REVIEW ARTICLE


Localization and
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Diagnostic Evaluation
of Peripheral Nerve
Disorders
By Peter H. Jin, MD

ABSTRACT
OBJECTIVE: This article provides a framework for the initial evaluation of
patients with suspected peripheral nerve disease. The key clinical
elements of peripheral nerve diseases can help the practicing neurologist
differentiate among peripheral neuropathies with similar presentations.

LATEST DEVELOPMENTS: The wide range of peripheral nerve diseases with

similar clinical presentations can pose a diagnostic challenge. The large
array of available testing modalities (including imaging and
electrodiagnostic, autonomic, laboratory, biopsy, and genetic testing)
further complicates clinical decision making. Recent developments (eg,
discovery of new autoantibodies, genetic variations, and histopathologic
techniques) across the peripheral neuropathy spectrum have resulted in
an increased need to evaluate patients logically and with a tailored
diagnostic approach.

A careful approach that focuses on key clinical elements

ESSENTIAL POINTS:
CITE AS: combined with an understanding of purposeful diagnostic testing can lead
CONTINUUM (MINNEAP MINN) to a successful diagnosis of peripheral nerve diseases.
2023;29(5, PERIPHERAL NERVE AND
MOTOR NEURON DISORDERS):
1312–1326.

Address correspondence to INTRODUCTION

T
Dr Peter H. Jin, 110 S Paca St, 3rd
Floor, Baltimore, MD 21201,
he practicing neurologist, regardless of specialty or practice
pjin@som.umaryland.edu. environment, will encounter patients with potential peripheral nerve
disorders. The presenting symptoms most associated with peripheral
RELATIONSHIP DISCLOSURE:
Dr Jin has received personal nerve disease (such as weakness, sensory disturbances, and
compensation in the range of imbalance) are nonspecific in isolation. Peripheral neuropathies with
$0 to $4999 for serving as a
different etiologies can have identical clinical presentations, and even those with
consultant for Ionis
Pharmaceuticals. distinct localizations can have significant overlapping clinical findings.
Furthermore, diseases outside of the peripheral nervous system can mimic
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
peripheral nerve disease. Failure in differentiating between similar clinical
USE DISCLOSURE: presentations and identifying crucial diagnostic features can lead to
Dr Jin reports no disclosure. misdiagnoses. A common disorder such as diabetic polyneuropathy may be
© 2023 American Academy misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy
of Neurology. (CIDP) based on misinterpreted findings of an electrodiagnostic study.

1312 OCTOBER 2023

Conversely, a devastating disorder such as amyotrophic lateral sclerosis KEY POINTS
presenting with right-hand weakness may be initially misdiagnosed as
● The clinical approach to
carpal tunnel syndrome, resulting in treatment-altering diagnostic delay. peripheral nerve disorders
The wide spectrum of peripheral nerve diseases combined with their should focus on identifying
penchant for overlapping clinical phenotypes results in frequent specific clinical elements in
diagnostic challenges. the history and examination
that include onset, pace of
Applying a clinical framework for patients with peripheral nerve disorders can
progression, modalities
help the practicing neurologist focus on specific differentiating clinical features affected, anatomic
that should ultimately yield a precise diagnosis. Several other reviews have distribution, and affected
detailed different approaches to peripheral nerve disorders and peripheral nerve fiber types.
neuropathies.1-3 This article focuses on the initial evaluation of these patients to
● Diabetic sensory
prepare the reader to answer the following questions posed during an initial polyneuropathy is an
patient encounter: acquired, chronic, slowly
progressive, length-
dependent, sensory-
u Where should I direct my attention in the history and physical examination? predominant, mixed large
u What should I order for appropriate and efficient initial testing? and small fiber, primarily
axonal polyneuropathy. This
u Which red flags should I never miss? is a pattern commonly seen
in polyneuropathies caused
by toxic and metabolic
TERMINOLOGY etiologies.
A foray into peripheral nerve disorders can be disorienting from the terminology
perspective alone. Both the medical literature and clinical documentation from ● Red flag findings for
neuromuscular specialists use an array of localizations (eg, radiculoplexus peripheral nerve disorders
include acute to subacute
neuropathy), acronym alphabet soup (eg, MADSAM [multifocal acquired
onset with rapid
demyelinating sensory and motor neuropathy], CANOMAD [chronic ataxic progression, motor-
neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl predominant involvement,
antibodies]), and pathologic terminology (eg, mixed sensorimotor with early involvement of
demyelinating and secondary axonal features). If the terminology and its proprioception (early
sensory ataxia), bulbar
rationale can be understood, then we can begin to appreciate the nuances of involvement, and a
peripheral nerve disorders. Elements of peripheral nerve disorders are multifocal or non–length-
summarized in TABLE 1-1. dependent distribution.
Using diabetic sensory polyneuropathy as an example, we can characterize the
onset and rate of progression of this disorder as chronic and very slowly
progressive. The anatomic distribution is symmetric and distal (ie, length-
dependent, stocking-glove), with sensorimotor involvement that is heavily
sensory predominant. The nerve fiber type involvement is a mixture of large and
small fiber sensory and motor nerves. Electrodiagnostic and pathologic testing
reveal primarily axonal degeneration. Dysautonomia is a commonly associated
clinical feature. Diabetic sensory polyneuropathy is an acquired neuropathy that
occurs in the context of the systemic medical disease diabetes. In summary,
diabetic sensory polyneuropathy is an acquired, chronic, slowly progressive,
length-dependent, sensory-predominant, mixed large and small fiber, primarily
axonal polyneuropathy with common concomitant dysautonomia associated
with a history of diabetes. With sufficient history, examination, and testing,
every peripheral nerve disorder can be described within a similar framework
with components of onset, pace of progression, modalities affected, anatomic
distribution, electrodiagnostic features, affected nerve fiber type, and associated
clinical context (TABLE 1-1). Furthermore, many peripheral nerve disease red
flags are the opposite or inverse of the features of diabetic sensory
polyneuropathy.

