Review Article
Chronic Demyelinating
Address correspondence to
Dr Jeffrey Allen, Department
of Neurology, 12-150 PWB,
MMC 295, 516 Delaware St SE,
Minneapolis, MN 55455,
jaallen@umn.edu.
Relationship Disclosure:
Dr Allen serves on
the global medical advisory
board of the GBC/CIDP
Foundation International, on
the organizing committee of
the Inflammatory Neuropathy
Consortium, and as a
consultant for CSL Behring
and Grifols. Dr Allen receives
research/grant support from
CSL Behring and has received
personal compensation for
speaking engagements
from Grifols.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Allen discusses the
unlabeled/investigational use
of alemtuzumab, azathioprine,
bevacizumab, chlorambucil,
cyclophosphamide,
cyclosporine, fludarabine,
interferon beta-1a,
lenalidomide, melphalan,
methotrexate, mycophenolate
mofetil, rituximab,
tacrolimus, and thalidomide
for the treatment of
chronic demyelinating
polyneuropathies.
* 2017 American Academy
of Neurology.
1310 ContinuumJournal.com
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Polyneuropathies
Jeffrey A. Allen, MD
ABSTRACT
Purpose of Review: This article reviews the chronic demyelinating neuropathies,
with a focus on the diagnosis and treatment of immune-mediated neuropathies
and the features that can help differentiate immune-mediated neuropathies from
other chronic demyelinating peripheral nerve conditions.
Recent Findings: Advances in clinical phenotyping and outcomes assessment have
enabled neurologists to improve disease recognition, treatment, and disease monitoring.
Our understanding of the immunopathogenesis of demyelinating neuropathies is
evolving. Identification of new antibodies and recognition that node of Ranvier
dysfunction may be an early pathogenic feature may herald further diagnostic and
treatment advancements.
Summary: The chronic demyelinating polyneuropathies are heterogeneous. The
clinical and diagnostic features are sometimes overlapping, and the specific disorders
are variable in pathogenesis, treatment, and prognosis. This heterogeneity underscores
the importance of achieving diagnostic accuracy and implementing disease-specific
treatment approaches.
Continuum (Minneap Minn) 2017;23(5):1310–1331.
INTRODUCTION on differentiating immune-mediated
The chronic acquired demyelinating polyneuropathies from one another
polyneuropathies first appeared in the and from nonimmune chronic demy-
medical literature as early as 1890, elinating polyneuropathies.
when Eichhorst described a patient
with clinical characteristics similar to CHRONIC INFLAMMATORY
Guillain-Barré syndrome (GBS).1 This DEMYELINATING
case and those that followed differed POLYRADICULONEUROPATHY
from GBS by nature of their chronic or Chronic inflammatory demyelinating
relapsing course. While the cardinal polyradiculoneuropathy (CIDP) affects
clinical, laboratory, and electrophysio- 1.0 to 8.9 persons per 100,000.3 It is
logic features of the demyelinating characterized by progressive or relaps-
polyneuropathies have since been ing motor or sensory symptoms, with
defined,2 much remains to be learned. variants differing in the relative distri-
Many disorders affect myelin. Which bution of those symptoms and elec-
syndromes should be given a distinct trophysiologic findings (Table 5-1).4
title, and which should be considered
variants of a parent condition? No Clinical Features of Typical Chronic
consensus exists on how to best Inflammatory Demyelinating
approach this spectrum of disorders. Polyradiculoneuropathy
This article discusses chronic demye- CIDP classically presents with relatively
linating polyneuropathies with a focus symmetric proximal and distal weakness
October 2017
TABLE 5-1 Typical Chronic Inflammatory Demyelinating Polyradiculoneuropathy and
Atypical Variants

Distinguishing
Disorder Acronym Symptoms Signs Electrophysiology
Typical CIDP CIDP Proximal and Absent or reduced Generalized demyelinating
distal weakness deep tendon reflexes features
and numbness in all limbs
Atypical CIDP DADS Predominantly Deep tendon reflexes Distally accentuated
distal sensory reduced or absent demyelination
more than motor distally, may be
normal or reduced
in proximal areas
MADSAM Asymmetric motor Deep tendon reflexes Multifocal demyelination;
(Lewis-Sumner and sensory may be normal in motor and sensory
syndrome) unaffected limb
Motor CIDP Proximal and Deep tendon reflexes Generalized motor
distal motor generally reduced demyelination;
sensory spared
Sensory CIDP; Proximal and Absent or reduced Normal or small
CISP distal sensory deep tendon reflexes sensory responses;
in all limbs prolonged somatosensory
evoked potentials;
motor spared
CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CISP = chronic immune sensory polyradiculopathy; DADS = distal
acquired demyelinating symmetric neuropathy; MADSAM = multifocal acquired demyelinating sensory and motor neuropathy.

