PUBLISHED AHEAD-OF-PRINT

Peripheral neuropathy: Clinical pearls

for making the diagnosis
Carrie Smith Nold, MPA, PA-C; Kenkichi Nozaki, MD, PhD

ABSTRACT
Peripheral neuropathy is a common condition that can
be encountered in a multitude of clinical settings. Treat-
ment must be tailored to the underlying cause. This article
reviews various causes of peripheral neuropathy and
offers recommendations for evaluating patients to deter-
mine the cause of peripheral neuropathy.
Keywords: peripheral neuropathy, plexopathy, radicu-
lopathy, diabetes, Charcot-Marie-Tooth, distal symmetric
polyneuropathy
1 2 3 4

Learning objectives
Outline an approach to the initial evaluation of a patient
with peripheral neuropathy.
Describe the clinical scenarios in which peripheral neuropa-
thy would warrant additional diagnostic testing and/or
referral.
FIGURE 1. Nerve function, from normal axoplasmic flow (1), to
numbness (2), peripheral neuropathy (3), and severe peripheral
neuropathy (4)
Peripheral neuropathy is a common condition with
diverse causes and varied clinical presentation. Due to
its heterogeneous nature and the numerous ways to

P
eripheral neuropathy can be encountered by clinicians
in a multitude of clinical settings: the patient with
Guillain-Barré syndrome who presents to the ED,
the patient with suspected carpal tunnel syndrome being
referred to orthopedic surgery, the patient with diabetes
seeing a primary care provider for new-onset paresthesias
in the feet, or the patient following up with the oncology
team about adverse medication reactions to chemotherapy
(Figure 1). Given the number of systemic conditions with
which peripheral neuropathy is associated, clinicians in all
specialties need to understand the basic diagnostic prin-
ciples of the condition.
Carrie Smith Nold is an assistant professor and didactic coordinator in
the PA program at the Philadelphia College of Osteopathic Medicine’s
Georgia campus in Suwanee, Ga. Kenkichi Nozaki is an associate
professor in the Department of Neurology at the University of Alabama
at Birmingham. The authors have disclosed no potential conflicts of
interest, financial or otherwise.
DOI:10.1097/01.JAA.0000615460.45150.e0
Copyright © 2020 American Academy of PAs
classify and define the condition, few epidemiologic
studies have examined peripheral neuropathy as a
whole.1 Available research suggests the prevalence of
peripheral neuropathy is 2% to 8%.1-3 However, the
actual prevalence of peripheral neuropathy may be
greater. For example, Gregg and colleagues found that
of the US population age 40 years and older, 14.8%
had peripheral neuropathy; this number increased to
28.5% in those with diabetes.4 Differences between
study results may exist based on the population exam-
ined and inclusion criteria.
CLASSIFICATIONS AND CAUSES
Peripheral neuropathy can be classified in many different
ways and commonly is categorized based on the distribu-
tion of affected nerves. Although in the broadest sense,
peripheral neuropathy refers to any disorder of the periph-
eral nervous system including plexopathy and radiculopa-
thy, these generally are considered discrete entities from
peripheral neuropathy.
PUBLISHED AHEAD-OF-PRINT
Key points
A detailed history provides important clues to the cause
of peripheral neuropathy.
A thorough physical examination will help rule out
central causes of sensory and motor symptoms as
well as classify the distribution pattern of peripheral
neuropathy.
Urgent evaluation is key for patients who may have acute
and rapidly progressive neuropathies.
This article focuses on disorders distal to the plexus.
Table 1 identifies different distribution patterns of
peripheral neuropathy and describes clinical features of
each. Of these patterns, distal symmetric polyneuropa-
thy (DSPN) is the most common.5 Diabetes is the most
common cause of DSPN and the most common cause
of peripheral neuropathy in the developed world.6,7
Other common causes of DSPN include vitamin B12
deficiency, alcohol use, inherited conditions, chemo-
therapy, chronic kidney disease, paraproteinemia, and
thyroid disease.5,8 Of the mononeuropathies, carpal
tunnel syndrome (median neuropathy at the wrist) is
the most common, followed by cubital tunnel syndrome
(ulnar neuropathy from compression at the elbow).5,6
Peripheral neuropathy also can be categorized by the
type of nerve fiber affected (motor, sensory, autonomic),
pathology (axonal versus demyelinating), and cause.