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TABLE 1-1 Clinical Elements of Peripheral Nerve Disease

Clinical element Differential diagnoses

Onset and pace of progression

Chronic onset with gradual progression (months to years) Toxic and metabolic polyneuropathies (eg, diabetes,
chemotherapy related, vitamin B12 deficiency, alcohol related),
human immunodeficiency virus (HIV) neuropathy, Charcot-
Marie-Tooth disease (CMT) and hereditary neuropathies,
multifocal motor neuropathy (MMN), motor neuron disease

Acute or subacute onset with rapid progression (days to Guillain-Barré syndrome (GBS), chronic inflammatory
months) demyelinating polyradiculoneuropathy (CIDP), paraproteinemic
neuropathies, vasculitic neuropathies, Lyme disease
neuropathy, hepatitis C–associated neuropathy, rheumatologic
neuropathies

Anatomic distribution

Length-dependent and symmetric Toxic and metabolic polyneuropathies (eg, diabetes,

chemotherapy related, vitamin B12 deficiency, alcohol related),
human immunodeficiency virus (HIV) neuropathy, Charcot-
Marie-Tooth disease (CMT), and hereditary neuropathies

Multifocal, non–length-dependent, or combination of GBS, CIDP, MMN, paraproteinemic neuropathies, vasculitic

distal and proximal involvement in motor, sensory, and neuropathies, hepatitis C–associated neuropathy, Lyme disease
muscle stretch reflex findings neuropathy, rheumatologic neuropathies, motor neuron disease

Bulbar involvement with dysphagia, dysarthria, and GBS, motor neuron disease, myasthenia gravis, bulbar myopathy
dyspnea

Monomelic Focal compression neuropathy, radiculopathy, plexopathy, early

motor neuron disease

Sensorimotor involvement

Prominent sensory involvement with minimal and late Toxic and metabolic polyneuropathies, HIV neuropathy
motor involvement

Prominent proprioception deficits Sensory neuronopathies, dorsal column spinal cord disease

Pure motor involvement MMN, motor neuron disease, myasthenia gravis, myopathy

Prominent early motor involvement alongside sensory GBS, CIDP, paraproteinemic neuropathies
involvement

Electrodiagnostic findings

Distal or length-dependent axonal loss Toxic and metabolic polyneuropathies, HIV neuropathy,
paraproteinemic neuropathies

Multifocal or non–length-dependent axonal loss Vasculitic neuropathies, hepatitis C–associated neuropathy,

Lyme disease neuropathy, rheumatologic neuropathies, MMN,
motor neuron disease

Segmental demyelination GBS, CIDP, paraproteinemic neuropathies

Diffuse demyelination CMT and hereditary neuropathies

1314 OCTOBER 2023

HISTORY
Like other neurologic disorders, the diagnosis of peripheral nerve disorders begins
with the history. Although the symptoms or reason for referral can be vague (eg,
neuropathy, numbness), the clarification of discreet historical elements can set the
foundation for guided examination and testing for efficient diagnosis.
Disease onset can range from hyperacute to chronic and is primarily inferred
from the duration of a patient’s symptoms. The most common peripheral nerve
disorders are chronic and include neuropathies from toxic, metabolic, and
genetic etiologies. Subacute onset is typically associated with progressive
peripheral nerve diseases with an autoimmune or inflammatory etiology.
Hyperacute- or acute-onset presentations are characteristic of autoimmune and
occasionally infectious peripheral neuropathies, although localization to the
central nervous system should also be considered in this setting.
The pace of progression should be considered separately from onset and refers
to the temporal course of a patient’s symptoms. Most peripheral nerve disorders
follow a gradual, slowly progressive course. In toxic, metabolic, and genetic
polyneuropathies, patients can have symptoms for years with barely noticeable
or detectable decline. Differentiating between a monophasic versus a chronically
progressive disorder is key to distinguishing the acute versus chronic
autoimmune neuropathies (eg, Guillain-Barré syndrome [GBS] and diabetic
lumbosacral radiculoplexus neuropathies are monophasic, whereas CIDP and
nonsystemic vasculitic neuropathies are often chronically progressive with
fluctuations). Rapid accumulation of peripheral nerve disorder deficits should
spark consideration for autoimmune neuropathies and motor neuron disease.
Similarly, a stepwise accumulation of deficits is highly suggestive of a vasculitic
etiology. Alternatively, stepwise progression may be caused by the accumulation
of a second, wholly different peripheral nerve disease (eg, cervical radiculopathy
superimposed on carpal tunnel syndrome).
The anatomic distribution is broadly ascertained in the history. A symmetric
and distal (ie, length-dependent, stocking-glove) distribution of sensorimotor
symptoms is classically associated with genetic, toxic, and metabolic
polyneuropathies. This pattern indicates a systemic etiology that affects the more
metabolically vulnerable distal nerves. A monomelic distribution of sensorimotor
symptoms can suggest a focal neuropathic process including compressive
mononeuropathies, isolated radiculopathies, or rarely autoimmune conditions
that impact the brachial and lumbosacral plexuses such as cervical or lumbosacral
radiculoplexus neuropathy, multifocal motor neuropathy, or multifocal CIDP. A
patchy distribution (ie, multifocal, non–length dependent) that is asymmetric
and involves both proximal limb regions along with the face and trunk can
suggest autoimmune neuropathies (eg, vasculitic neuropathies, sensory
neuronopathies, acquired demyelinating neuropathies) where seemingly
random segments of nerve root and peripheral nerve are “picked off” one by one.
Anatomic distribution is further clarified via examination, electrodiagnostic
testing, and imaging.
Consideration of nerve fiber involvement should include a comparison of
both severity and time course regarding sensory and motor symptoms. Most
peripheral nerve diseases are sensory predominant. Although most toxic,
diabetic, and nutritional polyneuropathies can affect both sensory and motor
function, sensory disturbances may precede motor involvement by years. Those
patients with small fiber involvement often report “positive sensory symptoms”

