Sensory Polyneuropathies

Review Article
Sensory
Address correspondence to
Dr Kelly Graham Gwathmey,
University of Virginia,
Department of Neurology,
Polyneuropathies PO Box 800394,

Charlottesville, VA 22908,
kgg2p@virginia.edu.
Kelly Graham Gwathmey, MD Relationship Disclosure:
Dr Gwathmey reports
no disclosure.
Unlabeled Use of
ABSTRACT Products/Investigational
Use Disclosure:
Purpose of Review: This article describes the methods of diagnosis and management Dr Gwathmey reports
of the sensory-predominant polyneuropathies. To simplify the approach to this no disclosure.
category of patients, sensory-predominant polyneuropathies are divided broadly into * 2017 American Academy
either small fiber (or pain-predominant) neuropathies and large fiber (or ataxia- of Neurology.
predominant) neuropathies, of which the sensory neuronopathies (dorsal root
ganglionopathies) are highlighted.
Recent Findings: Physicians can now easily perform skin biopsies in their offices,
allowing access to the gold standard pathologic diagnostic tool for small fiber
neuropathies. Additional diagnostic techniques, such as corneal confocal microscopy,
are emerging. Recently, small fiber neuropathies have been associated with a broader
spectrum of diseases, including fibromyalgia, sodium channel mutations, and voltage-
gated potassium channel antibody autoimmune disease.
Summary: Despite advances in diagnosing small fiber neuropathies and sensory
neuronopathies, many of these neuropathies remain refractory to treatment. In select
cases, early identification and treatment may result in better outcomes. ‘‘Idiopathic’’ should
be a diagnosis of exclusion and a thorough investigation for treatable causes pursued.
Continuum (Minneap Minn) 2017;23(5):1411–1436.
INTRODUCTION A% fibers and the small unmyelinated C

This article reviews the various condi- fibers that transmit noxious and thermal
tions that result in sensory polyneu- signals.1,2 In addition, the A% fibers
ropathies and guides the reader to the mediate preganglionic sympathetic and
optimal way to evaluate and treat parasympathetic function and the C
patients presenting with sensory symp- fibers mediate postganglionic auto-
toms. For the purpose of this article, nomic function.2,3 Dysfunction of these
the presentation, differential diagnosis, small myelinated and unmyelinated
pathophysiology, and treatment are fibers results in burning shooting pain
separated into small fiber (or pain- as well as paresthesia and loss of small
predominant) presentations and large fiber function on examination.2 In con-
fiber (or ataxia-predominant) presenta- trast, the large fiber neuropathies result
tions. Mixed small and large fiber from dysfunction of the A$ fibers that
sensory-predominant polyneuropathies mediate vibratory and touch sensation.1
(such as those caused by diabetes Patients who present with early-onset
mellitus) are covered briefly at the end. sensory ataxia may have pathology
Nerves are classified by size, which localized to the dorsal columns of the
correlates with their degree of mye- spinal cord, the dorsal root ganglia,
lination. Small fiber neuropathies are or the A$ nerve fibers, all of which
disorders that affect the small somatic carry large fiberYmediated propriocep-
fibers, including the small myelinated tive information. Although the clinical
Continuum (Minneap Minn) 2017;23(5):1411–1436 ContinuumJournal.com 1411

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Sensory Polyneuropathies
KEY POINTS
h Small fiber neuropathies hallmark of large fiber neuropathies is report that nonpainful stimuli are
result in burning pain ataxia, damage to the small and painful (allodynia) or that they perceive
and paresthesia, medium-sized fibers may also occur, painful stimuli as even more painful
whereas patients who resulting in the positive sensory symp- (hyperalgesia). Neuropathic pain will
present with early-onset toms described above. The sensory often worsen at night and impair sleep.
sensory ataxia typically neuronopathies (or dorsal root gang- Autonomic nerve dysfunction may
have pathology that lionopathies) are caused by dysfunction range from mildly decreased sweating
localizes to the dorsal of the dorsal root ganglia and are in the affected areas to more general-
columns, dorsal root described in this article as they classi- ized dysfunction, including dry eyes,
ganglia, or large cally present with sensory ataxia. dry mouth, orthostatic dizziness, erec-
nerve fibers.
The patient’s clinical presentation, tile dysfunction, palpitations, urinary
h Small fiber neuropathies examination, and evaluation, includ- retention, gastroparesis, constipation,
commonly present in ing electrophysiologic testing and hypohidrosis, hyperhidrosis, and skin
a length-dependent skin biopsy, will further support the discoloration.3,6,7 The time course varies
pattern. A patchy,
localization of the polyneuropathy to depending on the etiology. For exam-
nonYlength-dependent
either the small fibers or large fiber ple, treatment-induced neuropathy of
pattern suggests an
autoimmune etiology.
pathways (dorsal columns, dorsal root diabetes mellitus presents acutely,
ganglia, or large nerve fibers). This, in whereas idiopathic small fiber neuropa-
h In patients with small turn, will allow the physician to arrive thies are often indolent. Table 10-1 8Y13
fiber neuropathies,
at a differential diagnosis to guide lists various causes of small fiber neu-
large fiberYmediated
sensation, strength,
testing and management. ropathies along with their associated
reflexes, and gait features and diagnostic evaluations.
should be normal.
SMALL FIBER NEUROPATHY On examination, patients may have
HISTORY AND EXAMINATION dry, shiny, discolored, and atrophic skin
Patients presenting with small fiber in the affected areas due to loss of distal
neuropathies may have negative neuro- autonomic vasomotor control. Patients
pathic symptoms (loss of sensation) or will have decreased pain (often tested
positive neuropathic symptoms (burn- with pinprick) and temperature sensa-
ing, shooting, paresthesia) that typically tion in either a length-dependent or
follow a length-dependent or stocking- nonYlength-dependent pattern. Muscle
glove pattern. Rarely, patients will have a stretch reflexes, proprioception, and
nonYlength-dependent pattern with strength are preserved. As the dysfunc-
prominent involvement of the face, tion is localized only to the small nerve
trunk, and arms. This nonYlength- fibers, ambulation should be spared,
dependent pattern may be seen in although may be antalgic.
patients with autoimmune diseases,
such as Sjögren syndrome, celiac dis- SENSORY NEURONOPATHY
ease, sarcoidosis, and paraneoplastic HISTORY AND EXAMINATION
syndromes, as well as in patients with The clinical hallmark of sensory
diabetes mellitus, impaired glucose tol- neuronopathies is early-onset ataxia
erance, vitamin B12 deficiency, and due to damage to the afferent fibers
paraproteinemia.4 Loss of thermal sen- carrying proprioceptive information
sation leads to inability to sense hot from the proximal arms and legs.14
versus cold, and loss of noxious sensa- When severe, this results in writhing
tion results in painless injuries and movements of the fingers and toes
numbness. The pain caused by small when the eyes are closed called
nerve fiber dysfunction is often de- pseudoathetosis.14,15 When the small
scribed as burning, shooting, electrical, and medium-sized nerves are involved,
or tingling paresthesia.5 Patients may the patient may also experience painful
1412 ContinuumJournal.com October 2017

TABLE 10-1 Disorders Associated With Small Fiber Neuropathy
Etiology Associated Features Diagnostic Evaluation