Table 2 outlines some common and atypical causes of
peripheral neuropathy.
Because peripheral neuropathy is associated with many
conditions, treatment must be tailored to the underlying
cause of the disorder. Some patients require aggressive
immune therapy; others may be treated symptomatically.
Unfortunately, determining the underlying cause of
peripheral neuropathy can present a diagnostic challenge,
and no clear universal diagnostic algorithm exists. Also,
a patient’s peripheral neuropathy can be multifactorial
with multiple contributing causes, as in a patient with
alcohol abuse and vitamin deficiencies, or a patient with
diabetic polyneuropathy who develops carpal tunnel
syndrome.9
HISTORY AND PHYSICAL EXAMINATION
A thorough history and physical examination will help
clinicians classify the pattern of the patient’s neuropathy,
develop a reasonable differential diagnosis, and order
appropriate diagnostic tests. Asymmetrical signs or
symptoms are inconsistent with DSPN (Table 3) but
may indicate another pattern of peripheral neuropathy
such as mononeuropathy or mononeuropathy multiplex
(Table 4).10
Sensory abnormalities alone do not necessarily indicate
a diagnosis of peripheral neuropathy because central
nervous system disorders, especially myelopathy, can
cause sensory complaints. Literature shows that symp-
toms alone have relatively poor diagnostic accuracy in
predicting polyneuropathy; signs are a better predictor.10
Additionally, multiple neuropathic symptoms are more
accurate in predicting the presence of polyneuropathy
than a single symptom, and multiple abnormalities on
examination are more sensitive than a single abnormal-
ity.10 One study of patients with diabetes found that
absent ankle reflexes were the most sensitive sign to
detect neuropathy, and vibratory impairment was the
most specifi c. 11 Clinicians should look for multiple
symptoms and signs to best support the diagnosis.
Additional considerations about the history and physi-
cal examination include:
• Pay attention to family history. Because hereditary neu-
ropathies are an important cause of peripheral neuropathy,
obtain a comprehensive family history when working up
a patient with peripheral neuropathy.7
• Be sure to inquire about toxin exposure and medications.
Did the patient recently start a new medication that can
TABLE 1. Peripheral neuropathies classified by
distribution 2,5,6,12,14,26
Mononeuropathy
• Numbness, tingling, pain, and weakness in the distribution
of one nerve
• Possible causes: trauma, focal compression, and entrapment
• Examples: median neuropathy at the wrist (carpal tunnel
syndrome), ulnar neuropathy at the elbow (cubital tunnel
syndrome), and peroneal neuropathy at the fibular head
Mononeuropathy multiplex
• Neuropathic symptoms in the distribution of multiple,
noncontiguous nerves
• Frequently asymmetric and non-length dependent; may
summate to mimic a distal symmetric polyneuropathy
• Pain is a common presenting symptom; onset often acute or
subacute
• Can be associated with vasculitis, sarcoidosis, lymphoma,
carcinoma, leprosy, HIV, diabetes, Lyme disease, or amyloidosis
• May require urgent assessment to rule out vasculitis
DSPN
• Neuropathic symptoms in the distribution of multiple,
noncontiguous nerves
• Frequently asymmetric and non-length dependent; may
summate to mimic a distal symmetric polyneuropathy
• Pain is a common presenting symptom; onset often acute or
subacute
• Can be associated with vasculitis, sarcoidosis, lymphoma,
carcinoma, leprosy, HIV, diabetes, Lyme disease, or amyloidosis
• May require urgent assessment to rule out vasculitis

TABLE 2. Some causes of peripheral neuropathy
and corresponding clinical pearls1,6-9,12-15,27
Hereditary
Examples: CMT, hereditary amyloid neuropathy, hereditary
neuropathy with liability to pressure palsy, porphyria
• Hereditary neuropathies typically are insidious in onset with slow
progression
° Commonly distal and motor predominant
° DSPN is the predominant phenotype, but distribution can vary
• CMT is the most common cause of hereditary peripheral
neuropathy and may be demyelinating or axonal
° Pes cavus, claw toes, and stork legs are common but may not