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LOCALIZATION AND DIAGNOSTIC EVALUATION OF PERIPHERAL NERVE DISORDERS

such as neuropathic pain (“burning,” “electrical”), allodynia, dysesthesia, and

paresthesia. Those with large fiber sensory involvement, however, may report
imbalance and incoordination. Importantly, positive sensory symptoms often
represent an acquired cause of sensory polyneuropathy, whereas the absence of
positive sensory symptoms is commonly encountered in genetic neuropathies.
Motor involvement may not be noticed by the patient and might be detected by
the examiner only through subtle findings of weakness or electrodiagnostic
testing. In patients with sensory-predominant neuropathies, motor findings may
still be present, but to a minimal degree, and manifest as mild toe flexor and toe
extensor weakness. Findings of motor involvement that precede or are out of
proportion to sensory findings should alert the examiner to the possibility of
motor neuron disease or multifocal motor neuropathy, although motor
involvement can be appreciated in more chronically progressive genetic
neuropathies (eg, Charcot-Marie-Tooth disease).
Concomitant autonomic dysfunction (ie, dysautonomia) is associated with
many systemic peripheral nerve disorders. Symptoms associated with
dysautonomia include sensitivity to light, orthostatic presyncope or syncope,
early satiety from poor gastric emptying, sicca symptoms, constipation, diarrhea,
erectile dysfunction, vaginal dryness, and anhidrosis. The recognition of
dysautonomia can affect both diagnosis and patient symptom management.
Dysautonomia is particularly common in diabetic polyneuropathy and GBS and
is a hallmark of amyloid polyneuropathy (the hereditary transthyretin form of
which is treatable with RNA silencer therapy).
Various systemic medical diseases are associated with neuropathies. A careful
medical history and review of systems can reveal risk factors for neuropathies
that include diabetes, cancer, chemotherapy exposure, alcohol use disorder,
rheumatologic disorders, and vitamin deficiencies.
Peripheral nerve diseases can also be broadly categorized as hereditary,
acquired, or idiopathic. Inquiring about developmental and childhood history
can reveal subtle clues to long-standing neuromuscular dysfunction. A careful
family history may reveal specific diagnoses as well as a potential undiagnosed
history of peripheral nerve disease. Asking patients about family members with a
history of ambulation and pain disorders can reveal a latent family history of
peripheral nerve disease.

PHYSICAL EXAMINATION
The neurologic examination of peripheral nerve disorders naturally relies heavily
on motor, sensory, and muscle stretch reflex components. Other elements of the
neurologic examination should not be de-emphasized, however, because
alternative neurologic localizations may account for some “neuropathic”
patterns. Careful cranial nerve examination is particularly important. Cranial
neuropathies are seen in some peripheral nerve disorders, primarily those with a
multifocal or non–length-dependent anatomic distribution. Facial strength and
eye movement are frequently affected in GBS. Tongue and oropharyngeal
weakness are common in motor neuron disease. Tonic pupils may be suggestive
of dysautonomia.
The motor and reflex examination contains the key elements for determining
the anatomic distribution of a possible peripheral disorder. A patient’s
distribution of muscle weakness, atrophy, and diminished muscle stretch
reflexes may triangulate to a specific lesional localization (focal and asymmetric

