An Approach to the Evaluation of Peripheral

Neuropathies
Mark B. Bromberg, M.D., Ph.D.1

Requests for an evaluation for a peripheral neuropathy are common in the clinic
and electrodiagnostic laboratory. Lists of types of neuropathies are long as are diagnostic
tests. An approach to the evaluation of peripheral neuropathies is valuable as it permits full
characterization of the neuropathy after which the lists of possible types and tests becomes
much shorter and manageable. In this article, the author presents such an approach,
focusing on the clinical aspects.
KEYWORDS: Peripheral neuropathy, evaluation

350

ymptoms of a peripheral neuropathy are common neurologic complaints. The evaluation process may
seem daunting considering the long list of potential
underlying causes and formidable number of available
diagnostic tests. However, the evaluation is manageable
using a structured approach that describes the neuropathy in terms of anatomy and pathology. This is
accomplished in two stages; stage 1 is characterization
of the elements of the peripheral nervous system that are
involved based on symptoms and signs, and stage 2 is
defining the underlying pathology from electrodiagnostic testing (Table 1). This article focuses on stage 1, and
the role of electrodiagnostic testing will be discussed in
another article. It is important to keep in mind that the
two stages are complimentary and many of the elements
that characterize a neuropathy are approached from both
stages. At the point of full characterization, the list of
potential causes of the neuropathy becomes shorter and
the selection of informative tests more manageable. This
approach, in various forms, has been described elsewhere.1,2

WHAT PARTS OF THE PERIPHERAL

NERVOUS SYSTEM
There are several anatomic and physiologic principles to
keep in mind. The peripheral nervous system (PNS) is
divided into autonomic and somatic components and
both include afferent (sensory) and efferent (motor)
nerves. Although autonomic nerve fibers markedly outnumber somatic fibers and are frequently affected in a
neuropathy, symptoms and signs of autonomic nerve
dysfunction are rare compared with those associated
with somatic nerve dysfunction, and most diagnostic
efforts are based on somatic nerve dysfunction. Further,
electrodiagnostic testing assesses somatic nerve function
and autonomic nerve testing requires special equipment
and procedures.
The distribution of nerve involvement may not be
obvious from symptoms, but can be determined accurately by electrodiagnostic testing. Damage or loss of
sensory nerves results more frequently in symptoms than
damage or loss of motor nerves for several reasons.
Damage to sensory nerves disrupts connections between

1
Department of Neurology, Clinical Neurosciences Center, University
of Utah, Salt Lake City, Utah.
Address for correspondence and reprint requests: Mark B.
Bromberg, M.D., Ph.D., Department of Neurology, Clinical Neurosciences Center, 175 North Medical Drive, Salt Lake City, UT 84132
(e-mail: mbromberg@hsc.utah.edu).
Peripheral Neuropathy; Guest Editor, Mark B. Bromberg,

M.D., Ph.D.
Semin Neurol 2010;30:350355. Copyright # 2010 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0030-1267278.
ISSN 0271-8235.

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ABSTRACT

AN APPROACH TO THE EVALUATION OF PERIPHERAL NEUROPATHIES/BROMBERG

351

Table 1 Questions to Address when Evaluating Peripheral Neuropathies

Stage 1
Which parts of the peripheral nervous system?

Somatic (motor, sensory), autonomic

What is the distribution?

Distal predominant
Distal and proximal
Dermatomal
Radicular
Plexopathy

What is the time course?

Rate of progression (acute, chronic, insidious)

What are the clinical features?

Symptoms (pain, numbness, weakness)

Signs (abnormal sensory perception, weakness)
Physical features (high arches, hammer toes)
Medical conditions (contributing diseases, drugs)
Family history

What is the underlying pathology?

Confirm: somatic (motor, sensory), autonomic

Primary axonal, primary demyelinating
Conduction block

receptors and nerves, leading to a reduction in sensory

input. The same degree of damage to motor nerves
may not affect strength because collateral reinnervation of denervated muscle fibers preserves motor
function. Furthermore, most neuropathies affect distal
lower extremity muscles early on, and weakness of toe
flexion or extension will not be readily apparent to the
patient. An additional factor is that sensory nerves
have both peripheral and central branches, and damage to both distal portions represents a double disconnection.
It is important to determine the pattern and
distribution of nerve involvement; Table 2 lists patterns
with examples. Polyneuropathies are roughly symmetric
in distribution and tend to affect nerves in a lengthdependent manner, with longest nerves first (stocking-

glove distribution).3 A clinical presentation would include, in the extreme, initial numbness or pain in the feet
with progression of symptoms up the legs; when involvement reaches knee level, numbness will be described in
the fingers with progression up the arm. Eventually there
would be a foot drop and weakness of intrinsic hand
muscles. Polyradiculoneuropathies include nerve roots as
well as peripheral nerves, leading to diffuse symptoms in
both proximal and distal distributions, also in a roughly
symmetric distribution. A clinical presentation would
include numbness and tingling in both feet/legs and
hands/arms, and weakness of distal and proximal muscles.
Mononeuropathies are in the distribution of a single
nerve with motor and sensory involvement. Mononeuritis
multiplex may become confluent and relatively symmetric
over time, but a step-wise progression can usually be