always be present
° CMT can occur via a de novo mutation; therefore, a family
history may be lacking
Immune-mediated
Examples: GBS, CIDP, multifocal motor neuropathy
• GBS typically presents as an acute symmetric polyneuropathy
° Patients usually experience progressive ascending paralysis
and areflexia; sensory involvement varies; dysautonomia may be
present
° In the Western hemisphere, most cases are demyelinating
° Initial symptoms can be mild and result in misdiagnosis; rapid
diagnosis required as may progress to bulbar and respiratory
weakness
Toxins
Examples: Heavy-metal exposure or poisoning, seafood toxins
including ciguatera, organophosphates, alcohol, ethylene glycol,
diphtheria toxin
• Lead toxicity is the most common heavy metal toxicity
• Chronic alcohol abuse may lead to vitamin deficiencies which
can also cause peripheral neuropathy
Drug-induced
Examples: Cardiovascular drugs such as statins, amiodarone, and
procainamide; chemotherapeutic agents such as vinca alkaloids
(vincristine), taxanes (paclitaxel), platinum compounds (cisplatin,
oxaloplatin), thalidomide; antibiotics and antimycobacterials such
as isoniazid, linezolid, metronidazole, nitrofurantoin, or ethambutol;
triazoles such as itraconazle; immunosuppressants such as infliximab,
interferons, leflunomide, or tacrolimus; and nucleoside reverse
transcriptase inhibitors
• Drug-induced peripheral neuropathy often presents as sensory
polyneuropathy with paresthesia; motor signs and symptoms
generally minor but a range of sensory and motor severity possible
• Can begin weeks to months after drug initiation
• In most cases symptoms resolve when the drug is stopped;
however, in some cases, symptoms are not fully reversible
• Ethambutol is associated with optic neuropathy, but is not
clearly associated with polyneuropathy
Associated with systemic disease
Examples: Diabetes, sarcoidosis, infections (leprosy, HIV, Lyme disease,
viral hepatitis, syphilis), vasculitis and connective tissue disorders,
celiac disease, lymphoma, carcinoma, paraneoplastic syndrome,
multiple myeloma and monoclonal gammopathy of undetermined
significance, thyroid dysfunction, chronic liver or renal disease
• Although diabetes most commonly presents as DSPN, it also is
associated with asymmetric proximal neuropathy, polyradiculopathy
(including diabetic amyotrophy), mononeuropathy, cranial
neuropathy, and mononeuropathy multiplex.
Peripheral neuropathy: Clinical pearls for making the diagnosis
be neurotoxic or does the patient have a history of sig-
nificant alcohol use (Table 2)?
• What other significant medical history does the patient
have? Pay special attention to conditions listed in Table
2. A patient may have a significant condition that has not
been diagnosed, so be sure to look for findings on history
and examination that may raise concern for one of these
disorders.
• Clarify the onset and progression of the neuropathy.
Was the onset acute (less than 4 weeks ago), subacute (4
to 12 weeks ago), or chronic (more than 12 weeks ago)?12
Has it rapidly progressed? Most neuropathies are chronic
and develop over months or years, but those with more
acute development may represent serious disease such as
vasculitis or Guillain-Barré syndrome (GBS).6 In most
patients with DSPN, symptoms start in the feet and move
up the legs. Once symptoms reach the knee, patients also
may notice symptoms in the hands. Symptoms developing
in the hands and feet at the same time may raise concern
for coexisting carpel tunnel syndrome or another pattern
of neuropathy.13
• Perform an appropriate physical examination. Evaluate
the patient’s mental status, reflexes, cranial nerves, sen-
sation, and motor system including gait. When doing a
sensory examination, test different modalities such as
light touch, pain sensation, temperature, vibration, and
proprioception. Additionally, stay alert for signs of
autonomic dysfunction and any signs that may point to
underlying systemic disease that may be causing the
neuropathy. The extent of physical examination required
outside of the neurologic examination depends on patient
presentation and the other diagnoses being considered.