1316 OCTOBER 2023

peripheral nerve disease, eg, entrapment neuropathy) or a specific anatomic KEY POINTS
distribution (eg, symmetric, distal, multifocal). Although most peripheral nerve
● Positive sensory
disorders are associated with diminished or absent muscle stretch reflexes, they symptoms often represent
remain normal in small fiber polyneuropathies and very distal large fiber an acquired cause of
polyneuropathies and are expected to be hyperactive in amyotrophic lateral sensory polyneuropathy,
sclerosis. The motor and reflex examination may also reveal a central nervous whereas the absence of
positive sensory symptoms
system mimic. Careful examination for upper motor neuron signs should
is commonly encountered in
include assessment of relative hyperreflexia (presence of a normal muscle genetic neuropathies.
stretch reflex in the presence of an associated weak muscle) and pathologic
reflexes (toe responses, Hoffman response, frontal release signs, brisk jaw ● Subtle findings of motor
jerk reflex). weakness in patients with
chronic, sensory-
The sensory examination, although rife with poor interrater reliability because predominant, axonal
of examiner and patient subjectivity, is critical for several reasons. First, a careful polyneuropathies may
sensory examination revealing normal findings suggests a possible motor- include mild toe flexor and
predominant or pure motor pattern. Second, it provides information regarding toe extensor weakness.
nerve fiber type involvement. The presence of deficits in vibration or ● Prominent symptoms of
proprioception sense may suggest a localization to large fibers or their related chronic dysautonomia in a
proximal pathways (eg, dorsal columns). The rare but striking presentation of patient with an idiopathic
profound proprioceptive deficits, sometimes involving joint position loss of the neuropathy should prompt
evaluation for amyloid
knees and hips, may be suggestive of an acquired demyelinating polyneuropathy
neuropathy.
or a sensory neuronopathy. A sensory examination with isolated deficits in pin
and temperature sense with otherwise normal vibration and joint position sense ● Vibration sense testing
may favor the diagnosis of a small fiber neuropathy. Lastly, a careful sensory with a quantitative tool such
examination may reveal sensory signs even when a patient does not report as a Rydel-Seiffer tuning
fork allows for more
sensory symptoms.4 objective measurements
Because of the subjective nature of the sensory examination, quantitative and that can be tracked over
validated methods of testing are helpful. For vibration testing, the use of a time and correlate more
quantitative 64-Hz Rydel-Seiffer tuning fork can more precisely quantify the directly to electrodiagnostic
testing.
degree of vibration sense deficit. Unlike a traditional qualitative 256-Hz tuning
fork, the quantitative 64-Hz tuning fork findings correlate with abnormal ● Peripheral nerve disease
sensory nerve action potential findings on nerve conduction studies.5,6 Testing is unlikely in older adult
general sensation of the distal foot with a monofilament fiber has been repeatedly patients with isolated
findings of absent ankle
validated in the detection of diabetic sensory polyneuropathy and can be helpful
reflexes and mild decreased
as a screening tool. A 10-g monofilament test of the toes and feet has been vibration sense in the feet
validated to be highly predictive of diabetic foot ulcers and has similar sensitivity without other associated
and specificity for ulcer risk assessment as a qualitative 256-Hz tuning fork historical or examination
elements.
assessment.7,8 A less stiff 1-g or 2-g monofilament has been shown to be more
sensitive for the detection of diabetic sensory polyneuropathy than the standard
10-g monofilament.9 Biothesiometry devices deliver adjustable voltages of
vibration stimulus that are highly precise and validated. It may be marginally
better than tuning fork and monofilament testing for neuropathy detection, but
the cost of the device is likely a barrier for most practicing neurologists. Similarly,
various quantifiable thermal stimulus devices have been validated to detect small
fiber dysfunction, but their lack of incremental benefit over pin sensation and
monofilament testing makes their use difficult to justify.10
Of note, an age-related decline occurs in vibration sense and ankle jerks in
patients aged older than 65 years.11 Peripheral nerve disease is unlikely in older
adult patients with isolated findings of absent ankle reflexes and mild decreased
vibration sense in the feet without other associated historical or
examination elements.

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CASE 1-1 A 67-year-old right-handed man with a history of type 2 diabetes,

hypertension, and lung cancer presented to the neurology office
reporting hand weakness. About 1 year before presentation, the patient
noticed hand grip weakness in the left hand. About 4 months later, he
started to have similar symptoms in his right hand. He had noted muscle
wasting in his hands and forearms. He denied sensory symptoms in his
upper extremities. He had more remote symptoms of numbness and
tingling in his feet, which he reported began soon after he received
chemotherapy with cisplatin about 5 years earlier and overall had been
stable without progression.
On examination, he had normal mental status and cranial nerve
function. Examination of the upper extremities revealed weakness in
bilateral finger abduction, which was worse on the left. He had moderate
atrophy in the hypothenar eminence and first dorsal interossei bilaterally.
Fasciculations were frequent in the bilateral first dorsal interossei.
Strength examination of the lower extremities was normal. His muscle
stretch reflexes were absent throughout. He had absent Babinski and
Hoffman signs. Sensory examination of the feet revealed severe loss of
vibration sensation and pinprick sensation up to the midshin. In the upper
extremities, vibration testing of the second digit was normal, and pinprick
testing revealed mild loss of sharp sensation in the right thumb and
second digit. The patient was evaluated via electrodiagnostic testing and
laboratory testing, which led to a diagnosis of multifocal motor
neuropathy with associated GM1 antibodies superimposed on a more
long-standing length-dependent sensorimotor peripheral neuropathy
and median neuropathy at the wrist.