Table 2 Patterns of Peripheral Nerve Involvement and Examples of Neuropathies

Symmetric, length-dependent

Diabetes
Drugs
Toxins
Metabolic

Symmetric, proximal and distal

Acute inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy

Mononeuropathy

Entrapment neuropathy

Mononeuropathy multiplex

Vasculitis

Asymmetric, nerve or plexus distribution:

Diabetic amyotrophy
Idiopathic plexopathy

Asymmetric, unusual

Porphyria

Multifocal motor/sensory neuropathy

Mononeuritis multiplex
Leprosy
Tangier disease
Multifocal motor conduction block neuropathy
Autonomic, unusual

Amyloidosis

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Stage 2

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elicited from the history. Occasionally, a mononeuropathy or mononeuropathy multiplex will involve loss of
motor function only. Neuropathies that do not follow
these patterns are important to recognize, and the pathology may be identifiable based on their unusual pattern.

TIME COURSE
Every disease has a momentum or time course, and
neuropathies can be divided into acute and chronic types
based on inherent rates and patterns of progression.
Acute neuropathies progress over days to several weeks,
while chronic neuropathies progress over many months
to years, and may have an insidious onset where a patient
cannot date the onset. These time courses relate to the
rate of natural progression and not remissions and
exacerbations due to treatment. Table 3 lists examples
of acute and chronic neuropathies.

CLINICAL FEATURES
The next step is to determine the clinical features, which
include symptoms and signs, physical aspects, identification of potential underlying medical conditions and
drug use, and family history.

Localization
As the clinical features are being elicited, it is important
to appreciate that not all symptoms of numbness and
sensory loss and weakness are due to peripheral nerve
disease. The exercise of neurologic localization is an
essential element to assure peripheral nervous system
pathology. Errors in localization are to the central
nervous system and somatization. Clinical features suggestive of a myelopathy include numbness that does not
follow a stocking-glove or dermatomal distribution,

numbness involving both legs to the waist or above,

and pathologic tendon reflexes. In these circumstances,
other diagnostic tests can help confirm central nervous
system involvement.
Sensory symptoms attributable to somatization are
common and are challenging because the clinician does
not want to miss a neurologic disease. However, it is
equally inappropriate to carry forward a tentative neurologic diagnosis that is untenable. One approach is to
determine whether the symptoms make sense anatomically (based on the organization of the peripheral nervous
system) or pathophysiologically (based on types of peripheral nerve pathology). Electrodiagnostic studies can
determine the presence of peripheral nervous system
involvement. If there is no evidence for a neurologic basis
for the neurologic symptoms, a gentle but frank discussion
into issues in a patients life is appropriate. The rest of this
chapter assumes peripheral nervous system involvement.

Symptoms
Elicitation of a full spectrum of symptoms is essential in
defining the neuropathy. Neuropathic symptoms may be
positive or negative in nature,4,5 and sensory and motor
symptoms are listed in Table 4. Positive symptoms imply
spontaneous discharges of nerve fibers; negative symptoms imply loss of normally conducted discharges. Positive sensory symptoms are easily recognized and are
frequently volunteered by the patient as chief complaints. Positive motor symptoms may not be recognized
by the patient, and should be actively sought because
they may be the only clinical manifestation of motor
nerve involvement. The discrepancy between patient
perception of sensory and motor symptoms is due to
factors discussed above.

Signs
Table 3 Examples of Acute and Chronic Neuropathies
Acute (days to weeks)

Acute inflammatory demyelinating

polyradiculoneuropathy
Porphyria
Acute toxic exposure (arsenic)
Mononeuritis multiplex

Sensory Testing

Clinical testing of sensory function is a subjective endeavor. It is most important to appreciate that sensory
Table 4 Examples of Positive and Negative Sensory
and Motor Symptoms

Proximal diabetic neuropathy

Idiopathic plexopathy
Paraneoplastic sensory

Positive

neuronopathy
Chronic
(months to years)

