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General Approach to
Address correspondence to
Dr James A. Russell,
Lahey Hospital and Medical
Center, Department of
KEY POINTS
h Peripheral neuropathy is designations of distal symmetric inflammatory demyelinating poly-
a common neurologic polyneuropathy, chronic axonal poly- radiculoneuropathy [CIDP], the neu-
problem, affecting neuropathy, or chronic idiopathic ropathy of monoclonal gammopathy
approximately 5% of axonal polyneuropathy, which have of undetermined significance).12
adults and as many as subtle conceptual differences, are gen- Patients should be informed that
30% of patients who erally used synonymously. good treatment options do not neces-
are elderly. The etiologies of peripheral neu- sarily follow from a diagnosis, such as
h Although they have ropathy are legion, exceeding 200 hereditary neuropathy, estimated to
minor conceptual depending on the classification system include as many as one-third of cases.2
differences, used.2,5,9 Identification and assign- However, informed diagnostic pursuit
distal symmetric ment of an etiology are influenced by provides the opportunity for diag-
polyneuropathy, chronic variables that include the population nostic closure, education regarding
axonal polyneuropathy, studied, the nature and intensity of the disorder’s natural history, and
and chronic idiopathic the evaluation, and the willingness to counseling germane to the preven-
axonal polyneuropathy
assign causation to a laboratory abnor- tion and management of potential
may be considered
mality that may be coincidental.1Y3,7,10 future morbidity. In the case of distal
as essentially
synonymous terms.
One study reporting a 58% prevalence sensory polyneuropathy, the patient
of test abnormalities in patients with can be reassured that progression
h Although the primary peripheral neuropathy considered only to nonambulation or amputation is
goal in the evaluation
9% of these abnormalities to be diag- uncommon.7,13
of a patient with
peripheral neuropathy
nostically significant.11 To be confi-
dent of a causal relationship between ANATOMIC, PHYSIOLOGIC,
is to identify the cause
whenever possible, a a test abnormality and peripheral AND PATHOPHYSIOLOGIC
common category of neuropathy, the clinician should con- CONSIDERATIONS IN
polyneuropathy is sider the neuropathy pattern and the PERIPHERAL NEUROPATHY
chronic idiopathic contextual features in each case, Understanding peripheral nerve anat-
axonal polyneuropathy, allowing generation of a relevant dif- omy and physiology is required for
which may represent ferential diagnosis aligned with these adequate clinical assessment and
close to a half of features. Judicious testing in the proper electrodiagnostic study design. Under-
patients with neuropathy clinical context reduces the risk of false- standing the pathophysiology of the
in some populations.
positive testing. disorder allows for rational therapeu-
h Accurate diagnosis of As with any diagnostic assessment, tic strategy and prognostication. In
polyneuropathy directs the patient should be advised of the view of their unique anatomic and
treatment in a limited risks and benefits involved in the physiologic properties, peripheral
number of cases but
diagnostic workup. Ideally, a treatable nerves are vulnerable to multiple
also provides the benefit
disorder is identified; however, diag- potential insults.14
of diagnostic closure,
opportunities for
nosis may be elusive. Following eval-
uation, 20% to 50% of patients are Axonal Polyneuropathies
education regarding the
natural history of the designated as chronic idiopathic axo- The viability of peripheral nerves
disease, and a means nal polyneuropathy or chronic axonal depends on the metabolic capabilities
by which to prevent polyneuropathy.1,3,4,7,11 Although a of anterior horn cells and dorsal root
and address potential 2016 study reported that a diagnosis ganglia and effective axon transport.