Metabolic
Impaired glucose Central obesity, sedentary lifestyle, 2-hour glucose tolerance test, fasting
tolerance, impaired risk of developing type 2 diabetes blood sugar, glycosylated hemoglobin
fasting glucose mellitus
Diabetes mellitus Polyuria, polydipsia, retinopathy, Glycosylated hemoglobin, 2-hour glucose
nephropathy tolerance test, fasting blood sugar
Treatment-induced Acute onset of pain within Clinical diagnosis
neuropathy of 8 weeks of correcting hyperglycemia
diabetes mellitus
Hyperlipidemia Increased risk of coronary artery Lipid profile including triglycerides
(especially disease and cerebrovascular disease
hypertriglyceridemia)
Immune-mediated
Sarcoidosis Cough; dyspnea; chest pain due to Chest x-ray, serum angiotensin-converting
diffuse interstitial lung disease; enzyme, lymph node or other tissue biopsy
extrapulmonary involvement,
including kidneys, skin, heart,
joints, eyes, lymph nodes
Sjögren Sicca symptoms (xerophthalmia, Anti-Ro (SSA)/anti-La (SSB) antibodies,
syndrome xerostomia) rose bengal test, Schirmer test, lip/salivary
gland biopsy
Systemic lupus Rash, Raynaud syndrome, arthralgia, ANA, antiphospholipid antibodies,
erythematosus renal impairment, cardiac disease, complement levels, ESR/CRP, anti-dsDNA
hematologic abnormalities and anti-Smith antibodies
Celiac disease Diarrhea, flatulence, malabsorption Antigliadin antibodies (serum IgA
endomysial and tissue transglutaminase
antibody), IgG-deamidated gliadin
peptides, small bowel biopsy, testing
for HLA DQ2/DQ8
Inflammatory Abdominal pain, diarrhea, bloating, Routine laboratory studies, including
bowel disease rectal bleeding inflammatory markers, endoscopy,
(Crohn disease barium studies
and ulcerative
colitis)
Paraneoplastic Malignancy association likely with Voltage-gated potassium channel
anti-Hu antibodies; with CASPR2 antibodies, CASPR2 and anti-Hu antibodies
antibodies, subtype of voltage-gated
potassium channel antibodies may
have encephalitis and peripheral
nerve hyperexcitability; with anti-Hu,
often have large fiber involvement
and may have associated limbic
encephalitis, cerebellar dysfunction,
autonomic dysfunction
Continued on page 1414

TABLE 10-1 Disorders Associated With Small Fiber Neuropathy Continued from page 1413
Etiology Associated Features Diagnostic Evaluation

Infectious
Leprosy Affects cool regions; skin changes, enlarged Serum antibodies to phenolic
nerves, anhidrosis glycolipid-I, skin biopsy or nerve
biopsy for acid-fast bacilli
HIV Associated with lower CD4 counts and higher HIV viral load and CD4 count
viral loads
Hepatitis C Hepatitis, cirrhosis, may occur without Hepatitis C virus antibody,
cryoglobulinemia hepatitis C PCR
Cryoglobulinemia Typically occurs with hepatitis C virus and mixed More often associated with
cryoglobulinemia, purpuric cutaneous lesions, mixed cryoglobulinemia; check
arthralgia; often with large fiber involvement cryoglobulins, hepatitis C virus
antibody and PCR
Toxins
Drugs Many associations, including antiretrovirals, Temporal relation to drug use
bortezomib, flecainide, metronidazole, and duration of use
nitrofurantoin, and others
Alcohol Cirrhosis, platelet dysfunction, anemia, pancreatitis Temporal relation to alcohol
use and duration of alcohol use
Hereditary
Hemochromatosis Fatigue, cirrhosis, pancreatic involvement High serum ferritin
(diabetes mellitus), arthritis, cardiomyopathy,
hyperpigmented skin, hypogonadotrophic
hypogonadism
Fabry disease Males (X-linked), episodic pain, strokes, hearing !-Galactosidase A mutation
loss, angiokeratomas, corneal opacities; female (enzyme assay to measure
carriers may have a milder phenotype !-galactosidase A activity)
Familial Sensory and autonomic neuropathy, carpal Genetic testing for transthyretin
amyloidosis tunnel syndrome, cardiac and renal involvement (TTR), apolipoprotein A1
(APOA1), and gelsolin
(GSN) mutations
Ehlers-Danlos More common in hypermobile type Clinical diagnosis, includes
syndrome hypermobile joints
and hyperextensible skin
Other
Fibromyalgia Diffuse muscle pain and fatigue Several published diagnostic
criteria for fibromyalgia8Y13
Sporadic Cardiomyopathy, renal failure with nephrotic Serum protein electrophoresis,
amyloidosis syndrome, hepatosplenomegaly, enlarged immunofixation, light chains,
muscles, skin changes, increased bleeding, abdominal fat pad biopsy,
autonomic dysfunction rectal mucosa biopsy
Idiopathic Diagnosis of exclusion
ANA = antinuclear antibody; CASPR2 = contactin-associated proteinlike 2; CRP = C-reactive protein; dsDNA = double-stranded
deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus; HLA = human leukocyte antigen;
IgA = immunoglobulin A; IgG = immunoglobulin G; PCR = polymerase chain reaction; SSA = Sjögren syndrome A; SSB = Sjögren
syndrome B.

KEY POINTS
positive sensory symptoms. These dis- Sensory neuronopathies are charac- h Sensory neuronopathies
orders often result in numbness and terized by absent or reduced-amplitude are characterized by
positive sensory symptoms in a sensory nerve action potentials (SNAPs) early-onset sensory
nonYlength-dependent and multifocal with normal or slightly reduced sensory ataxia. The numbness is
pattern, which differentiates them from conduction velocities.19 Motor nerve classically multifocal and
the typical length-dependent sensory conduction studies should be normal. nonYlength dependent.
and motor polyneuropathies. Nystag- Paraneoplastic sensory neuronopathies, h Nerve conduction
mus has been reported due to failure such as anti-Hu syndromes, may have studies and EMG
of proprioceptive input from the ex- motor nerve involvement and conduc- are normal in small
traocular or vestibular system.16,17 tion abnormalities in either an axon loss fiber neuropathies.
Strength is usually spared, although it or demyelinating pattern.19 h The most helpful
is not uncommon for the motor fibers Blink reflexes have been demon- autonomic tests for
to be affected in paraneoplastic sensory strated to be abnormal in patients with small fiber neuropathies
neuronopathies. Patients may appear Sjögren syndromeYassociated, idio- are the quantitative
weak, however, as they have difficulty pathic, and paraneoplastic sensory sudomotor axon
sustaining steady motor output be- neuronopathies.20 Figure 10-1 shows reflex test and
cause of lack of proprioceptive feed- a diagnostic algorithm for small fiber thermoregulatory
back. Muscle stretch reflexes are often neuropathies, and Figure 10-2 shows sweat test; however,
these tests are not
unelicitable.14 The time course for a diagnostic algorithm for sensory
widely available.
sensory neuronopathies is variable and neuronopathies.
can be subacute in paraneoplastic,
immune-mediated, or postinfectious Autonomic Testing
cases or indolent in the idiopathic A number of neurophysiologic tests
forms.14,16,18 Table 10-2 lists ataxic neu- other than nerve conduction studies
ropathies, their symptoms, clinical char- and EMG have been studied and used
acteristics, and diagnostic evaluations. in small fiber neuropathies, including
autonomic testing, quantitative sensory
DIAGNOSTIC STUDIES testing for hot and cold sensation,
The diagnosis of sensory polyneu- sympathetic skin response, laser-evoked
ropathies relies heavily on neurophys- potentials recording, and electrochemi-
iologic testing and pathologic studies, cal skin conductance.21
including skin biopsy and corneal Autonomic testing is particularly
confocal microscopy. Imaging is typi- helpful in the evaluation of small fiber
cally only used in the context of neuropathies, especially in the pres-
sensory neuronopathies. ence of dysautonomia.22 Standard
tests of autonomic function include
Nerve Conduction Studies and sympathetic adrenergic, parasympa-
Electromyography thetic cardiovagal, and sudomotor
Routine nerve conduction studies and function testing. In small fiber neu-
EMG should be normal in small fiber ropathies, the two most helpful tests
neuropathies, although many neu- are the quantitative sudomotor axon
ropathies that are clinically small fiber reflex test (QSART) and thermoregu-
predominant will have electrophysio- latory sweat testing7 neither of which
logic evidence of large fiber involve- is widely available. QSART measures
ment. An electrodiagnostic study local sudomotor function mediated by
showing no evidence of polyneurop- postganglionic unmyelinated sympa-
athy (including presence of sural and thetic axons by detecting change in
plantar responses) does not exclude sweat production after acetylcholine
a pure small fiber polyneuropathy. is transported into the skin using a
TABLE 10-2 Causes of Ataxic Neuropathies and Neuronopathies
Associated Symptoms and