COMMENT This case illustrates the layering of clinical elements commonly

encountered in peripheral nerve disease. Rather than classifying the onset
and pace of progression of all symptoms together, the neurologist must
parse the potential clinical entities and describe them accordingly.
Although the patient had sensory neuropathy symptoms for many years in
the feet, possibly from diabetes or chemotherapy (sensorimotor
peripheral neuropathy), the most striking part of his presentation is the
progressive hand weakness findings in the past year that may suggest a
superimposed disorder (multifocal motor neuropathy). Although there is a
combination of sensorimotor findings, the clinical details regarding the
hand symptoms reveal a strong motor predominance with notable atrophy
and muscle strength loss with only minimal associated sensory deficits.
The pinprick loss in the right first and second digits represents an
incidentally discovered carpal tunnel syndrome (median neuropathy at the
wrist) that overlaps with his subacute motor-predominant hand symptoms.

1318 OCTOBER 2023

 In addition to the neurologic examination, a general medical examination can KEY POINTS
reveal evidence of undiagnosed systemic medical diseases or hereditary diseases.
● Skin and joint examination
Orthostatic blood pressure testing can help screen for autonomic insufficiency. can reveal key diagnostic
The clinician should give particular attention to the skin and joints, which may elements in diseases of
provide the basis for suspicion of rheumatologic disorders and hereditary peripheral nerves. Ideally,
peripheral nerve disorders. Asking the patient to change into a gown can aid in patients should change into
a gown to allow for
the inspection of skin and joints. Inspection of skin and joints can reveal
inspection of the proximal
facial erythema, joint enlargement and deformities of the fingers, areas of extremeties and trunk.
hyperpigmentation and hypopigmentation, and livedo reticularis and racemosa,
which may suggest rheumatologic disease. In the feet, the presence of high arches ● Patients with potential
(ie, pes cavus) and hammer toes may suggest hereditary neuropathy (ie, peripheral nerve disorders
may have multiple diagnoses
Charcot-Marie-Tooth disease) or other long-standing neuropathies. In patients that overlap. Although this
with neuroma-forming diseases such as neurofibromatosis or leprosy, palpation overlap is most common
of extremities may reveal subcutaneous mass lesions. with other peripheral nerve
disorders, disorders of the
central nervous system can
DIFFERENTIAL DIAGNOSIS also manifest with
After a comprehensive history and physical, the initial evaluation of a symptoms and signs
potential peripheral nerve disorder will usually generate a substantial list of traditionally associated with
differential diagnoses. Many presentations of peripheral nerve disorders are the peripheral nervous
system.
nonspecific and require further elucidation via additional laboratory and
electrodiagnostic workup. This is particularly true for the etiology, as peripheral ● Non-neurologic disorders
nerve disorders of various etiologies can have identical clinical presentations. can mimic peripheral nerve
For example, a chronic, slowly progressive, length-dependent sensory disease and should be
considered in the presence
polyneuropathy from diabetes, HIV, and kidney disease can present similarly
of inconsistent neurologic
on examination. Also, Hickam’s dictum, or the absence of a singular examination findings and
parsimonious diagnosis, applies routinely in neuromuscular settings. Separate electrodiagnostic testing.
disease processes with distinct localizations can mimic or magnify symptoms of
the peripheral nerve disease of interest and lead to a layering effect, where
multiple neurologic localizations can contribute to the same clinical findings
(CASE 1-1). For example, a patient presenting with a foot drop may have a
simultaneous contribution from a focal fibular mononeuropathy and an
L5 radiculopathy.
When considering a neuromuscular diagnosis, the most likely alternatives
typically localize to other parts of the peripheral nervous system. Cervical and
lumbar radiculopathies can mimic focal mononeuropathies and, if bilateral,
can also mimic polyneuropathies. Myopathies and neuromuscular junction
disorders can mimic pure motor neuropathies. In the central nervous system,
myelopathies can present with bilateral symmetric sensorimotor abnormalities,
and a parafalcine brain lesion can present with bilateral lower extremity
sensorimotor deficits. Many symptoms and signs of central nervous system
disorders (eg, weakness, numbness, ataxia, dysautonomia) overlap with
peripheral nerve disorders. The evaluation of central nervous system
disorders may be further complicated by the concomitant presence of peripheral
nervous system disease, which can mask the expected upper motor
neuron findings.
Non-neurologic disorders can also mimic peripheral nerve diseases.
Musculoskeletal disorders including joint disorders and tendinopathies can
mimic the pain and fatigue of neuropathies. Chronic pain conditions such as
fibromyalgia and complex regional pain syndrome can present similarly to
polyneuropathies with numbness, tingling, and burning pain.

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DIAGNOSTIC EVALUATION
Beyond the history and examination, diagnostic testing for peripheral nerve
disorders includes electrodiagnostic studies, autonomic function tests, laboratory
studies, imaging, and biopsy. The choice of tests and order to pursue them is
based on the initial clinical impression.