• Rule out a central cause for sensory or motor abnor-
malities. Diseases of the central nervous system such as
stroke, multiple sclerosis, and brain and spinal cord tumors
also can cause sensory and motor symptoms that can mimic
peripheral neuropathy, so stay alert for physical examina-
tion findings such as hyperreflexia or increased tone that
may steer the differential toward a central process.14 In
patients with evidence of lower and upper motor neuron
dysfunction without sensory loss, consider the diagnosis
of amyotrophic lateral sclerosis.15
Screening for peripheral neuropathy is prudent in asymp-
tomatic patients at increased risk for peripheral neuropa-
thy secondary to a systemic disease. Because only 10% to
15% of patients with diabetic neuropathy are symptomatic,
annual screening for peripheral neuropathy is recommended
for patients with diabetes.13 Multiple methods of screening
exist, but the combination of testing vibration with a tun-
ing fork and light touch with a monofilament is considered
efficient, sensitive, and specific.13
DIAGNOSTIC TOOLS
Because the treatment for peripheral neuropathy must be
tailored to the underlying cause, determining the cause
PUBLISHED AHEAD-OF-PRINT
is important when a patient presents with history and
physical examination findings suggestive of peripheral
neuropathy. No agreed-upon algorithm exists for evalu-
ating the condition, and the cost of workup can be sig-
nificant. Notably, substantial variation exists within and
between provider types when working up DSPN.16 One
study identified more than 400 patterns of testing in the
initial evaluation of peripheral neuropathy.3 The study
also found that Medicare expenditures in patients being
evaluated for peripheral neuropathy rose substantially
during the diagnostic period, with almost one-quarter of
patients in the study receiving high-cost, low-yield MRIs.3
Another study found that 51% of patients underwent
unnecessary investigations during evaluation of their
chronic polyneuropathy.17 Considerations for various
diagnostic studies used in the evaluation of peripheral
neuropathy are discussed below.
Electrodiagnostic studies Details of electrodiagnostic
studies (such as nerve conduction studies and needle elec-
tromyography [EMG]) and their interpretation are beyond
the scope of this article, but studies typically take 30 to 60
minutes to complete and can be uncomfortable for
patients.12,18 These studies are very operator-dependent
and should be performed by someone (such as a neurolo-
gist) with adequate experience interpreting the results.
Although state laws vary regarding who may perform
EMGs, this procedure typically is not in the scope of prac-
tice for physician assistants.
Although electrodiagnostic studies are considered sensi-
tive and specific in defining polyneuropathy, fewer than
half of all patients with suspected DSPN undergo them.19
These studies are limited in their ability to detect small-fiber
neuropathy.10,14 The American Academy of Neurology
(AAN) definition of DSPN states that the highest likelihood
of polyneuropathy occurs with a combination of signs,
symptoms, and abnormal electrodiagnostic studies, and a
modest likelihood of polyneuropathy occurs with multiple
signs and symptoms (when electrodiagnostic studies are
not available).10
Given the sensitivity and specificity of electrodiag-
nostic studies, some clinicians and researchers favor
routinely performing EMGs or nerve conduction stud-
ies in most patients with suspected DSPN and using
the results to help guide further diagnostic studies.6,12,19-21
Not only can electrodiagnostic studies help establish
the distribution pattern and involvement of motor and
sensory fibers, they also can determine if the underly-
ing pathophysiology is demyelinating or axonal and
can differentiate peripheral neuropathy from myopathy
or a neuromuscular junction defect.6,22 This informa-
tion can help determine the underlying cause of the
peripheral neuropathy.6 In some patients, such as those
with multifocal motor neuropathy or chronic inflam-
matory demyelinating polyradiculoneuropathy (CIDP),
electrodiagnostic studies are crucial to making the
TABLE 3. Symptoms and signs of DSPN 6,10,12,13
Symptoms (typically begin in the feet but patients can be
asymptomatic in early stages)
• Sensory: can be intermittent or continual
° Positive: burning, pain, pins-and-needles sensation
° Negative: numbness, loss of sensation, balance impairment
° Sensory symptoms usually precede weakness; symptoms
travel up leg and can develop in hands around the time they
develop in the knee
• Motor: weakness
• Autonomic: may include sweating and circulatory
abnormalities, postural hypotension, dizziness or syncope,
anhidrosis, bladder atony or constipation, erectile dysfunction
Signs
• Sensory and motor signs should not be isolated to one nerve
distribution
• Sensory signs may include abnormalities with pain, light touch,
temperature, vibration, and proprioception testing
• Motor signs may include weakness and atrophy (especially
intrinsic foot muscles); weakness may progress in a distal to
proximal pattern
• Decreased to absent tendon reflexes (especially ankle reflex)
• May have gait abnormalities or a positive Romberg sign due to
proprioceptive loss
TABLE 4. Clinical presentations of select
mononeuropathies5,28,29
Carpal tunnel syndrome
• Pain and paresthesia in the first three digits and radial half of
fourth digit
• Later may develop weakness of thumb abduction and opposition
• May have thenar atrophy
Cubital tunnel syndrome
• Pain and paresthesia in the fifth digit, ulnar half of the fourth
digit, and medial aspect of the hand
• Weakness with finger abduction; loss of dexterity and
decreased grip and pinch strength
• May have atrophy of hand intrinsic muscles and hypothenar
eminence
Peroneal neuropathy at fibular head
• Foot drop and sensory loss over the dorsum of the foot and
mid and lower lateral calf
Radial neuropathy at the spiral groove (Saturday night palsy)
• Wrist drop and sensory loss to the dorsum of the hand
Facial neuropathy (Bell palsy)
• Acute upper and lower facial weakness
• May also have decreased taste on anterior two-thirds of
tongue, hyperacusis, and decreased tearing.