future morbidities. could be achieved in two-thirds of The latter is bidirectional and essential
284 patients with chronic idiopathic for axonal nutrition and support for
axonal neuropathy when reevaluated, the normal turnover of organelles
over half of these individuals were (particularly mitochondria) and pro-
assigned a diagnosis that should have teins (such as microtubules and
been apparent on initial evaluation neurofilaments).15 Anterograde trans-
(eg, diabetic neuropathy, chronic port from cell body to neuromuscular
1242 ContinuumJournal.com October 2017
KEY POINT
h In some cases, good juxtaparanodal regions of the internode autoantibodies, found in the vast
correlation appears to (Figure 1-1).24,25 Identifiable auto- majority of patients with Miller Fisher
exist between the antibodies in some of these disorders syndrome, are concentrated in the
anatomic location of have diagnostic or, in some cases, paranodal regions of cranial nerves III,
peripheral nerve probable pathogenic relevance.26Y33 IV, and VI. They have been demon-
antigenic targets, Their presence serves to justify immu- strated to block nerve conduction and
autoantibodies against nomodulating treatment in certain represent the most convincing example
these targets, and syndromes.31Y34 Some peripheral nerve of peripheral nerve disease linking an
specific peripheral antigens associated with well-defined autoantibody with a specific neuropathy
neuropathy syndromes. peripheral nerve syndromes are found syndrome.29Y33
exclusively in peripheral nerves (eg, The concept that autoantibodies
sulfoglucuronyl glycosphingolipid and might cause neuropathy is also rein-
the distal acquired demyelinating forced by the observation that the
symmetric [DADS] neuropathy associ- blood-nerve barrier is less well estab-
ated with IgM monoclonal proteins). lished at the nerve roots, dorsal root
Other autoantibodies demonstrate ganglia, and terminal nerve twigs. This
strong correlations between the pre- correlates with the pathologic observa-
dominant location of their target anti- tion that these regions are often pref-
gens and the clinical neuropathy erentially involved in the inflammatory/
pattern they are associated with.24,25,29 immune polyradiculoneuropathies.24,33
For example, the ceramide content of Additional support for immune-mediated
gangliosides differs between motor and nerve injury comes from the observa-
sensory nerves. Autoantibodies directed tion that the sera of patients with cer-
against GM1, GD1a, and GT1b ganglio- tain immune-mediated neuropathies
sides preferentially affect motor nerves (eg, multifocal motor neuropathy) is
and are most commonly found in high disruptive to the blood-nerve barrier.35
titer in motor-predominant neuropa- Little or no overlap appears to exist
thies. Conversely, GD1b autoantibodies in the molecular targets of autoimmune
preferentially target sensory nerves and and hereditary neuropathy.33 In general,
are most commonly associated with hereditary neuropathies are associated
ataxic neuropathy syndromes. GQ1b with genes coding for structural myelin
FIGURE 1-1 Diagram of a myelinated axon, showing subdivision into sections with
different diameters.
Modified with permission from Franssen H, Straver DC, Muscle Nerve.24 B 2013 Wiley Periodicals, Inc.
onlinelibrary.wiley.com/doi/10.1002/mus.24068/full.
KEY POINT
h The primary benefit
of neuropathy
classification is to limit
differential diagnostic
considerations in order
to generate a rational
and targeted
diagnostic strategy.
Modified with permission from Visser NA, et al, Neurology.1 B 2014 American Academy of
Neurology. neurology.org/content/84/3/259.full.
% of Patients
With the
% of Sensory Disease Who
Neuropathy Have Sensory
Categories Notable Examples Patients Neuropathy
Idiopathic NA 50 NA
Inflammatory/ Sjögren syndrome 5 39
immune
Paraneoplastic sensory neuronopathy Unknown 74
mediated
(anti-Hu positive)
Autoimmune hepatitis Unknown Unknown
Toxic Pyridoxine toxicity Unknown Unknown
Platin chemotherapy Unknown Unknown
Infectious Herpes zoster Unknown Unknown
Epstein-Barr virus Unknown Unknown
Human T-cell lymphotropic virus type 1 (HTLV-1) Unknown Unknown
Human immunodeficiency virus (HIV) Unknown Unknown
Hereditary/ Mitochondrial: polymerase + (POLG), sensory Unknown Unknown
degenerative ataxic neuropathy, dysarthria, and
ophthalmoplegia (SANDO)
Cerebellar ataxia, neuronopathy, vestibular Unknown Unknown
ataxia syndrome (CANVAS)
Spinocerebellar degeneration Unknown Unknown
Facial-onset sensory and motor neuropathy Unknown Unknown
(FOSMN)
NA = not applicable.
a
Data from Gwathney KG, Muscle Nerve.38 onlinelibrary.wiley.com/doi/10.1002/mus.24943/full.
painful length-dependent neuropa- ropathy is the ataxic sensory neurop- KEY POINT
thies, but one-fourth to a one-third athy associated with IgM monoclonal h Although the majority
of length-dependent
may be non-length dependent based proteins related, in many cases, with
polyneuropathies fall
upon distribution of symptoms and MAG autoantibodies.24,29 Hereditary into the chronic
intraepidermal nerve fiber density length-dependent neuropathies include idiopathic axonal
assessment.40Y42 Despite their charac- Charcot-Marie-Tooth disease (CMT) and polyneuropathy
teristic length-dependent clinical pat- the hereditary motor neuropathies (also category, acquired
tern, it has been postulated that small referred to as distal forms of spinal demyelinating
fiber neuropathies may represent dor- muscular atrophy).2,19,22,23 neuropathies and
sal root ganglionopathies.40Y44 NonYlength-dependent polyneu- motor-predominant
Length-dependent presentations may ropathies include neuronopathies, heritable neuropathies
also occur with demyelinating neuropa- multifocal neuropathies, polyradiculo- may occur in this
thies, both acquired and inherited.24,29 pathies, and polyradiculoneurop- pattern is well.