Sensory Symptoms

Motor Symptoms

Paresthesias

Fasciculations

Pain

Cramps

-burning

Diabetic polyneuropathy

-squeezing or tightness
-electric-like

Chronic inflammatory demyelinating

polyradiculoneuropathy
Charcot Marie Tooth hereditary
neuropathy
Idiopathic

Negative

-hypersensitivity
Numbness

Weakness

Reduced or absent sensation

Atrophy

Postural instability

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testing requires that the patient apply your request or

instructions to a process of sensory integration and give a
meaningful answer. An important variable is patient
attention and understanding, and a patient must be fully
alert and must understand that you want them to
determine when a stimulus completely dies away or
that you want them to determine when the joint first
moves. Another issue is what is being assessed. Although
attempts are made to assess several individual sensory
modalities and nerve fiber types, true distinctions are not
possible. Although there are examples of large fiber
neuropathies (Friedreich ataxia) and small fiber neuropathies (Tangier disease), most sensory modalities (light
touch through pain) can be conveyed by both large and
small diameter fibers. Further, clinical testing (light
touch, stroking, sharp instruments) usually activates a
variety of receptor types. Thus, distinctions between
modalities and fiber types may be more apparent than
real.
Findings from formal psychophysical laboratory
testing of sensory perception should be factored into a
set of informative clinical tests of sensory function.6 A
variety of cutaneous receptor types convey low-threshold mechanoreception, and mechanoreceptors are most
sensitive to moving stimuli. In formal testing, controlled stimuli are applied to restricted areas of skin. In
contrast, clinical testing of mechanoreception may include touch or stroking, and likely activates a variety of
receptor types. Psychophysical testing for vibration
perception confirms equal sensitivity for frequencies
from 64 Hz to 512 Hz. Nociceptive stimulation is
perhaps the most challenging. It is difficult to separate
stimulus properties of nociception from pressure, and it
is possible for a subject to distinguish a sharp from a
dull stimulus without feeling pain. Nociceptive stimuli
are considered to be conveyed by small fibers, but
some nociceptive receptors are innervated by myelinated fibers. Formal testing of noxious stimuli has been
by hot and cold stimuli using special equipment, and it
is not clear how well temperature detection can be
assessed with clinical testing using the cold end of a
tuning fork.
It is advisable to develop an individual set of tests
that are informative and not become bogged down in
incongruities during the examination with a large battery
of tests. Reliable and informative results can be obtained
from the following clinical tests.
Touch threshold: Patient detection of the lightest touch
or stroking on the dorsum of the hand and foot
represents a measure of low threshold sensory
perception. Use of a 10 g filament is another
method to distinguish light touch thresholds.
Vibration threshold: Patient perception of when a tuning fork applied to a finger or toe dies out is a
measure of vibration threshold. Vibration per-

ception is felt to represent large fiber function. A

128 Hz tuning fork dies out more slowly than a
256 Hz tuning fork and is easier to use. The
patient must understand the need to indicate
complete disappearance. The time interval (in
seconds) from when the vibration extinguishes
in the patient compared with the observer is a
measure of impairment.
Sharp stimulus threshold: A patients ability to distinguish between the lightly applied pokey feeling
from the sharp end of a safety pin compared with
the similarly lightly applied dull end likely represents discrimination of more noxious stimuli from
light touch.
Position threshold: Patient perception of changes in
joint position is usually exquisite. Any errors in
direction, or false perception of movement, are
abnormal. The tests of light touch, the safety
pin, and position sense should be performed
with the patient blinded to the stimuli application.
The sensory examination can be focused to
answer several useful clinical questions. Most
information about the neuropathy should come
from the patients history, and the sensory examination should be confirmatory. There are two
questions related to a symmetric polyneuropathy:
(1) Is there a distal-to-proximal gradient, and (2)
what is the severity of nerve damage? Patients can
contribute to determining sensory gradient and
severity, and it is surprising how readily a patient
can mark a point on their limb below which
sensation is abnormal and above which it is
normal. The gradient can be confirmed clinically
by asking if light touch is perceived less strongly at
a distal point compared with a proximal point.
Severity of light touch loss can be addressed by
asking the patient to estimate the relative percentage value of light touch sensation at the
involved site compared with the face. Severity of
vibration loss can be estimated by the time difference between when the vibration extinguishes for
the patient compared with the examiner.
Questions to answer for an asymmetric
neuropathy are whether the sensory loss follows
a nerve distribution, a radicular distribution, or a
complex pattern best explained by a plexopathy.
Tendon reflexes. Reflex testing is an objective measure of
sensory nerve function. The deep tendon reflex is
a monosynaptic reflex arc with sensory and motor
nerve components, but the arc is much more
vulnerable to sensory nerve damage. As an example, ankle plantar flexion strength is relatively
preserved in all but the most severe neuropathies,
yet ankle reflexes are lost early on. Accordingly,
an absent Achilles tendon reflex is an objective

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SEMINARS IN NEUROLOGY/VOLUME 30, NUMBER 4