Etiology Clinical Characteristics Diagnostic Evaluations
Immune-mediated
Connective tissue disease
Sjögren syndrome Sicca symptoms (xerophthalmia, Anti-Ro (SSA)/anti-La (SSB)
xerostomia); usually presents as antibodies, rose bengal test,
a sensory neuronopathy Schirmer test, lip/salivary
gland biopsy
Systemic lupus erythematosus Rash, Raynaud syndrome, ANA, antiphospholipid
arthralgia, renal impairment, antibodies, complement
cardiac disease, hematologic levels, ESR, CRP,
abnormalities anti-dsDNA and
anti-Smith antibodies
Demyelinating polyneuropathies
Ataxic Guillain-Barré syndrome Without ophthalmoplegia Antibodies against
(differentiates from Miller anti-GD1b and GQ1b, CSF
Fisher syndrome), with albuminocytologic
preceding infection, dissociation
distal paresthesia, impaired
sensation, prominent gait ataxia
Miller Fisher syndrome Ophthalmoplegia, ataxia, areflexia, Anti-GQ1b antibodies
preceding infection
Distal acquired demyelinating Sensory ataxia with minimal Anti-MAG antibodies, IgM
symmetric (DADS) neuropathy weakness, symmetric, distal monoclonal gammopathy,
or anti-MAG neuropathy sensory and motor deficit, characteristic
slowly progressive, more electrophysiologic studies
common in older people with very prolonged
distal motor latencies and
lack of conduction block
Chronic ataxic neuropathy, Sensory loss, mild weakness, Anti-GD1b antibodies,
ophthalmoplegia, M protein, ophthalmoplegia, trigeminal elevated ESR; CSF may
agglutination with disialosyl neuropathy, bulbar dysfunction demonstrate elevated
antibodies (CANOMAD)a protein
Chronic inflammatory Gait ataxia, sensory symptoms, Normal nerve conduction
sensory polyradiculopathy (CISP) loss of large fiberYmediated studies, abnormal SSEPs;
sensation, frequent falls enlarged nerve roots and
elevated CSF protein
Gait ataxia, late-onset, Ataxia, sensory-predominant Monoclonal gammopathy
polyneuropathy (GALOP) polyneuropathy (IgM), autoantibodies
against central
myelin antigen (CMA)

TABLE 10-2 Causes of Ataxic Neuropathies and Neuronopathies Continued from page 1416

Other autoimmune
Paraneoplastic Associated malignancy, often small cell lung Anti-Hu and anti-CV2/
sensory cancer; may have prominent pain and some CRMP-5 antibodies,
neuronopathy motor involvement; may have associated malignancy workup
limbic encephalitis, cerebellar dysfunction,
autonomic dysfunction
Celiac disease Diarrhea, flatulence, malabsorption Antigliadin antibodies
(serum IgA endomysial
and tissue
transglutaminase
antibody),
IgG-deamidated
gliadin peptide, small
bowel biopsy, testing
for HLA DQ2/DQ8
Autoimmune Hepatomegaly, jaundice, liver failure AntiYsmooth muscle
hepatitis antibodies, ANA, ALKM-1
and ALC-1 antibodies
Fibroblast growth Severe painful sensory neuronopathy FGFR3 antibodies
factor-3 (FGFR3) with ataxia and frequent trigeminal
antibody associated involvement
Nutritional deficiencies
Vitamin B12 Distal weakness, spasticity and upper Vitamin B12, MMA,
(subacute motor neuron findings, megaloblastic homocysteine
combined anemia, cognitive impairment
degeneration)
Copper Zinc toxicity predisposes (from zinc Copper, CBC with
supplements, denture cream); associated differential, consider
with spasticity/hyperreflexia, sensory spine MRI (T2 signal
ataxia, large fiber involvement, progressive increased in posterior
asymmetric weakness; may have associated columns)
hematologic features
Folic acid Progressive leg numbness and ataxia Red blood cell folate
and serum homocysteine
(high)
Vitamin E Deficiency can be due to malabsorption/ Vitamin E
malnutrition; prominent large fiber
dysfunction, sensory ataxia
Thiamine Polyneuropathy may be acute or chronic; sensory Do not wait for levels
(vitamin B12) and motor symptoms, neuropathic pain (eg, serum thiamine,
erythrocyte transketolase
If associated with Wernicke syndrome, will also
activation assay) to come
have acute onset of confusion, ataxia,
back before treating
ophthalmoplegia

TABLE 10-2 Causes of Ataxic Neuropathies and Neuronopathies Continued from page 1417

Toxic
Chemotherapy Sensory ataxia with paresthesia Use of platinum drugs
(platinum-based)
Pyridoxine (vitamin B6) Sensory ataxia Vitamin B6
Nitrous oxide Pansensory neuropathy and Clinical history of nitrous
myelopathy, megaloblastic anemia oxide abuse
Hereditary
Friedreich ataxia Cerebellar ataxia, gait instability, Frataxin mutation, expansion
dysarthria, dysphagia, large fiber of number of GAA repeats
sensory loss, weakness, spasticity
Sensory ataxic neuropathy, Large and small fiber neuropathy, POLG mutations, dominant
dysarthria, and sensory ataxia, variable strength, or recessive
ophthalmoparesis (SANDO) ptosis, ophthalmoplegia
Neuropathy, ataxia, Sensory neuropathy, cerebellar Adenosine triphosphate (ATP)
retinitis pigmentosa (NARP) ataxia, retinitis pigmentosa synthase 6 mutation, maternally
inherited
Abetalipoproteinemia, Prominent large fiber dysfunction, Vitamin E; microsomal triglyceride
vitamin E transporter sensory ataxia transfer protein mutations;
deficiency low circulating $-lipoproteins,
VLDL, LDL, chylomicrons
Infectious
Syphilis (tabes dorsalis) Impaired large fiberYmediated MHA-TP or FTA-ABS
sensation, lightening pain, Argyll
Robertson pupils, autonomic
dysfunction, Charcot joints, aortitis
Human T-cell lymphotropic Myelopathy, sensory ataxia, urinary HTLV-I / II, MRI with increased T2
virus type I (HTLV-I)/ and fecal incontinence signal in the lateral columns
human T-cell lymphotropic and cord atrophy
virus type II (HTLV-II)
Other
Cerebellar ataxia, Cerebellar ataxia, nystagmus, Brain MRI with cerebellar atrophy,
neuropathy, vestibular sensory polyneuropathy, abnormal vestibulo-ocular reflex,
areflexia syndrome autonomic abnormal autonomic testing
(CANVAS)
ALC-1 = anti-liver cytosol antigen; ALKM-1 = anti-liver/kidney microsome antibody; ANA = antinuclear antibody; CBC = complete blood
count; CRMP-5 = collapsin response mediator protein-5; CRP = C-reactive protein; CSF = cerebrospinal fluid; dsDNA = double-stranded
deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; FTA-ABS = fluorescent treponemal antibody absorption; HLA = human
leukocyte antigen; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; LDL = low-density lipoprotein; MAG =
myelin-associated glycoprotein; MHA-TP = microhemagglutination assay for Treponema pallidum antibodies; MMA = methylmalonic acid;
MRI = magnetic resonance imaging; POLG = polymerase DNA gamma; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B; SSEP =
somatosensory evoked potential; VLDL = very-low-density lipoprotein.
a
The term chronic ataxic neuropathy with disialosyl antibodies (CANDA) has been adopted by some experts as a more inclusive (and less
limiting) term.