Electrodiagnostic Testing
Electrodiagnostic testing is the most common diagnostic tool for patients
with suspected peripheral nerve disorders. The standard components include
nerve conduction studies and needle EMG, collectively referred to as
electrodiagnostic testing, which is considered an extension of the neurologic
examination. Electrodiagnostic testing can help clarify historical and
examination elements by demonstrating a neuropathy’s anatomic distribution
and nerve fiber type involvement. Nerve conduction studies can elegantly
demonstrate a predominance of sensory or motor nerve conduction deficits.
Nerve conduction studies and EMG both can assist in determining if a peripheral
nerve disease is length dependent (distal), proximal, or multifocal and provide
more precise localization for peripheral nerve disorders. For example, a patient
with interossei weakness assessed to have potential ulnar neuropathy at the
elbow may be determined by electrodiagnostic studies to instead have an ulnar
neuropathy at the wrist. A patient with distal vibration loss in the feet with
absent lower extremity reflexes who is clinically assessed to have a
length-dependent sensory polyneuropathy may be revealed by electrodiagnostic
evaluation to instead have bilateral S1 radiculopathies. Furthermore,
electrodiagnostic studies can reveal nerve fiber involvement not apparent on
history and examination alone. For example, in a patient with primarily sensory
clinical findings, electrodiagnostic testing may demonstrate a mixed
sensorimotor nerve disorder.
EMG specifically can elucidate the chronicity of peripheral nerve disorders if a
motor component exists. The earliest EMG abnormality in acute motor processes
is reduced recruitment of motor unit action potentials. Over time, with chronic
reinnervation, motor unit potentials will have a higher amplitude and longer
duration. This process takes months to occur and would not be expected in the
acute setting. If there is active or ongoing denervation (axonal loss) for at least 14
to 21 days, EMG may show fibrillation potentials. Although fibrillation potentials
may resolve with reinnervation in a monophasic disorder, their presence may
persist in diseases where denervation progresses, such as in motor neuron
disease. Sometimes EMG findings can be dissonant with clinical findings as well.
For example, a patient with neuropathy symptoms for only a few months may
have EMG findings that suggest a more chronic process, which can help
inform diagnosis.
Unlike the history and examination, electrodiagnostic evaluation can
differentiate the presence of an axonal versus demyelinating peripheral nerve
disorder. Although certain historical and examination features may be more
suggestive of a demyelinating disorder (eg, diffuse areflexia, proximal and distal
weakness), it can be confirmed via electrodiagnostic studies. Furthermore,
electrodiagnostic evaluation can help distinguish patterns of demyelinating
peripheral nerve disorders as acquired versus hereditary. For example, acquired
demyelinating disorders are commonly associated with compound muscle action
potential temporal dispersion or conduction block.

1320 OCTOBER 2023

 Similar to a neurologic examination, electrodiagnostic evaluation is better KEY POINT
equipped to clarify localization than specify disease etiology. Electrodiagnostic
● Except in clinically
results must be interpreted in the clinical context and other supportive testing. As definitive cases,
a corollary for the practicing neurologist, an electrodiagnostic evaluation request electrodiagnostic testing
should include both relevant clinical details and diagnostic considerations. Each should be considered for
electrodiagnostic evaluation is uniquely tailored for the specific patient based on most patients with
peripheral nerve disease
the clinical context. The absence of this clinical context can result in
because there are many
uninformative electrodiagnostic studies. mimics with similar clinical
Not all patients with peripheral neuropathy require an electrodiagnostic presentations.
evaluation. A common rationale for deferring electrodiagnostic testing is that the Electrodiagnostic testing
often identifies the
results do not alter the clinical impression and will not change management.
presence of multiple
Even in patients with distal sensory neuropathies, electrodiagnostic testing has concomitant diseases.
been shown to not only change management but also change diagnosis and
provide additional diagnoses.12 However, patients with known diabetic sensory
polyneuropathy with no red flag symptoms typically do not need to undergo
electrodiagnostic evaluation. Electrodiagnostic studies can be helpful to parse
overlapping peripheral nervous system diseases and can help to discover
unexpected diagnoses such as rare “mimicker” peripheral nerve disorders.

Autonomic Function Testing

Autonomic function testing should be considered in the workup of peripheral
nerve disorders. Dysautonomia is a prominent component of many neuropathy
syndromes. In particular, it is commonly seen in diabetic neuropathies, amyloid
neuropathies, and GBS. Because of the nonspecific nature of dysautonomia
symptoms and many non-neurologic mimics (eg, lightheadedness, heart
palpitations, gastrointestinal symptoms, temperature intolerance), obtaining
autonomic function testing can be useful to ascertain if a related deficit in the
autonomic nervous system is present.
Autonomic function testing is not universally available, and testing protocols
are variable. Autonomic function testing generally includes tests of
cardiovascular adrenergic function, cardiovagal function, and sudomotor
function. Testing of cardiovascular adrenergic function involves a tilt-table test
and Valsalva test. Testing of cardiovagal function includes heart rate variability
to breathing and determination of the Valsalva ratio. Sudomotor function testing
is carried out in two ways. Quantitative sudomotor axon reflex testing (QSART)
evaluates postganglionic sympathetic sudomotor function via measuring sweat
response to acetylcholine that is iontophoresed into the skin. QSART can be
helpful in diagnosing and characterizing small fiber neuropathy and
distinguishing peripheral from central causes of dysautonomia (in which the
QSART is normal). Thermoregulatory sweat testing can evaluate both
preganglionic and postganglionic sudomotor function. In this test, a powder
indicator that changes color with sweat is applied to the patient’s body surface.
The patient is then placed in a controlled environment with monitoring of
ambient temperature, skin temperature, and humidity. Digital photographs and
computerized images are captured to assess for distributions of anhidrosis.13