A notable example of an acquired athies. 2,45 Multifocal neuropathies
demyelinating length-dependent neu- commonly result from disorders that
KEY POINTS
h Multifocal neuropathies TABLE 1-4 Motor Neuropathies/Neuronopathies
typically result from
disorders that infarct, Pattern Notable Examples
inflame, or infiltrate
Length-dependent Hereditary motor neuropathy, hereditary spastic
nerves or render
pure motor paraparesis (some genotypes)
them more susceptible
to compression. Length-dependent Charcot-Marie-Tooth disease, toxins
motor predominant (arsenic, lead)
h The recommended
approach to peripheral Monomelic Benign focal amyotrophy/monomelic amyotrophy
neuropathy begins with Monomelic Amyotrophic lateral sclerosis/progressive muscular
pattern recognition progressing atrophy, infectious (polio/postpolio/West Nile
followed by to generalized virus/enterovirus D68), paraneoplastic (rare)
consideration of
Proximal symmetric/ Spinal muscular atrophy, acute motor axonal
contextual features,
generalized neuropathy (Guillain-Barré variant),
such as the chronologic hexosaminidase deficiency
course, risk factors,
and potential Multifocal Multifocal motor neuropathy (MMN)
involvement of other
organ systems. Testing
is then applied to
confirm or refute the infarct, inflame, or infiltrate nerves or ating. Guillain-Barré syndrome (or
potential causes render them more susceptible to acute inflammatory demyelinating
generated from compression (Table 1-5). Diabetes polyradiculoneuropathy [AIDP]) and
this strategy. mellitus and vasculitides are common CIDP are the most common forms of
h The intensity of both causes.45,46 Most are associated with this neuropathy syndrome (Table 1-7).
diagnostic evaluation axon loss and have both motor and
and treatment should sensory characteristics, dependent, in CLINICAL APPROACH
be influenced by the part, on the fiber types within the Polyneuropathy is initially suspected
impact of the affected nerve(s). Those with demyelin- based on characteristic symptoms
neuropathy on the
ating characteristics include multifocal occurring in characteristic patterns.
patient’s lifestyle,
motor neuropathy (MMN), multifocal The clinical strategy employed begins
including considerations
of both comfort
acquired demyelinating sensory and with identification of the pattern of
and function. motor neuropathy (MADSAM), heredi- involvement, with subsequent consid-
tary neuropathy with liability to pres- eration of contextual features such as
sure palsies (HNPP), and CMT type X the time course and risk factors,
in some cases.2,23,45 including any indication of other end
Polyradiculopathies are disorders organ involvement. A differential diag-
that affect multiple nerve roots. Lum- nosis is then generated in consider-
bosacral spinal stenosis is the most ation of these features and knowledge
common cause, resulting in mechanical of the causes of neuropathy known to
compression of lumbosacral nerve roots behave in this manner. Ancillary testing
within an anatomically compromised is then applied to confirm or refute
spinal canal. Polyradiculopathies may these suspicions. The clinical approach
also result from disorders that inflame to neuropathy should include an assess-
or infiltrate meninges and the nerve ment of how the neuropathy impacts
roots and cranial nerves that traverse the patient’s lifestyle, considering both
them (Table 1-6). comfort and function. Appreciation of
Polyradiculoneuropathies are typi- these factors allows rational testing and
cally acquired and axonal or demyelin- treatment determination.
Estimated
Prevalence of
Category Notable Examples All Types
Diabetes Large fiber sensory predominant 33%
mellitus
Small fiber 10Y25% of
above
Impaired glucose tolerance Unknown
Chronic Idiopathic 25Y55%
idiopathic
axonal
polyneuropathy
Small fiber Idiopathic 2%
neuropathy
Hereditary Charcot-Marie-Tooth disease 5Y33%
(hereditary motor sensory
neuropathy), hereditary sensory
and autonomic neuropathy,
hereditary motor neuropathy
Metabolic Vitamin B12/other nutritional 12%
deficiency, end organ failure/critical
illness polyneuropathy
Toxic Chemotherapy, industrial/ 14%
environmental toxins
Inflammatory Distal acquired demyelinating 9%
symmetric neuropathy associated
with IgM monoclonal protein
IgM = immunoglobulin M.