FIGURE 10-1 A diagnostic algorithm for small fiber neuropathies.
ACE = angiotensin-converting enzyme; ANA = antinuclear antibody; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate;
HIV = human immunodeficiency virus; SPEP = serum protein electrophoresis; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B.
small electrical current (iontophoresis). the core body temperature in a hot and
Four standard sites are used (proximal humid environment.7 An indicator dye
foot, distal leg, proximal leg, and is applied to the body and measures
forearm), and the sweat response is maximal sweating. The percentage of
recorded from sweat chambers that are anhidrosis is calculated from photo-
separated from the stimulus compart- graphs of the sweat distribution on the
ment.7 The addition of QSART to the anterior body. Thermoregulatory sweat
clinical examination, quantitative sen- testing has been reported to be abnor-
sory testing, and skin biopsy increases mal in up to 91% of patients with small
the diagnostic yield in small fiber fiber neuropathy.7 In a large series of
polyneuropathies.23 A correlation exists patients with small fiber polyneu-
between the severity of loss of intra- ropathy, 98% had abnormal sudomotor
epidermal nerve fibers (somatic C-fiber testing, and a length-dependent pattern
involvement) and QSART abnormalities of sudomotor dysfunction was appreci-
testing autonomic C-fiber involvement.24 ated in most.7
Thermoregulatory sweat testing dem- Testing of cardiovagal function is
onstrates sweat production by raising assessed through the heart rate response
FIGURE 10-2 A diagnostic algorithm for sensory neuronopathies.
ANA = antinuclear antibody; CMRP-5 = collapsin response mediator protein-5; CRP = C-reactive protein; CT = computed tomography;
dsDNA = double-stranded deoxyribonucleic acid; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; FDG-PET = fludeoxyglucose
positron emission tomography; HIV = human immunodeficiency virus; HTLV = human T-cell lymphotrophic virus; MRI = magnetic resonance
imaging; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B; TTG = tissue transglutaminase; VZV = varicella-zoster virus.
Modified with permission from Gwathmey KG, Muscle Nerve.18 B 2015 Wiley Periodicals, Inc.
onlinelibrary.wiley.com/wol1/doi/10.1002/mus.24943/abstract.
KEY POINT to deep breathing and the Valsalva ra- sensory testing and intraepidermal
h Skin biopsy is the tio. Sympathetic adrenergic testing is nerve fiber density) are considered inde-
pathologic gold assessed by beat-to-beat blood pres- pendent and complementary measures
standard for diagnosing
sure response during Valsalva maneuver of small fiber function.25
small fiber neuropathy.
and head-up tilt. Adrenergic function is
measured by phase 2 and phase 4 of the Skin Biopsy
blood pressure response to Valsalva The majority of patients with small
maneuver. While these studies may fiber neuropathy do not need a skin
demonstrate cardiovagal and sympa- biopsy to support the diagnosis; the
thetic adrenergic dysfunction in small history and examination findings are
fiber polyneuropathies, the changes are sufficient. However, skin biopsy is a
typically mild.7 Autonomic testing and validated efficient technique used to
somatic sensory testing (quantitative diagnose small fiber neuropathy and is

considered the pathologic gold stan- Corneal Confocal Microscopy in
dard.22,26 The diagnostic sensitivity and Small Fiber Neuropathies
specificity of skin biopsy have not been Corneal confocal microscopy is an emer-
independently verified, so currently ging noninvasive diagnostic tool for
they have been defined through a assessment of corneal trigeminal small
clinical standard.27 Sensitivities of skin sensory fibers and immune cells that
biopsy have ranged from 45% to 90%22 has been applied to the study of small
and specificities from 95% to 97%.22,27 fiber neuropathies.30 At present, this
These procedures are easily performed technique is primarily used in the re-
in the outpatient setting. A 3-mm punch search realm and is not commonly used
skin biopsy is taken typically at the by clinical neurologists. Corneal nerve
distal leg 10 cm above the lateral fiber density is decreased and tortuosity
malleolus.2 Sites are added at the increased in patients with small fiber
lateral distal thigh, lateral proximal thigh, neuropathies.30,31 Abnormalities have
and upper extremity to explore the been described in patients with impaired
presence of a nonYlength-dependent glucose tolerance,31 diabetes mellitus,32
pattern.2 and idiopathic small fiber neuropathy.33
Intraepidermal nerve fiber density
Imaging
is the criterion most accepted to sup-
port a clinical diagnosis of small fiber Imaging has a role in the sensory neu-
neuropathy. Exposure of skin biopsy ronopathies. Most often, imaging is used
preparations to the antibody to protein to identify an underlying malignancy in
gene product 9.5, a neuronal form those with a suspected paraneoplastic
of ubiquitin carboxyl-terminal hydro- etiology. MRI may demonstrate in-
lase transported with the slow compo- creased T2-weighted signal in the dorsal
nent of axonal transport, allows for columns as the result of degeneration of
central sensory projections.17 Recently,
visualization and quantification of the
techniques such as multiple-echo data
small fiber innervation of the epider-
image combination (MEDIC) and turbo
mis.28 In addition, the sudomotor fibers
inversion recovery magnitude (TIRM)
around the sweat glands and pilomotor
have shown characteristic changes in
fibers within the arrectores pilorum
sensory neuronopathies.34
muscles can be quantified to support
involvement of the autonomic nervous SPECIFIC SMALL FIBER
system.2,5 NEUROPATHIES
A study of small fiber neuropathy Small fiber neuropathies are associated
reported that patients lose epidermal with a number of etiologies, ranging
nerve fibers at similar rates, whether the from metabolic diseases to drug toxic-
etiology is impaired glucose tolerance, ities, infections, autoimmune diseases,
diabetes mellitus, or idiopathic.29 No and inherited causes. Only a few specific
difference was seen in loss of epidermal small fiber neuropathies are discussed
nerve fibers at proximal and distal in detail here. Refer to Table 10-1 for a
biopsy sites, suggesting that these small more comprehensive list.
fiber polyneuropathies are nonYlength-
dependent terminal axonopathies. Skin Small Fiber Neuropathy Due to
biopsy in small fiberYpredominant sen- Diabetes Mellitus, Impaired
sory neuronopathies may also demon- Glucose Tolerance, and
strate a nonYlength-dependent pattern Metabolic Syndrome
of reduced intraepidermal nerve fiber Diabetes mellitus is the most com-
density.14 mon cause of peripheral neuropathy