Serum Laboratory Testing

Serum laboratory testing can help determine the specific etiology of peripheral
nerve disorders, and some patients may have multiple etiologies. The American
Academy of Neurology recommends testing for fasting glucose, vitamin B12

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TABLE 1-2 Recommended Blood Testing for Patients With Peripheral Nerve Disordersa

Consider in all patients

◆ Basic metabolic function panel with fasting glucose
◆ Complete blood cell count
◆ Liver function
◆ Vitamin B12
◆ Methylmalonic acid with or without homocysteine
◆ Serum protein electrophoresis with immunofixation
◆ Antinuclear antigen
◆ Sjögren syndrome antibodies A and B (anti-Ro, anti-La)
Consider in select patients depending on risk factors and clinical findings
◆ 2-Hour glucose tolerance test
◆ Hemoglobin A1c
◆ Thyroid function
◆ Vitamin B1 whole blood
◆ Vitamin E
◆ Vitamin B6
◆ Copper
◆ Zinc
◆ Human immunodeficiency virus (HIV)
◆ Lyme disease
◆ Hepatitis B and hepatitis C
◆ Cryoglobulin
◆ Rheumatoid factor
◆ Erythrocyte sedimentation rate
◆ C-reactive protein
◆ Antigliadin antibodies
◆ Antitransglutaminase antibodies
◆ Antineutrophil cytoplasmic antibodies
◆ Serum light chains
◆ Urine electrophoresis, immunofixation, and light chains
◆ Ganglioside antibodies
◆ Paraneoplastic antibodies
◆ Genetic testing for neuropathy

a
Modified with permission from Jin PH, Clin Geriatr Med.26 © 2021 Elsevier Inc.

1322 OCTOBER 2023

deficiency, and monoclonal gammopathies as the highest-yield blood tests for KEY POINTS
peripheral neuropathy.14 Previous practice guidelines recommended testing for
● All patients with sensory
monoclonal gammopathies only in patients older than 50 years, but this age peripheral neuropathy
cutoff has since been removed because of the increased prevalence of should be tested for fasting
monoclonal gammopathy of undetermined significance and multiple myeloma in blood glucose, vitamin B12
younger patients. levels, and serum
electrophoresis with
When testing for monoclonal gammopathy disorders, ordering both a serum
immunofixation.
protein electrophoresis and immunofixation increases diagnostic sensitivity.15
Beyond these tests, limited evidence-based guidance exists. In patients with ● Patients with idiopathic
atypical, acute, or subacute, non–length-dependent presentations, expanded sensorimotor
laboratory testing will be necessary. Peripheral nerve disease can be a heralding polyneuropathy, bilateral
carpal tunnel syndrome,
presentation in various other diseases, particularly rheumatologic disorders, lumbar stenosis, and
which may warrant further testing in some patients.16-18 dysautonomia should be
Complicating the challenge of testing for etiology, specifically in distal considered for amyloid
polyneuropathies, is the entity of idiopathic polyneuropathies. Despite thorough testing including genetic
testing for hereditary
workup, 11% to 31% of polyneuropathy cases have no identifiable cause.19 Repeat transthyretin amyloidosis.
laboratory testing generally does not yield additional information.20,21 Some of
these cases have been classified as chronic idiopathic axonal polyneuropathy,
which typically occurs between the ages of 50 to 60 years, and has a generally
benign course.19,22 Previously classified idiopathic neuropathies are occasionally
revealed to be adult-onset hereditary neuropathies. Genetic testing should be
considered in patients with phenotypes expected in genetic neuropathies and in
those with a family history of these conditions. An example of a genetic
phenotype is neuropathy secondary to transthyretin amyloidosis, which presents
as idiopathic sensorimotor polyneuropathy, bilateral carpal tunnel syndrome,
lumbar stenosis, and dysautonomia. Currently, evidence is insufficient to
suggest routine genetic testing in patients with idiopathic neuropathy.14,23 This
practice decision is complicated by the evolving context of increased accessibility
to genetic testing, the advances in specific disease-modifying treatment for
hereditary neuropathies (namely hereditary transthyretin amyloidosis
polyneuropathy), and the greater understanding of the clinical heterogeneity
and nonspecific presentations of hereditary peripheral nerve disorders.24,25
For a summary of recommended blood tests for polyneuropathy, see
26
TABLE 1-2.
CSF testing is occasionally warranted in the evaluation of peripheral nerve
disorders. Albuminocytologic dissociation can be helpful as a secondary
diagnostic marker for immune-mediated polyradiculoneuropathies such as
CIDP. Tests of malignancy including cytology and flow cytometry can be
diagnostic of neurolymphomatosis and carcinomatous meningitis. Testing for
cerebrospinal pleocytosis and microbial markers can establish a diagnosis for an
infectious polyneuropathy.