KEY POINTS
h Patients with an mal individuals. Proponents point out
TABLE 1-9 Neuropathy
indolent neuropathy Characteristics that denervation potentials in normal
and a chronic idiopathic Suggesting the individuals are rare, foot muscles are
axonal polyneuropathy Need for a More Intensive the most likely place to find early
pattern may require Evaluationa abnormalities, denervation potentials
limited testing as indicate motor involvement, and
recommended by b Acute to subacute onset examination of foot muscles facilitates
American Academy of b Rapid progression definition of length dependency and
Neurology guidelines. symmetry.
b Motor predominance
h Although the routine
use of electrodiagnosis b Non-length dependence Blood and Cerebrospinal
in peripheral neuropathy b Associated dysautonomia Fluid Testing
evaluation has been AAN guidelines suggest that routine
challenged, it remains b Associated systemic disease
laboratory work include vitamin B12,
a valuable diagnostic a
Modified with permission from
Watson JC, Dyck PJB, Mayo Clin
methylmalonic acid, and glucose levels
tool in the confirmation
Proc.7 B 2015 Mayo Foundation for and serum protein immunofixation in
and characterization Medical Education and Research.
of large fiber neuropathy
patients with distal symmetric poly-
mayoclinicproceedings.org/article/
and other conditions S0025-6196(15)00378-X/pdf. neuropathy patterns (Supplemental
that might mimic it. Digital Content 1Y1; links.lww.com/
CONT/A224).11,46 However, the guide-
h Acute to subacute
onset, significant
warrant consideration of more exten- lines also recognize the need for
asymmetry, motor sive testing.2,45,47 physician judgment in the evaluation
predominance, of patients with neuropathy based
dysautonomia, and Electrodiagnostic Testing upon the clinical situation, which may
evidence of other end An American Academy of Neurology justify additional testing.11 Additional
organ development (AAN) practice parameter endorses testing should be considered when a
are justifications for the use of electrodiagnostic testing patient does not conform to a distal
a more intensive in patients with suspected neuropa- symmetric polyneuropathy or chronic
evaluation in a patient thy.8,11,46 Patients with long-standing idiopathic axonal polyneuropathy
with neuropathy. symptoms and minimal morbidity pattern and has clinical or electro-
do not need electrodiagnostic test- diagnostic features suggesting an alter-
ing unless results are likely to influ- native cause (Table 1-9). CSF analysis
ence diagnosis and treatment. The is not routinely recommended in the
routine use of electrodiagnostic test- evaluation of distal symmetric poly-
ing in the evaluation of patients with neuropathy but should be considered
suspected neuropathy has recently with a polyradiculopathy or poly-
been both challenged and sup- radiculoneuropathy pattern.11
ported.6,9 For more information on Diabetes mellitus is estimated to be
electrodiagnostic testing, refer to the the cause of neuropathy in one-third
article ‘‘Neurophysiologic Studies in or more of cases in population-based
the Evaluation of Polyneuropathy’’ by studies and is widely recognized as the
John C. Kincaid, MD, FAAN,51 in this most common cause in developed
issue of Continuum. countries.1,3,5,6 The prevalence of
The role of needle examination of neuropathy is estimated at 8% at the
intrinsic foot muscles in the evaluation time of diagnosis with diabetes
of suspected peripheral neuropathy mellitus, increasing with disease dura-
has been debated. Detractors point tion to eventually affect as many as
to discomfort and the possibility of two-thirds of individuals with long-
finding denervation potentials in nor- standing disease.5 Of these, 10% to
1254 ContinuumJournal.com October 2017
KEY POINTS
h Current recommendations onset and absence of family history neuropathy pattern and clinical con-
for genetic evaluation of reduced the yield to 5%.55 text. In consideration of invasiveness,
chronic neuropathies is A proposed algorithm has been cost, low yield, and sacrifice of sensory
to initially test for the recently offered in consideration of nerve fibers, nerve biopsy is con-
PMP22 deletion/ these refined next-generation sequenc- sidered a diagnostic procedure of
duplication in an ing capabilities.55 This algorithm con- last resort. It may be performed as a
individual with siders nerve conduction velocity, age at research tool on motor nerve branches
demyelinating which the neuropathy is recognized, but is almost always clinically per-
conduction velocities. and family history to direct the genetic formed on sensory nerves, such as
Targeted evaluation of a patient with a chronic the sural, superficial fibular (peroneal),
next-generation
length-dependent neuropathy pattern. or superficial radial.61,62 In general,
sequencing is
In an individual with demyelinating nerve biopsies are always performed
recommended in those
individuals with
conduction velocities, PMP22 deletion/ on nerves whose SNAP is reduced or
negative PMP22 duplication testing is recommended as absent. Nerve biopsy is rarely clinically
analysis or in patients the initial test performed following used in patients with a distal sensory
with chronic axonal electrodiagnostic studies. Targeted polyneuropathy, hereditary neuropa-
neuropathies who are next-generation sequencing with copy thy, or inflammatory demyelinating
younger than 40 years number evaluation (if possible) is polyradiculopathy pattern. Biopsy in
of age, have a motor recommended in patients with a nega- patients with diabetes mellitus should
predominant pattern, tive PMP22 analysis with demyelinating be avoided unless a serious concern
or have other similarly conduction velocities or in patients with exists for a secondary (nondiabetic)
affected family unexplained chronic neuropathy who cause because of its limited value and
members.