KEY POINTS
h Metabolic syndrome is worldwide and may cause a small and likely prevents neuropathy in pa-
associated with small fiber neuropathy, large fiber sensory- tients with type 2 diabetes mellitus.46
fiber polyneuropathy. predominant neuropathy, or sensori- The amount of benefit derived from
Lifestyle intervention motor neuropathy.35 Diabetes mellitus glucose control is limited, as patients
may have a role in is diagnosed with a glycosylated he- may progress to clinical neuropathy
preventing the moglobin (hemoglobin A1c) higher despite intensive glucose control.41
development of and than 6.5%, a glucose of 200 mg/dL Some patients stabilize without im-
treating established following a 2-hour oral glucose toler- provement.47 Diet and exercise may
neuropathy in patients ance test, or a fasting glucose of delay the transition from impaired
with impaired greater than or equal to 126 mg/dL.36 glucose tolerance to diabetes mellitus
glucose tolerance.
Individuals classified as prediabetic and may prevent the onset of neurop-
h Treatment-induced have a glycosylated hemoglobin be- athy in patients with type 2 diabetes
neuropathy of diabetes tween 5.7% and 6.4%, a 2-hour glucose mellitus. 48 The Impaired Glucose
mellitus is an acute tolerance test glucose of 140 mg/dL Tolerance Neuropathy Study demon-
small fiber neuropathy
to 199 mg/dL, or a fasting blood strated improvement in small fiber
with severe neuropathic
glucose of 100 mg/dL to 125 mg/dL.36 neuropathy measures (intraepidermal
pain that occurs in
the setting of
Diabetes mellitus and glucose intol- nerve fiber density, QSART, and pain
rapid correction erance are present in one-third of scores) and features of metabolic
of hyperglycemia. patients with a distal sensory poly- syndrome (body mass index, oral glu-
neuropathy.37 Nearly 50% of those cose tolerance test, cholesterol, and
who would otherwise be labeled as triglycerides) at 1 year with lifestyle
having idiopathic sensory neuropathy interventions.39 For most patients,
have evidence of impaired glucose management also includes treatment
tolerance, although whether this is an of neuropathic pain. Commonly used
association or causative is unclear.38Y40 neuropathic pain medications are
Metabolic syndrome is diagnosed in listed in Table 10-3.
the presence of a combination of Treatment-induced neuropathy of
dyslipidemia, elevated blood pressure, diabetes mellitus. Treatment-induced
central obesity, and either diabetes neuropathy of diabetes mellitus, previ-
mellitus or prediabetes and has a ously also called insulin neuritis, is an
prevalence of 35% to 38% in the US acute small fiber neuropathy that oc-
population.3,41 Metabolic syndrome has curs with rapid correction of hypergly-
been reported to be an association or cemia (Case 10-1). This entity has
possible risk factor for distal sensory been described in patients treated with
neuropathy.42Y44 A cross-sectional study insulin, oral hypoglycemics, and weight
of 548 patients with type 2 diabetes loss who experience rapid glycemic
mellitus demonstrated that those with control.49 Severe neuropathic pain can
metabolic syndrome were twice as develop acutely within 8 weeks, may
likely to have a distal sensory neu- be length dependent or diffuse, and
ropathy as those without.42 Indepen- usually has associated hyperalgesia and
dent of hyperglycemia, obesity and allodynia. Autonomic dysfunction may
dyslipidemia are heavily associated follow the onset of neuropathic pain.49
with neuropathy.43,44 Hypertriglyceri- The pathophysiology of this disorder
demia in particular may be associated is unclear. One study reported a
with the development of small fiber strong correlation between the change
neuropathy.45 in glycosylated hemoglobin and the
Tight glucose control in type 1 severity of neuropathic pain.49 The
diabetes mellitus is known to prevent incidence of treatment-induced neu-
the development of clinical neuropathy ropathy of diabetes mellitus increases

TABLE 10-3 Common Neuropathic Pain Medications
Mechanism Total Daily

Class/Drug of Action Side Effects Dosing Range Precautions
Serotonin
norepinephrine
reuptake
inhibitor (SNRI)
Venlafaxine Inhibits reuptake Nausea, blood 75Y225 mg/d Use with caution
of serotonin and pressure increase, as a single dose in cardiac disease
norepinephrine headache, sleep (venlafaxine XR) or as may cause
disturbance in 2 to 3 divided tachycardia and
doses (venlafaxine) hypertension;
dosage adjustment
needed for
impaired renal and
hepatic function
Duloxetine Inhibits reuptake Nausea, vomiting, 60Y120 mg/d; Avoid use in
of serotonin and dizziness, headache, may be divided significant renal
norepinephrine sleep disturbance into twice daily impairment or
dosing for doses liver disease
greater than
60 mg/d
Tricyclic
antidepressants
Amitriptyline Inhibits serotonin, Anticholinergic effects 25Y150 mg nightly Use with caution
norepinephrine (dry eyes/dry mouth, in cardiac disease
reuptake; blocks orthostatic hypotension, and conduction
sodium channels urinary retention), abnormalities
and has somnolence, weight
anticholinergic gain, constipation
properties
Nortriptyline Inhibits serotonin, Anticholinergic effects 25Y150 mg nightly Use with caution
and has somnolence, weight gain
anticholinergic
properties
Desipramine Inhibits serotonin, Anticholinergic effects 25Y150 mg nightly Use with caution
and has somnolence, weight gain
anticholinergic
properties

TABLE 10-3 Common Neuropathic Pain Medications Continued from page 1423

Calcium channel
!2% ligands
Gabapentin Acts on the !2% subunit Sedation, peripheral 300Y3600 mg Dose adjustment
of voltage-gated calcium edema, weight gain, divided 3 times needed with
channels, decreasing dizziness, a day; extended renal dysfunction
central sensitization incoordination formulation
available
Pregabalin Acts on the !2% subunit Sedation, peripheral 150Y600 mg Dose adjustment
of voltage-gated calcium edema, weight gain, divided up to needed with
channels, decreasing dizziness, 3 times a day renal dysfunction;
central sensitization incoordination use with caution
in severe
cardiovascular
disease
Opioid agonist
Tramadol 2-Receptor agonist Constipation, nausea 100Y400 mg May lower seizure
and norepinephrine and vomiting, divided up to threshold; dosage
and serotonin dizziness, somno- 4 times a day adjustment
reuptake inhibitor lence, needed with
headache renal dysfunction;
can be associated
with serotonin
syndrome when
combined with
other serotonergic
drugs
Tapentadol 2-Receptor agonist Constipation, nausea 100Y500 mg Dosage
and norepinephrine and vomiting, divided twice adjustment
reuptake inhibitor dizziness, daily; needed with
somnolence extended hepatic
release dysfunction
formulation
available
Opioids 2-Receptor agonists Constipation, nausea, Varies Dependency;
(examples vomiting, dizziness, depending opioid-induced
include somnolence on formulation respiratory
oxycodone, depression in
hydromorphone, vulnerable
morphine) individuals
Topical lidocaine Sodium channel Skin reaction, Up to three Do not use in
patch inhibition including patches, on for individuals with
erythema/pruritus 12 hours, off for a history of
12 hours; also amide local
available as an anesthetic
ointment, cream, sensitivity
and gel

TABLE 10-3 Common Neuropathic Pain Medications Continued from page 1424

Capsaicin
Patch Transient receptor Associated allodynia Apply to affected area, Use with
potential vanilloid initially, erythema, not more than four caution in
1 agonist and elevated blood patches per application those with
depletes substance P pressure for 60 minutes; hypertension
effective for 3 months
Cream Transient receptor Associated allodynia Apply 4 times a day Use with
potential vanilloid initially, erythema, caution in
1 agonist and elevated blood those with
depletes substance P pressure hypertension
!-Lipoic Antioxidant Nausea, vomiting, 600 mg/d in two None
acid dizziness, skin rash divided doses
when the glycosylated hemoglobin to Nav1.7 mutations were extensively KEY POINT
decreases by more than 2 percentage phenotyped.51 The majority of patients h Both Nav1.7 and
points over 3 months.49 The polyneuro- had onset of clinical signs within the Nav1.8 voltage-gated
pathy is characteristically small fiber as first decade of life. Feet and hands sodium mutations can
supported by normal nerve conduction were the most commonly affected result in a painful small
fiber polyneuropathy.
studies5,50 and is characterized by loss parts of the body, showing reddening
of intraepidermal nerve fiber density and swelling of the skin exacerbated
on skin biopsy.5 Although the pain by heat and exercise and alleviated
may be refractory at first, it tends to by cooling. Most patients also had
improve within 24 months.49 Relaxa- pain between the acute episodes.
tion of tight glucose control is not Inherited erythromelalgia is also asso-
recommended. ciated with gain-of-function mutations
of the SCN10A gene that encodes
Sodium Channelopathies voltage-gated Nav1.8 channels, also
Mutations of voltage-gated sodium expressed in the dorsal root ganglia
channels, both Nav1.7 and Nav1.8, have and peripheral nerve axons.52,53 These
been reported to cause painful small mutations result in dorsal root ganglia
fiber neuropathies and inherited hyperexcitability.53 In addition, Nav1.7
erythromelalgia. Patients with inherited and Nav1.8 mutations have been reported
erythromelalgia present with episodic to result in otherwise idiopathic painful
pain and reddening of the distal upper small fiber neuropathy.52Y54
extremity and lower extremity skin.51 It
is genetically linked to a dominant Autoimmune Small Fiber
gain-of-function mutation of the SCN9A Neuropathy
gene encoding Nav1.7, which results The small fiber neuropathies that have
in hyperpolarizing shifts in channel an underlying autoimmune mecha-
activation and dorsal root ganglia nism include those associated with
hyperexcitability.51 Recently, 13 patients sarcoidosis, Sjögren syndrome, celiac
with inherited erythromelalgia due disease, and paraneoplastic diseases