Peripheral Nerve Imaging

Peripheral nerve imaging can add diagnostic value in the correct context. Precise
diagnosis via clinical findings and electrodiagnostic testing can be limited by
various factors. Layering of multiple peripheral nerve diseases can lead to
electrodiagnostic test results that are difficult to interpret definitively. For
example, a patient with a sensorimotor distal polyneuropathy may have their
physical examination findings and electrodiagnostic testing results clouded by an
incidental presence of a lumbar radiculopathy. Additionally, the differentiation

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LOCALIZATION AND DIAGNOSTIC EVALUATION OF PERIPHERAL NERVE DISORDERS

of peripheral nerve disease based on clinical and electrodiagnostic findings

becomes increasingly more difficult in more advanced and severe presentations.
For example, advanced forms of a demyelinating peripheral nerve disease such as
CIDP can demonstrate findings of secondary axonal loss on electrodiagnostic
testing. Also, in the context of very proximal conduction block, routine nerve
conduction studies may fail to capture findings of acquired demyelination
sufficient to make a diagnosis, and imaging may enable diagnosis.27
MRI is a common diagnostic tool in the evaluation of peripheral nerve
disorders. Most commonly, MRI of the spine is considered to evaluate for
differential diagnoses of radiculopathy and myelopathy. MRI of the extremities,
particularly MRI neurography, can assess for extraneural and intraneural
mass lesions, abnormal signal and enlargement of nerves, contrast-enhancement
of nerves suggestive of blood-nerve barrier breakdown, and nerve
continuity.28
Neuromuscular ultrasound is a validated tool for the evaluation of peripheral
nerve disorders.29 The most common application in peripheral nerve disease is
the measurement of a cross-sectional area of peripheral nerves in the limb.
Neuromuscular ultrasound can determine areas of focal enlargement indicative
of focal or multifocal neuropathic disease. Although the most validated use of
neuromuscular ultrasound is the identification of common focal compressive
mononeuropathies such as carpal tunnel syndrome, the same principle of
identifying focal enlargement has been applied to the diagnosis of autoimmune
multifocal demyelinating polyneuropathies such as CIDP and multifocal motor
neuropathy.30 A pattern of focal areas of enlargement is distinct from axonal
peripheral nerve diseases such as distal sensory polyneuropathy, where the
peripheral nerve caliber is unchanged or mildly diffusely increased. Additionally,
neuromuscular ultrasound can identify fasciculations, mass lesions, myopathy,
muscle denervation, nerve continuity in traumatic injury, and the presence of
intraneural vascularity via power Doppler.31
Both MRI and neuromuscular ultrasound of peripheral nerves carry their
strengths and weaknesses. Neuromuscular ultrasound provides higher resolution
of peripheral nerve anatomy compared with MRI, but neuromuscular ultrasound
is limited by sonographic penetrance and has limited utility for studying deep
nerves such as the sciatic nerve in the thigh.32 Neuromuscular ultrasound
carries the advantage of dynamic imaging and can assess for fasciculations,
compressibility, muscle and tendon subluxation, and vascular flow.
Neuromuscular ultrasound technical proficiency is less common and is less
accessible compared with MRI. Unlike MRI, neuromuscular ultrasound is not yet
validated for contrast-enhanced studies.33

Skin Biopsy
Skin biopsy can assist in the evaluation of small fiber neuropathy. Testing is
typically pursued in select clinical contexts if evaluation for a polyneuropathy via
electrodiagnostic studies is normal. Testing involves a 3-mm punch biopsy of a
single limb (generally lower extremity) at sites of interest including the distal leg,
distal thigh, and proximal thigh. Biopsy samples are assessed for intraepidermal
nerve fiber density, which is expected to be reduced in small fiber neuropathies.
The pattern of density loss can also speak to the distal (length-dependent) or
multifocal (non–length-dependent) nature of the neuropathy. In addition to
intraepidermal nerve fiber density, biopsy samples can be stained to assess for

1324 OCTOBER 2023

the presence of amyloid deposition and for sudomotor innervation of KEY POINTS
sweat glands.34
● Imaging studies are most
helpful when clinical
Nerve Biopsy
suspicion for a specific
Nerve biopsy is considered in cases of progressive peripheral nerve disease diagnosis is high but
without identified etiology. A sensory nerve is typically selected, most commonly electrodiagnostic testing
the sural nerve. Nerve biopsy remains most useful in cases of suspected vasculitic results are ambiguous or
inconclusive.
neuropathy, neurolymphomatosis, nerve sheath tumors, amyloidosis,
sarcoidosis, and leprosy. With these diseases, other diagnostic testing is often ● Although neuromuscular
insufficient, and specific histopathologic diagnosis can lead to disease-modifying ultrasound provides greater
treatment. Beyond these diseases, the utility of nerve biopsy overall is limited. In resolution of peripheral
cases of ambiguous demyelinating and axonal polyneuropathies, histopathology nerve anatomy, it is
currently limited to the
often provides information already retrieved from electrodiagnostic testing.35 study of superficial nerves.
The study of deeper
(generally more proximal)
CONCLUSION peripheral nerves can be
accomplished via MRI
The initial clinical assessment of peripheral nerve diseases can be challenging neurography.
because of nonspecific presentations. A careful history and examination that
focuses on key clinical elements, with additional electrodiagnostic and laboratory ● Nerve biopsy is most
evaluation, can differentiate between diverse causes of peripheral nerve diseases useful in cases of suspected
vasculitic neuropathy and
as well as diseases that extend beyond the peripheral nervous system. Although
neurolymphomatosis. It can
the available potential workup for peripheral nerve disease is broad, the also be useful for the
practicing neurologist should focus and prioritize testing based on the initial diagnosis of nerve sheath
clinical and electrodiagnostic assessment. tumors, amyloidosis,
sarcoidosis, and leprosy.

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