whereas untreated
systemic vasculitic neuropathy is often fatal. Approx-
imately 10% of cases that initially appear to be non-
systemic vasculitic neuropathy ultimately become
144 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
systemic vasculitis, so early on it may be difficult to
distinguish nonsystemic vasculitic neuropathy from
systemic vasculitic neuropathy.117,118 Many autoim-
mune, monophasic, or relapsing plexopathies—or,
more accurately, radiculoplexus neuropathies—are
also likely nerve microvasculitides. These include
diabetic lumbosacral radiculoplexus neuropathy (also
known as diabetic amyotrophy, proximal diabetic
neuropathy, and other names), nondiabetic lumbosac-
ral radiculoplexus neuropathy, and immune and in-
herited brachial plexus neuropathies (also called
neuralgic amyotrophy and hereditary neuralgic amyo-
trophy).111
NEUROPATHY
Mononeuritis multiplex, the most common presenta-
tion of vasculitic neuropathy, is acute to subacute in
presentation and almost always painful. It can begin
in the upper or lower extremities, typically at water-
shed 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 polyneurop-
athy.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 vas-
culitic 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 antineu-
trophilic cytoplasmic autoantibody (ANCA) and mye-
loperoxidase (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 electropho-
resis, and HIV. CSF analysis is usually not helpful,
except to aid in the investigation of mimickers, includ-
ing infectious (e.g., Lyme) or other inflammatory eti-
ologies (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 nor-
mal.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 per-
formed 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 radiculo-
plexus 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 asym-
metrical and unilateral onset; however, the majority of
cases become bilateral within 3 months but remain asym-
metrical.121 The illness is typically monophasic with
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progression lasting weeks to months. Autonomic symp-
toms 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 ele-
vated protein concentration.123 Electrodiagnostic testing
demonstrates an asymmetrical, axonal process affecting
the nerves, plexus, and roots, often with more wide-
spread findings than seen on clinical examination.123
Nerve biopsy demonstrates evidence of ischemia with
focal or multifocal fiber loss, focal perineurial degener-
ation, neovascularization, and injury neuroma. There is
often epineurial perivascular inflammation involving
vessel walls suggestive of microvasculitis.123
Sjögren’s Syndrome
ASSOCIATION WITH NEUROPATHY
Sjögren’s syndrome is a systemic autoimmune disease
that primarily affects middle-age women.124 The diag-
nosis 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 keratocon-
junctivitis, evidence of chronic lymphocytic sialoadenitis,
and the presence of either anti-SS-A or anti-SS-B
antibodies. Rash, arthralgias, and Raynaud’s 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 neu-
ropathies, in part because different case series use differ-
ent clinical criteria for study inclusion. Furthermore,
presence of sicca complex does not always imply
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
glandular inflammation (e.g., parotid), as sometimes
dry eyes and mouth may be a manifestation of con-
current 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 infiltra-
tion 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 com-
mon accompaniments to many of these neuropathies.
Sensory ataxic neuropathy typically presents with asym-
metrical paresthesias and ataxia, and gradually becomes
more widespread.124,132 Painful sensory neuropathy
without ataxia may present insidiously with asymmet-
rical, painful positive neuropathic sensory symptoms that
gradually progress in a length-dependent manner.128,133
Laboratory testing of suspected cases should in-
clude 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 anti-
SS-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, anti–SS-A or SS-B
antibodies were detected in 30% of lip biopsy-positive
patients and in only 6% of lip biopsy-negative pa-
tients.127 For all SS patients (with or without neuro-
pathy), antibodies to SS-B (seen in 50 to 70% of patients
with SS) are more sensitive than anti-SS-A anti-
bodies.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 T2-
weighted hyperintensity in the posterior columns.128
Nerve biopsy may demonstrate loss of large myelinated
145
fibers with increased axonal degeneration.128 The elec-
trodiagnostic 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
ASSOCIATION WITH NEUROPATHY
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. Neuro-
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pathy 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 sen-
sitivity 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 neuro-
pathic sensory symptoms.
Where? Variable, but often length dependent.
When? May be gradual onset.