are younger than 40 years of age, have risk of poor wound healing.
h Peripheral nerve biopsy a motor-predominant pattern, or have Skin biopsy is primarily performed
remains a valuable tool other family members with the same to assess the density of intraepidermal
in a very select group disorder.55 A& or C nerve fibers.44 The specimen
of individuals whose
As with all algorithms, exceptions can be obtained by different tech-
pattern suggests a
exist. Testing for an IgM monoclonal niques and from different locations,
cause for which biopsy
is likely to provide a
protein should be considered before but the standard is 10 cm proximal to
diagnosis that cannot genetic testing in an individual with a the lateral malleolus. The biopsy is
be confirmed with less chronic demyelinating length-dependent considered diagnostic of small fiber
invasive means. neuropathy that is sensory predominant neuropathy if the intraepidermal nerve
h Assessment of without other affected family members. fiber density is less than 5% of age-
epidermal nerve fiber Conversely, testing for hereditary neu- and gender-matched controls. Other
density through skin ropathy should be considered in older morphologic changes, such as axonal
biopsy is useful in individuals without a family history or swelling, are considered less accurate.
support of a diagnosis demyelinating electrophysiology if the In general, skin biopsy is performed
of small fiber phenotype is characteristic of a hered- with the goal of identifying the exis-
neuropathy but rarely itary neuropathy. CMT type 1B is one tence, but not the cause, of small fiber
identifies the genotype recognized to present at an neuropathy. Intraepidermal nerve fiber
underlying cause. older age without demyelinating elec- density has been reported to have a
trophysiologic features.58 sensitivity of 90%, a specificity and
positive predictive value of 95%, and a
Histologic Testing negative predictive value of 91% in the
Peripheral nerve biopsy is a valuable detection of small fiber neuropathy.44
tool for the evaluation of select pa- As these numbers have been acquired
tients with peripheral neuropathy.7,61,62 in the absence of an ideal gold stan-
Table 1-12 lists the disorders for which dard, their accuracy is not universally
biopsy can be useful as suggested by accepted.20,44 A normal study effectively
1258 ContinuumJournal.com October 2017
b Disorders for which nerve biopsy can be diagnostic where nerve biopsy is
endorsed if not readily achieved by less invasive means
Vasculitic neuropathy (systemic or nonsystemic)
Amyloidosis (primary systemic)
b Disorders for which nerve biopsy has characteristic or diagnostic features
where diagnosis is preferably achieved by less invasive means
Amyloidosis (hereditary)
Leprosy
Sarcoidosis
Neurofibromatous neuropathy
Neurolymphomatosis
Hereditary metabolic/multisystem diseases
Fabry disease, metachromatic leukodystrophy, Krabbe disease,
adrenomyeloneuropathy, polyglucosan body disease, giant axonal
neuropathy, Tangier disease
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP),
Guillain-Barré syndrome
Distal acquired demyelinating symmetric (DADS) neuropathy
Hereditary neuropathy with liability to pressure palsies (HNPP)
Hexacarbon toxicity
b Rare conditions for which nerve biopsy has been diagnostic in isolated reports
Silver toxicity
Hereditary disorders of uric acid metabolism
reassurance without intervention when 11. England JD, MD Gronseth GS, Franklin G,
et al. Practice parameter: evaluation of
it is not. Despite advances in our under- distal symmetric polyneuropathy: role of
standing of these disorders, this pro- laboratory and genetic testing (an
cess still begins at the bedside with evidence-based review). Neurology
2009;72(2):185Y192. doi:10.1212/
a physician who is skilled in pattern 01.wnl.0000336370.51010.a1.
recognition, knowledgeable about as-
12. Farhad K, Traub R, Ruzhansky KM,
sociated causes, and capable of evalua- Brannagan TH. Causes of neuropathy in
tion and management. patients referred as ‘‘idiopathic neuropathy’’.
Muscle Nerve 2016;53(6):856Y861.
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