diagnosis.18 In patients with mononeuropathies, elec-
trodiagnostic studies are key in localizing the site of
injury, and may reveal that a suspected mononeuropa-
thy is actually due to mononeuropathy multiplex or
associated with a more generalized neuropathy.6 Like-
wise, what appears on examination to be a DSPN may
actually be revealed via electrodiagnostic studies to be
mononeuropathy multiplex.12
Conversely, some research suggests that electrodiag-
nostic testing may be less helpful in diagnosing periph-
eral neuropathy or leading to management changes.8,17
One study found that inexpensive and simple blood
tests for diabetes, thyroid dysfunction, and vitamin
B12 deficiency allowed neurologists to identify a new
cause for a patient’s DSPN about 15% of the time; more
expensive testing such as electrodiagnostic studies and
MRIs rarely led to a change in management.8 Other
studies suggest that electrodiagnostic testing results in
diagnosis and management changes more frequently.19,21
Thus, even among neurologists, no universal approach
exists to using EMGs and nerve conduction studies in
the workup of peripheral neuropathy. Some clinicians
prefer to order targeted laboratory studies first and
then consider further testing if no underlying condi-
tion is found and the patient’s symptoms persists.2,14
Although the role of EMGs and nerve conduction stud-
ies in patients with chronic neuropathy is not agreed
on, clinicians seem to concur that they are vital in
patients with acute neuropathies, motor-predominant
neuropathies, asymmetrical or non-length-dependent
neuropathies, mononeuropathy and mononeuropathy
multiplex, genetic neuropathies, and severe or disabling
neuropathies.12,13,18,23 When electrodiagnostic studies
are performed, they should be considered an extension
of the clinical assessment and do not replace a proper
history and physical examination.18
Laboratory studies and imaging No specific routine
laboratory test can diagnose peripheral neuropathy, but
tests can help screen patients with suspected peripheral
neuropathy for a specific cause. The AAN recommends
that screening laboratory tests be considered for all
patients with polyneuropathy.7 Based on their evidence-
based review, the tests that provide the highest yield of
abnormality in evaluating DSPN are blood glucose,
serum B12 with metabolites, and serum protein immu-
nofixation electrophoresis.7 Specifically, in patients with
DSPN, blood glucose was elevated in 11%, serum
protein electrophoresis was abnormal in 9%, and B12
was low in 3.6%. 7 Though the etiological role of
impaired glucose tolerance in peripheral neuropathy is
unclear, other tests for prediabetes, such as glucose
tolerance tests, may be considered if blood glucose
testing is not clearly abnormal.7
Serum protein immunofixation electrophoresis testing
can help identify monoclonal gammopathies, which are
Peripheral neuropathy: Clinical pearls for making the diagnosis
more common in patients with polyneuropathy; abnor-
malities on a serum protein electrophoresis warrant
further evaluation and possible referral to a hematolo-
gist.7,13,20 Clinical judgment will help guide when other
laboratory tests are appropriate based on patient pre-
sentation (Table 5).
Skin biopsy is
particularly useful in
diagnosing small-fiber
sensory neuropathy.