What setting? No family history of neuropathy,
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
146 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
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
ASSOCIATION WITH NEUROPATHY
When encountering a patient with a neuropathy asso-
ciated with a paraprotein, such as MGUS, the clinician
must try to determine whether the neuropathy is idio-
pathic 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 PO-
EMS syndrome (polyneuropathy, organomegaly, endo-
crinopathy, M protein, and skin changes), neuropathy
associated with Waldenström’s macroglobulinemia, neu-
ropathy associated with multiple myeloma, and neuro-
pathy associated with Castleman’s syndrome. The
history and electrodiagnostic testing are particularly
helpful in sorting this out: accompanying systemic
symptoms raise concern for primary systemic amyloido-
sis, POEMS, or malignancy; autonomic symptoms and
signs are common in primary systemic amyloidosis;
electrodiagnostic testing features of primary demyelina-
tion are commonly seen in neuropathies of DADS-M,
POEMS, Waldenström’s macroglobulinemia and
Castleman’s syndrome, whereas the neuropathy is
usually axonal when associated with primary systemic
amyloidosis. The demyelinating neuropathies associ-
ated with a paraprotein are not discussed further in this
article. Please refer to David Saperstein’s 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 prom-
inent 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 paresthe-
sias, 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 Immuno-
fixation 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 pa-
tients.21 Electrodiagnostic testing demonstrates a sym-
metrical, axonal sensorimotor neuropathy. Diagnosis
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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., gas-
trointestinal dysmotility) is common. Positive neuro-
pathic sensory symptoms are typical.
Where? Usually not length dependent, often
asymmetrical.
When? Definite date of onset with rapid pro-
gression; usually leading to severe impairments.
What setting? No family history of neuropathy,
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 paraneo-
plastic syndrome present with neurologic symp-
toms.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 anti-
neuronal nuclear antigen-1 (ANNA-1 [anti-Hu] anti-
body) 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
 EVALUATION OF CHRONIC AXONAL POLYNEUROPATHIES/MAUERMANN, BURNS
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, brain-
stem 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. Sub-
acute onset with rapid progression is typical.13,148 Sen-
sory symptoms such as paresthesias, dysesthesias, and
pain predominate, whereas motor involvement is typi-
cally mild and may only be found on electrodiagnostic
evaluation.14,147 There may be prominent upper extrem-
ity involvement and pseudoathetosis.13,14 Autonomic
involvement is found in up to one fourth of patients,
most commonly orthostatic hypotension and gastropa-
resis, although many other dysautonomic symptoms may
manifest.13–15 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. Electro-
diagnostic testing often shows axonal sensory or sensor-
imotor neuropathy or sensory ganglionopathy.14 Any
workup should also include investigation for a malig-
nancy.13,14,148,150 With a paraneoplastic syndrome asso-
ciated 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 neg-
ative neuropathic sensory symptoms (particularly so for
CMT1A, the most common inherited neuropathy).
Where? Distal, symmetrical (i.e., length de-
pendent).
When? Insidious onset without definite date.
Very slowly progressive.
147
What setting? Family history of neuropathy, foot
deformities, onset at any age but often the first through
third decades. Absence of systemic symptoms or ac-
quired 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 neuro-
pathies seen in neurology practice.6 CMT disease (a.k.a.
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hereditary motor and sensory neuropathy [HMSN]) is a
genetically heterogeneous group of disorders with a
similar clinical phenotype that affects
1 in 2500 in-
dividuals.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 typi-
cally have high arches or hammer toes, distal weakness
and atrophy (especially the peroneal muscles), and ab-
normalities of gait and difficulty running.31 Positive
neuropathic sensory symptoms, for example neuropathic
pain or paresthesias, are uncommon in inherited neuro-
pathies, 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 inher-
itance 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 accord-
ing 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, ‘‘Charcot-
Marie-Tooth Neuropathies: Diagnosis and Manage-
ment,’’ by Agnes Jani-Acsadi, Karen Krajewski, and
Michael Shy.
Other less common inherited neuropathies in-
clude the hereditary sensory and autonomic neuro-
pathies (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
148 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
presents in a distal-predominant distribution. For
the neuropathies associated with inborn errors of
metabolism, onset of neuropathy may be more sub-
acute.154
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