Case 10-1
A 16-year-old girl presented with a 4-week history of lower extremity
pain and paresthesia. Seven weeks earlier, she was diagnosed with
type 1 diabetes mellitus when she presented to the emergency
department with vomiting and abdominal pain. She was found to have
a blood glucose of 400 mg/dL. Her glycosylated hemoglobin was 14.8%.
She was in diabetic ketoacidosis and was transferred to the pediatric
intensive care unit. She was started on an insulin drip and ultimately
discharged on insulin glargine and insulin lispro. In the weeks following
her discharge, her blood sugars ranged from 100 mg/dL to 130 mg/dL.
Three weeks following hospitalization, she developed burning pain
in her toes that was associated with sharp, shooting pain that progressed
up to her knees over the next 2 to 3 weeks. The pain worsened in the
evenings and interrupted her sleep. The patient also reported a purple
discoloration of her toes and reduced sweating in her feet. She had
lightheadedness with standing. She had a depressed mood and was unable
to participate in her regular activities. She had tried acetaminophen,
ibuprofen, aspirin, capsaicin cream, and a diabetic foot pain lotion without
any improvement. Cold compresses and placing a fan near her feet helped
with the burning.
Her neurologic examination showed normal muscle strength, bulk,
and tone. She reported allodynia to pinprick in her feet and legs and
hyperesthesia to light touch in the same distribution. She reported reduced
sensation to cold temperature in her feet and legs but normal vibratory and
proprioceptive sensation. Her muscle stretch reflexes were normal.
She was diagnosed with treatment-induced neuropathy of diabetes
mellitus given the temporal association of her small fiber dysfunction
to the rapid correction of her hyperglycemia. She was started on
gabapentin and titrated up aggressively to 2700 mg/d, with improvement
in her symptoms.
Comment. This is a classic case of treatment-induced neuropathy of
diabetes mellitus. The patient presented with an acute small fiber
neuropathy associated with refractory pain and autonomic features. Her
neuropathy started 3 weeks after rapid correction of her hyperglycemia.
A skin biopsy was not pursued given the straightforward diagnosis.
(Case 10-2). The recently described both the peripheral and central nervous
voltage-gated potassium channel systems, and leucine-rich glioma inac-
complexYassociated small fiber neu- tivated 1 protein (LGI1), which is
ropathies are discussed in detail here, isolated to the central nervous sys-
but Table 10-1 provides a more com- tem.55 Voltage-gated potassium channel
plete list of autoimmune small fiber complex autoimmunity and, in particu-
neuropathies. The voltage-gated potas- lar, CASPR2 antibodies have been
sium channel complex autoantibodies reported with chronic idiopathic pain
are distributed widely throughout the without evidence of peripheral nervous
central and peripheral nervous sys- system dysfunction.56 Patients with
tems. The autoantibodies do not bind CASPR2 antibodies may also have a
to voltage-gated potassium channels painful neuropathy, although in a 2016
but to contactin-associated proteinlike series of five patients, most had evi-
2 (CASPR2), which is expressed in dence of large fiber involvement.55

Case 10-2
A 57-year-old man with a past medical history remarkable only for hyperlipidemia reported that
he had acutely developed paresthesia in his feet 3 months earlier. Within weeks, the paresthesia
spread to his hands, followed by his lips, tongue, and nose. The symptoms worsened over weeks,
spreading up his legs and his arms. He denied any weakness. He was no longer able to play golf or
exercise because of the severe neuropathic pain. He blinked frequently because of dry eyes and
had frequent dry mouth. Gabapentin and duloxetine were not effective. His workup at an outside
institution within 2 months of symptom onset included normal nerve conduction studies and EMG
and normal heavy metal testing, paraneoplastic panel, serum protein electrophoresis, antinuclear
antibodies, antineutrophil cytoplasmic antibodies, complement levels, erythrocyte sedimentation
rate, C-reactive protein, glycosylated hemoglobin, and antiYSjögren syndrome A (SSA)/Sjögren
syndrome B (SSB) antibodies. Brain and cervical spine MRI were unremarkable.
His neurologic examination showed normal muscle bulk, tone, and strength throughout. He had
normal symmetric reflexes. On sensory examination, he had a length-dependent loss of temperature
and pinprick sensation, with relative preservation of vibratory and proprioceptive sensation. His
gait was normal without a Romberg sign. His repeat nerve conduction studies and EMG were again
normal. Testing for angiotensin-converting enzyme, hepatitis B and C, and vitamins B6 and B12
was normal. A skin biopsy demonstrated abnormal intraepidermal nerve fiber density at all sites,
consistent with a severe neuropathy affecting the small nerve fibers (Figure 10-3). A lip biopsy was
obtained, which demonstrated minor salivary gland lobules with multiple foci of chronic
inflammation. Based on this information and the rapid progression of his small fiber neuropathy,
he was treated with 20 mg/d oral prednisone for presumed seronegative Sjögren syndromeYassociated
small fiber neuropathy. This resulted in dramatic improvement of his neuropathic pain and disability.
FIGURE 10-3 Epidermal nerve fiber analysis with protein gene product 9.5 stain of the patient in Case 10-3.
A, Right foot: Nerve fiber density is significantly decreased to 0.0/mm (normal greater than
3.0/mm). B, Right calf: Nerve fiber density is significantly decreased to 0.0/mm (normal greater
than 3.5/mm). Both specimens were stained with hematoxylin and eosin stain and Congo red. No abnormal
Congo red staining was seen on either specimen.
Courtesy of Corinthian Reference Lab.
Comment. This case illustrates that autoimmune small fiber neuropathies may be acute in
onset and progress rapidly. Taking a careful history led the physician to obtain a lip biopsy, which
demonstrated inflammation and supported a diagnosis of seronegative Sjögren syndrome (up to
50% of patients with neuropathy and Sjögren syndrome will initially have negative antibodies).
Making this diagnosis resulted in effective treatment for this patient who was otherwise
unresponsive to conventional neuropathic pain medications.