Routine cerebrospinal fluid (CSF) analysis with lum-
bar puncture generally has low diagnostic yield in
patients with peripheral neuropathy, with the exception
of those with suspected infectious neuropathy, neoplasm,
or demyelinating polyneuropathy such as GBS or
CIDP.6,7,20 Imaging of the brain and spinal cord typically
is not needed in the diagnosis of isolated peripheral
neuropathy. Although MRIs rarely lead to management
changes when evaluating patients with DSPN, one study
found that 23.2% of patients received an MRI of the
brain and/or spinal cord during the workup of their
peripheral neuropathy.3,8 Imaging of the brain or spinal
cord should be considered in patients with physical
examination findings consistent with central nervous
system damage. Imaging such as skeletal radiographic
surveys; chest radiography; or CT or MRI of the chest,
abdomen, and pelvis may be useful in patients with
suspected malignancy.6
Genetic testing New genetic information continues
to shape the possible genetic tests available in heredi-
tary neuropathy. Of the hereditary neuropathies, the
demyelinating form of Charcot-Marie-Tooth (CMT)
disease is most prevalent, and most patients with this
condition have a duplication of the PMP22 gene
(CMT1A).7 CMT2 (axonal CMT) is most commonly
caused by MFN2 mutations.7 The AAN recommends
genetic testing to accurately diagnose hereditary neu-
ropathies, with initial genetic testing guided by clinical
phenotype and inheritance pattern as well as electro-
diagnostic features.7 Genetic testing can be expensive
and picking the correct genetic test may not be straight-
forward: phenotypes can vary within the same family
and different genetic mutations can present with a
similar phenotype.7 Therefore, it is reasonable to refer
patients with suspected hereditary neuropathy to a
neurologist who can perform electrodiagnostic testing
and the indicated genetic testing based on clinical
features and electrodiagnostic results.
PUBLISHED AHEAD-OF-PRINT
Autonomic testing, nerve biopsy, and skin biopsy Accord-
ing to the AAN evidence-based review, autonomic testing
should be considered as part of the evaluation of patients
with polyneuropathy, particularly patients with suspected
autonomic neuropathy or distal small-fiber sensory poly-
neuropathy.24 Some conditions associated with autonomic
neuropathy include diabetes, GBS, alcohol abuse, and
amyloidosis.14 The multiple ways to test for autonomic
function include tilt-table testing, heart rate variability
testing, thermoregulatory sweat testing, and skin vasomo-
tor reflex testing.24
Nerve biopsy should not be performed as part of the
standard workup for peripheral neuropathy but may be
useful in certain clinical situations, such as in patients with
suspected amyloid neuropathy, vasculitis, or atypical forms
of CIDP.24 The sural nerve is the most common site to use.6
Nerve biopsy also may be helpful in patients with tumors,
other inflammatory disorders such as sarcoidosis, infectious
disease such as leprosy, or when CMT cannot be confirmed
by other methods such as genetic testing.6,24 Skin biopsy is
increasingly being used when evaluating peripheral neu-
ropathy. Skin biopsy typically involves taking a punch
biopsy from the leg and is particularly useful in diagnosing
small-fiber sensory neuropathy.24
PUTTING IT ALL TOGETHER
Although researchers and clinicians have varying
approaches to the order of diagnostic testing when work-
ing up a patient with peripheral neuropathy, most meth-
ods emphasize the importance of the history and
physical examination in considering studies ordered. Use
data gathered from the history and physical examination
to localize the dysfunction to the peripheral nerves,
categorize the distribution of the peripheral neuropathy,
and assess which nerve fibers are likely affected. Also,
review other etiologic clues discovered during the history
and physical examination; these will be key in shaping
the differential diagnosis and appropriate workup.15 For
example, although most neuropathies are mixed, a purely
motor neuropathy may raise concern for multifocal motor
neuropathy.12
Neurologists play an important role in diagnosing
and treating patients with peripheral neuropathy. 8
However, it may not be feasible for every patient to be
referred to a neurologist given expense and travel con-
siderations. Clinicians must be alert in looking for alarm
signs that warrant immediate referral to a neurologist.