2010

indication of a significant degree of sensory nerve

damage. It is important to be assured that the
reflex is truly absent by using several reinforcing
maneuvers while testing.
Motor signs. Motor signs include muscle atrophy and
weakness. Mild distal atrophy can be appreciated by assessing the prominence of extensor
tendons in the feet and finding a thin foot, as
prominent tendons and thin feet suggest loss of
intrinsic foot muscle bulk. A certain amount of
denervation and atrophy occurs with age over
65 years. Weakness can be appreciated by testing muscles that can be just overcome in
normal individuals. Accordingly, flexion and
extension of the lesser toes and extension of
the great toe are informative when weakness is
subtle. Ankle dorsiflexion weakness will occur
with greater severity of the neuropathy, but it is
rare for plantar flexion to be weak until very
late in a neuropathy. Both fallen and high
arches also suggest intrinsic foot weakness. In
the hands, atrophy of the first dorsal interosseous muscle and weakness of finger abduction
are informative.
Orthopedic signs. Further inspection of the foot for high
arches and hammertoes is informative because it
suggests a long-standing neuropathy. The shape
of the foot is determined by the interplay of
muscular forces acting on the various bones in
the foot. Weakness of extensor muscles leads to a
foreshortened foot (high arches) and hammertoes. Fallen arches can also be a sign of a longstanding neuropathy.
Autonomic signs. Autonomic nerve dysfunction is indicated by symptoms of orthostatic dizziness,
and impotence in men. Clinical signs of autonomic dysfunction are an orthostatic blood pressure change. Dry eyes and mouth (sicca
syndrome) represent reduced tear and salivary
gland activity, and raise the question of Sjogren
syndrome that can be associated with sensory
neuropathies.

Medical History
Lists of medical conditions that cause or predispose to
peripheral neuropathy are long, but careful review of the
literature reveals that some associations are rare and may
reflect chance occurrences. Medication use, both current
and past, should be sought, but causative agents are
rarely found. Similarly, patients frequently raise the
question of toxic exposures, but these are very rare,
especially when the exposure in question is remote in
time from the onset of the neuropathy. Medical conditions, medications, and toxins are reviewed in other
articles.

Family History
It is likely that among mild and chronic idiopathic
neuropathies a larger than appreciated percentage has a
hereditary basis.7 Interestingly, among large families
with known hereditary neuropathies, only 20% of affected family members seek medical attention because of
symptoms. Accordingly, a full family history can be
fruitful. It is important to inquire in detail about symptoms and signs that may suggest a hereditary neuropathy. Importantly, hereditary neuropathies may not
become symptomatic until adult life.8 Questions that
can be addressed to the patient and relatives are listed in
Table 5. With the availability of cellular phones with a
camera, family members can send photographs of their
legs and feet for review.

Electrodiagnostic Features
Electrodiagnostic testing is the second stage in the
evaluation of a neuropathy and will be covered in
another article, but it is important to appreciate that
nerve conduction and needle electromyelogram (EMG)
studies provide objective information about the peripheral nervous system not available from the history and
clinical examination. Characterization by electrodiagnostic testing can answer the following specific questions: (1) Confirm which portions of the peripheral
nervous system are involved: sensory only, motor only,
or both. (2) Confirm the distribution of involvement:
symmetric polyneuropathy, single nerves, or another
pattern. (3) Determine the pathologic mechanism:
primary axonal, primary demyelination, or a mixture.
(4) Determine the severity and time course: mild or
severe, recent or chronic.

Other Diagnostic Tests

After full characterization of the neuropathy the differential diagnostic list becomes reasonable.9Several ancillary diagnostic tests are available for special
circumstances. These tests should be used when there
is good evidence from the history and examination that
Table 5 Questions Pertinent to a Long-standing
(Familial) Neuropathy
Difficulty with running, sports, or military activities
High arched feet or flat feet
Hammer or curled-up toes
Claw hands
Wasting of muscles
Foot troubles, foot ulcers
Use of braces
Arthritis or poliomyelitis (incorrect diagnosis)
Difficulty walking on heels and toes
Rising from kneeled position

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354

they will be informative. These tests will be discussed in

detail in the other articles.
SUMMARY
At the conclusion of the clinical and electrodiagnostic
evaluation for a peripheral neuropathy, a specific characterization of the peripheral neuropathy should emerge
from the data. The differential diagnostic list is relatively
short under each type of neuropathy.9 At this point, a
meaningful series of laboratory tests can be ordered.
Despite best efforts, it is important to appreciate that a
good percentage (20%) of neuropathies will remain
undiagnosed despite an exhaustive evaluation.7

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AN APPROACH TO THE EVALUATION OF PERIPHERAL NEUROPATHIES/BROMBERG