KEY POINTS
h Autoimmune small The pathophysiologic basis of this autonomic nervous system involvement also
fiber neuropathies, immune neuropathy is hyperexcita- occurs.64 Less commonly, anti-CV2/
such as those bility of sensory fibers.55 Recognizing collapsin response mediator protein-5
associated with these patients is important as they may (CRMP-5) antibodies are associated with
contactin-associated respond to immunotherapy.55 a mixed axonal and demyelinating motor
proteinlike 2 antibodies, polyneuropathy.65
may respond Fibromyalgia A search for paraneoplastic autoanti-
to treatment. Fibromyalgia, characterized by wide- bodies is recommended in any patient
h Anti-Hu paraneoplastic spread pain and fatigue, is prevalent in with a sensory neuronopathy, although
sensory neuronopathy 2% to 8% of the population57 and is the absence of antibodies does not ex-
is characterized by likely a heterogeneous group of diseases clude an underlying malignancy, as the
subacute sensory ataxia with similar symptoms.58 Studies have sensitivity is about 82%.66 Although small
and pain in the setting reported that nearly half of patients cell lung cancer is the most common
of malignancy. with fibromyalgia have small fiber neu- underlying malignancy, many other
h Treatment for the ropathy, characterized by decreased cancers have been reported.18,67 Sen-
paraneoplastic sensory intraepidermal nerve fiber density.28,58,59 sory neuronopathy may precede the
neuronopathies is cancer diagnosis by up to 8 months or
broadly divided into SPECIFIC SENSORY longer.19,64
three categories: NEURONOPATHIES Imaging to look for an underlying
tumor treatment,
Compared to axonal sensory neuropa- malignancy is mandatory in the pres-
immunosuppression/
immunomodulation,
thies, relatively few causes of sensory ence of antibodies and if no alternative
and symptomatic neuronopathy are known. A descrip- diagnosis (such as Sjögren syndrome or
management. tion of the most common sensory chemotherapy-induced neuronopathy)
neuronopathies follows. is thought to be likely. Routine chest
radiographs and CT of the chest are
Paraneoplastic Sensory occasionally negative, in which case
Neuronopathies fludeoxyglucose positron emission
Paraneoplastic sensory neuronopathy tomography (FDG-PET) should be
is one of the most common paraneo- pursued.68 If this is negative, then
plastic syndromes.60 It is character- repeat imaging should be performed
ized by an immune reaction that is every 6 months for up to 4 years.68
directed against neuronal proteins or CSF analysis is almost always abnor-
cross-reacting proteins expressed by mal, with elevated protein, pleo-
cancer cells.61 Chief among these, anti- cytosis, and sometimes oligoclonal
Hu antibodies react against neural bands.69
intracellular antigens through cell- Given the rarity of these disorders,
mediated immune mechanisms.62 The treatment recommendations are mostly
way in which anti-Hu antibodies react based on expert opinion. Treatment is
to intracellular antigens is still being very broadly divided into three categories:
investigated, and it appears that sen- tumor treatment, immunosuppression/
sory neuronopathies are cytotoxic immunomodulation, and symptomatic
T-cellYmediated disorders.63 Anti-Hu management. Tumor treatment may
paraneoplastic sensory neuronopathy is stabilize or perhaps even improve the
characterized by subacute onset of paraneoplastic syndromes associated
sensory ataxia and often neuropathic with intracellular antigens.70 Immuno-
pain.19 Patients can develop concomi- suppressant medications used to treat
tant motor neuropathy and weakness, paraneoplastic sensory neuronopathies
cerebellar degeneration, limbic enceph- include corticosteroids, cyclophospha-
alitis, and brainstem involvement.18 Auto- mide, sirolimus, and rituximab.64,67

KEY POINTS
Immunomodulatory therapy includes inal and autonomic involvement is h Sjögren syndrome is
IV immunoglobulin (IVIg) and plasma common.76 the autoimmune
exchange.64,67 One published treat- It is recommended to screen all sen- disease most frequently
ment strategy supports using high- sory neuronopathy patients for Sjögren associated with
dose corticosteroids with or without syndrome by checking for antiYSjögren sensory neuronopathy.
IVIg followed by cyclophosphamide if syndrome A (SSA [anti-Ro]) and h Toxic sensory
the cancer is not found.71 Symptomatic antiYSjögren syndrome B (SSB [anti- neuronopathies are
treatment consists of neuropathic pain La]), although they are often nega- caused by
medications (Table 10-3). tive.73 Should the initial laboratory platinum-based
In general, patients with anti- screen be negative, additional testing chemotherapy and
HuYassociated paraneoplastic syn- should be obtained, including the megadoses of
dromes have a poor prognosis with a Schirmer test, rose bengal test, and pyridoxine.
median survival of less than 1 year lip or salivary gland biopsy.74 The
and a 20% survival at 36 months.70 sensitivity of the Schirmer test and
Early identification of the tumor and salivary gland biopsy were both excel-
initiation of treatment results in im- lent (93%) in one series of patients.76
proved outcomes. As with paraneoplastic sensory
neuronopathies, no randomized con-
Immune-mediated Sensory trolled treatment trials exist to guide
Neuronopathies treatment of the Sjögren-associated
Sjögren syndrome is the autoimmune sensory neuronopathies. A number of
disease most frequently associated treatments have been used, including
with sensory neuronopathies. Others, plasma exchange, IVIg, rituximab,
such as systemic lupus erythematosus, corticosteroids, cyclophosphamide,
autoimmune hepatitis, and celiac dis- and azathioprine.18,72,75 One protocol
ease (Table 10-2), are not discussed in proposes treating with IVIg (2 g/kg
detail here. Sjögren syndrome is char- divided over 5 days) followed by
acterized by sicca symptoms (xeroph- monthly infusions.75
thalmia and xerostomia) and affects
between 1% and 2% of the popula- Toxic Sensory Neuronopathies
tion.72 In a large series of patients, over Toxic sensory neuronopathies may
half developed neurologic symptoms be caused by chemotherapeutic
before other symptoms of Sjögren agents and megadoses of pyridoxine
syndrome and over half had isolated (vitamin B6). Certain platinum-based
neurologic symptoms.73 Sjögren syn- chemotherapeutic agents are partic-
drome may have peripheral nervous ularly toxic to the dorsal root ganglia,
system manifestations in 5% to 15% including cisplatin, carboplatin, and
of patients, although the estimates oxaliplatin.77 These drugs result in
vary widely from 0% to 56%.74,75 Up apoptosis of the sensory neurons in
to 40% of patients with Sjögren the dorsal root ganglia78,79 and slow
syndromeYrelated polyneuropathies fast axonal transport.80 Cisplatin is
will have sensory neuronopathies (5% associated with a dose-dependent
of all patients with Sjögren syn- neurotoxicity, and patients experience
drome).72 The presentation of sensory neuropathic pain typically after a
neuronopathy in patients with Sjögren cumulative dose of 300 mg/m2.15
syndrome is usually subacute, with the Because of the coasting effect, pa-
average age in the sixties to seventies tients may experience worsening of
(Case 10-3).72 In contrast to other their neuropathy for several months
forms of sensory neuronopathy, trigem- after treatment.77
Case 10-3
A 76-year-old woman presented with progressive ataxia. She went from
working 9-hour shifts to being wheelchair dependent within 2 weeks.
She denied any weakness and reported she could not walk because her
legs were numb and ‘‘did not know where they wanted to go.’’ Initially
diagnosed with Guillain-Barré syndrome, she was hospitalized and
given 2 g/kg IV immunoglobulin (IVIg) over a 5-day course, with some
improvement in her symptoms. She received four more monthly IVIg
infusions. She reported progression of her numbness and neuropathic
pain despite these infusions, ascending to her waist, hands, and then
forearms. Her pain was adequately controlled on gabapentin, duloxetine,
and oxycodone.
She had carried a diagnosis of Sjögren syndrome for 2 years in the
setting of a several-year history of sicca symptoms and a positive
antiYSjögren syndrome A (SSA) antibody. Erythrocyte sedimentation
rate, C-reactive protein, antinuclear antibody, serum protein electrophoresis,
antineutrophil cytoplasmic antibodies, vitamin B12, thyroid-stimulating
hormone (TSH), paraneoplastic panel, and hepatitis B and C studies obtained
prior to her referral were unremarkable. She had previously had an
unremarkable MRI of the brain and full spine. CSF analysis had demonstrated
0 white blood cells and a protein level of 89 mg/100 mL.
Her examination showed normal muscle bulk, tone, and strength.
She had decreased pinprick sensation in the bilateral lower extremities
to the level of the waist and in her upper extremities up to the mid
forearms. Proprioception was severely impaired in the legs to the level
of the hips and in the upper extremities to the level of the wrists.
Pseudoathetosis of the fingers was present and more pronounced with
her eyes closed. Reflexes were normal in the upper extremities and
absent in the lower extremities. She was unable to ambulate without
maximum assistance because of severe ataxia.
Her nerve conduction studies demonstrated absent sensory responses
throughout. Motor responses were normal apart from mildly
low-amplitude left ulnar and fibular (peroneal) compound muscle
action potentials (CMAPs). Concentric needle EMG was entirely normal.
Her nerve conduction velocity/EMG was interpreted as electrophysiologic
evidence of a sensory neuronopathy.
She had already been previously prescribed mycophenolate mofetil,
high-dose corticosteroids, and hydroxychloroquine in addition to the
IVIg without any benefit. A trial of rituximab was recommended.
Comment. This case is a classic description of Sjögren syndromeYassociated
sensory neuronopathy, which is characterized by acute to subacute onset
of severe sensory ataxia. Often patients will be very treatment refractory.
Although this patient carried a diagnosis of Sjögren syndrome at the time
of neuronopathy onset, it is not uncommon for a patient to have sensory
neuronopathy as the initial manifestation of the disease.
Pyridoxine is an essential vitamin who were taking over 2 g/d for