Neurologists are best equipped to carry out special
testing such as EMGs and nerve conduction studies,
genetic testing, nerve and skin biopsies, and specific
antinerve antibodies. For patients with mild, sensory-
predominant, length-dependent peripheral neuropathy,
specialty consultation may not be required.13 Situations
that warrant referral to a neurologist or neuromuscular
specialist include:5,13
TABLE 5. Selected laboratory studies for peripheral
neuropathy 2,6,7,12-14,16,20
Highest yield
• Blood glucose
• Serum B12 with metabolites
• Serum immunofixation and serum protein electrophoresis
Commonly ordered
• Complete blood cell count
• Erythrocyte sedimentation rate or C-reactive protein
• Comprehensive metabolic panel
• Thyroid function tests
• Urinalysis and urine protein electrophoresis
May be useful in selected patients (not recommended for
routine use in all patients with peripheral neuropathy)
• Blood or CSF tests for infectious conditions such as HIV,
hepatitis B and C, Lyme disease, and syphilis
• Rheumatologic tests for vasculitis and connective tissue
disease such as antinuclear antibodies (ANA), rheumatoid
factor, antineutrophil cytoplasmic antibodies (ANCA), and
antibodies to SSA and SSB [[AU: please spell out]]
• Serum antibodies or endoscopic biopsy for celiac disease
• Serum and CSF angiotensin-converting enzyme (ACE) [[AU:
add “test” here?]] for sarcoidosis
• Blood or urine analysis for suspected heavy metal toxicity
• Blood, urine, or stool tests for porphyria
• Other vitamins such as B1, B6, E and folic acid [[AU: tests for
vitamin deficiencies?]]
• Paraneoplastic antibody profiles
• Dysimmune tests such as GM1 antibodies in suspected
multifocal motor neuropathy, anti-GQ1b in suspected Miller
Fischer syndrome, or anti-myelin associated glycoprotein
antibodies in demyelinating polyneuropathy with disproportionately
prolonged distal motor latency.
• Symptoms are motor or autonomic predominant
• Symptoms are rapidly progressive or acute/subacute in onset
• Peripheral neuropathy is severe and affects the patient’s
activities of daily living
• Hereditary neuropathy is suspected
• Non-length-dependent, asymmetric, or multifocal pattern
• Cause is unclear or clinical uncertainly exists about
appropriate treatment.
These recommendations are not meant to deter referral
to neurology in other appropriate situations based on a
clinician’s clinical acumen. Concern for diagnoses such as
GBS, vasculitis, or other acute neuropathies requires urgent
evaluation and treatment. If a patient presents with DSPN
and does not meet any criteria for immediate referral to
neurology, ordering targeted laboratory examinations and
diagnostic testing may be reasonable based on patient
presentation.
In the event of a nonurgent referral to neurology, consider
some first-line screening laboratory tests as discussed previ-
ously if the patient cannot be seen quickly. Remember that

laboratory results cannot be interpreted in isolation, and
a patient can have more than one cause of peripheral neu-
ropathy. For example, up to 10% of patients with diabetes
may have an alternative cause contributing to neurologic
deficits.13 In particular, consider an alternative cause of
peripheral neuropathy in patients with diabetes when the
patient has no evidence of retinopathy or nephropathy.13
When the cause of peripheral neuropathy is unclear, par-
ticularly when the question of the cause may affect treat-
ment, refer the patient to neurology for further evaluation.
About 25% of the time, no clear cause is discovered after
thorough evaluation of chronic polyneuropathy; most of
these idiopathic chronic neuropathies are mild with pre-
dominant sensory involvement.6,25 Some of these patients
may have small-fiber peripheral neuropathy.6 When initial
laboratory testing is normal, follow the patient and treat
symptomatically in the absence of red flags or progression.20
However, patients with progression or any concern for a
serious diagnosis should be referred to neurology.
CONCLUSION
Because many conditions cause peripheral neuropathy,
no one approach to diagnosis will work for every
patient. Ordering every possible test is seldom the right
course of action. 21 The extent of diagnostic testing
required should be driven by the data gathered from a
thorough history and physical examination, and clini-
cians should rule out findings that suggest an underly-
ing central cause. Finally, clinicians should recognize
situations where referral to neurology or more urgent
evaluation is warranted. JAAPA
Earn Category I CME Credit by reading both CME articles in this
issue, reviewing the post-test, then taking the online test at http://
cme.aapa.org. Successful completion is defined as a cumulative
score of at least 70% correct. This material has been reviewed and
is approved for 1 hour of clinical Category I (Preapproved) CME
credit by the AAPA. The term of approval is for 1 year from the
publication date of January 2020.
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