that plays a role in amino acid metab- several months.81 The recommended
olism. The original cases of pyridoxine- daily intake of pyridoxine is 1.3 mg.
associated neuropathy/neuronopathy Subsequently, pyridoxine toxicity with
were reported in the 1980s in patients doses as low as 200 mg/d has been

TABLE 10-4 Causes of Small and Large Fiber Sensory Neuropathies
Etiology Evaluation
Diabetes mellitus Glycosylated hemoglobin, fasting glucose, 2-hour glucose tolerance
Sporadic amyloidosis Serum and urine protein electrophoresis, immunofixation, light chains,
fat aspirate, rectal mucosa biopsy, or nerve biopsy with Congo red staining
Sjögren syndrome Sicca symptoms, anti-Ro (SSA)/anti-La (SSB) antibodies, rose bengal test,
Schirmer test, lip/salivary gland biopsy
Celiac disease Antigliadin antibodies (serum IgA endomysial and tissue transglutaminase
antibody), IgG-deamidated gliadin peptides, small bowel biopsy, testing
for HLA DQ2/DQ8
Sarcoidosis Chest x-ray, serum angiotensin-converting enzyme, lymph node or other
tissue biopsy for necrotizing granulomas
Leprosy Serum antibodies to PGL-1, skin biopsy or nerve biopsy for acid-fast bacilli
Systemic lupus erythematosus ANA, antiphospholipid antibodies, complement levels, ESR, CRP, anti-dsDNA
and anti-Smith antibodies
Sensory chronic inflammatory Diagnosis is supported by nerve conduction studies and CSF analysis
demyelinating
polyradiculoneuropathy (CIDP)
Human immunodeficiency Fourth-generation antigen/antibody immunoassay, HIV viral load testing
virus (HIV)
Hepatitis C virus AntiYhepatitis C virus antibody, hepatitis C virus RNA
Cryoglobulinemia (typically Cryoglobulin levels, hepatitis C virus antibody and PCR
associated with hepatitis C
virus)
Lyme disease Tick exposure, serum ELISA with Western blot confirmation
Vitamin deficiencies Vitamin B12 and methylmalonic acid levels; folic acid, vitamin E, vitamin B6
and thiamine levels
Tangier disease ATP binding cassette (ABC) transporter mutation
Toxins Chemotherapy (taxols, platinum drugs, bortezomib), metronidazole,
phenytoin, ethambutol, isoniazid, thallium, mercury, lead
Alcohol History of drinking alcohol
Hypothyroidism TSH, free T4 levels
Hereditary neuropathies Genetic testing for hereditary sensory and autonomic neuropathies,
mitochondrial mutation testing
Familial amyloid Genetic testing for transthyretin (TTR), apolipoprotein A1 (APOA1), and
gelsolin (GSN) mutations
Paraneoplastic Voltage-gated potassium channel antibodies (CASPR2 specifically), anti-Hu
antibodies, anti-CV2/CRMP-5 antibodies
Other antibody-mediated Sulfatide antibodies, GD1b antibodies, anti-galactocerebroside antibodies
ANA = antinuclear antibody; ATP = adenosine triphosphate; CASPR2 = contactin-associated proteinlike 2; CRMP-5 = collapsin
response mediator protein-5; CRP = C-reactive protein; CSF = cerebrospinal fluid; dsDNA = double-stranded deoxyribonucleic acid;
ELISA = enzyme-linked immunosorbent assay; ESR = erythrocyte sedimentation rate; HLA = human leukocyte antigen;
IgA = immunoglobulin A; IgG = immunoglobulin G; PCR = polymerase chain reaction; PGL-1 = phenolic glycolipid-1; RNA = ribonucleic
acid; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B; T4 = thyroxine; TSH = thyroid-stimulating hormone.

KEY POINT
h The most common reported,82 and daily doses greater with pain, in clinical practice, sensory-
sensory polyneuropathy than 50 mg should be discouraged. predominant polyneuropathies with in-
is caused by Pyridoxine-associated sensory neuro- volvement of both small fibers (A%
diabetes mellitus. nopathy results in large fiber dysfunction fibers and small unmyelinated C fibers)
and prominent sensory ataxia.81 Discon- and large sensory fibers (A$ fibers) is
tinuation of the pyridoxine may result frequently encountered. By far the most
in some improvement of symptoms, common cause of small and large fiber
but residual deficits are possible.81 sensory polyneuropathies worldwide is
diabetes mellitus.35 Table 10-4 provides
Differential Diagnosis of a comprehensive list of small and large
Sensory Neuronopathies sensory fiber polyneuropathies.
In nearly half of patients, an underly-
ing etiology of the sensory neu- CONCLUSION
ronopathy is not identified and the The presentations of sensory poly-
disease is considered to be idio- neuropathies are varied. Patients will
pathic.14,16 In contrast to the autoim- often present with painful burning
mune and paraneoplastic sensory feet. This, in combination with normal
neuronopathies, patients with idio- nerve conduction studies, supports
pathic sensory neuronopathy have an localization to the small nerve fibers.
indolent slowly progressive course.16 Infrequently, patients present with
The diagnosis of idiopathic sensory dramatic sensory ataxia early in the
neuronopathy is a diagnosis of exclu- course of the neuropathy, which sup-
sion and thought to have an auto- ports localization to the dorsal root
immune pathophysiology.16 Despite ganglia, dorsal columns, or the large
treatment with immunosuppressants heavily myelinated nerves. These dif-
in a small series, patients had rela- ferent presentations are associated
tively poor outcomes.16 with distinct diagnostic and treatment
Sensory loss, ataxia, and areflexia may algorithms.
also be seen in distal acquired demye-
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Review Article

Polyneuropathies PO Box 800394,

Continuum (Minneap Minn) 2017;23(5):1411–1436.

INTRODUCTION A% fibers and the small unmyelinated C

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Etiology Associated Features Diagnostic Evaluation

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Etiology Associated Features Diagnostic Evaluation

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TABLE 10-2 Causes of Ataxic Neuropathies and Neuronopathies

Associated Symptoms and

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Associated Symptoms and

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Associated Symptoms and

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FIGURE 10-2 A diagnostic algorithm for sensory neuronopathies.

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Mechanism Total Daily

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Mechanism Total Daily

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Mechanism Total Daily

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Courtesy of Corinthian Reference Lab.

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Pyridoxine is an essential vitamin who were taking over 2 g/d for

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29. Khoshnoodi MA, Truelove S, Burakgazi A, neuropathy. Diabetes Care 2006;29(6):

1434 ContinuumJournal.com October 2017

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