and sensory dysfunction. The neuro-
logic examination invariably shows
reduced or absent muscle stretch re-
flexes. Although other symptoms, in-
cluding pain and fatigue, can occur,
they should never be the defining
clinical feature without motor and
sensory deficits (Table 5-2). Symp-
toms evolve over at least 2 months in
a progressive, stepwise, or relapsing
course. Up to 16% of patients have an
acute GBS-like presentation.5 The pres-
ence of prominent sensory signs and
the absence of autonomic dysfunction,
facial weakness, preceding infectious
illness, or respiratory failure are find-
ings that raise suspicion for acutely
presenting CIDP as opposed to GBS.6
Pathogenesis
The immunopathogenesis of CIDP has
yet to be well characterized but has
Continuum (Minneap Minn) 2017;23(5):1310–1331
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components of cellular and humoral KEY POINTS
immunologic dysfunction.7 Invasion h Chronic inflammatory
and delamination of myelin lamellae demyelinating
by T cells and macrophages support polyradiculoneuropathy
cellular-mediated demyelination. Immu- is a syndrome with
typical and
noglobulin and complement deposits
atypical variants.
seen on nerve biopsies, as well as
induction of demyelination in animals h The core clinical
by sera from patients with CIDP, impli- features of all
chronic inflammatory
cate humoral immunity. Although anti-
demyelinating
bodies likely play a key role, in most
polyradiculoneuropathy
patients no single major target anti- variants are numbness
gen has been identified. Contactin-1 or weakness. Although
(CNTN1) and neurofascin-155 (NF155) other symptoms can
IgG4 isotype paranodal protein anti- occur, they should never
bodies have been found in a minority be the defining feature
of patients and may provide diagnostic, without the core
prognostic, and therapeutic clarity in clinical features.
some subsets of patients that are more
broadly referred to as having CIDP.8
Although the literature pertaining to
CNTN1 and NF155 antibodies is limited
ContinuumJournal.com 1311
 Chronic Demyelinating Polyneuropathies
KEY POINTS
h No reliable biomarker
exists by which to
diagnose chronic
inflammatory
demyelinating
polyradiculoneuropathy.
h Chronic inflammatory
demyelinating
polyradiculoneuropathy
electrodiagnostic
criteria, such as those
proposed by the
European Federation of
Neurological Societies
and the Peripheral
Nerve Society, are
valuable resources
when diagnosing the
disease. The absence
of demyelination on
nerve conduction
studies should prompt
exploration for an
alternative diagnosis.
h Although 80% to 95%
of patients with typical
chronic inflammatory
demyelinating
polyradiculoneuropathy
show CSF
albuminocytologic
dissociation, it is a
nonspecific abnormality.
1312 ContinuumJournal.com
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tion may be treatment-induced rever-
TABLE 5-2 Chronic
Inflammatory sal of antibody-mediated ion channel
Demyelinating alterations at the nodes of Ranvier.11
Polyradiculoneuropathy
Symptoms Other Than Laboratory Testing
Weakness and Numbness Other than the clinical characteristics,
documentation of demyelination on
Symptom Frequency
nerve conduction studies is the most
Pain, usually in 33% important feature that differentiates
distal extremities CIDP from other acquired chronic
Fatigue, Up to 75% polyneuropathies. Classic demyelinat-
occasionally severe ing abnormalities include slowed mo-
Tremor 50% tor conduction velocity, prolonged
distal motor latency and F waves,
Autonomic 25%
dysfunction, temporal dispersion of compound
usually mild muscle action potential (CMAP) con-
Cranial nerve 5Y20% figurations, and motor conduction
dysfunction, blocks. Especially when demyelinating
most often changes are equivocal or accompanied
facial nerve
with axon loss, referencing one of the
Respiratory failure Very rare many electrodiagnostic criteria sets is
encouraged. The European Federa-
tion of Neurological Societies (EFNS)/
to case reports and small case series, Peripheral Nerve Society (PNS) criteria
most have observed that patients have the most favorable balance of
harboring anti-NF155 antibodies have sensitivity and specificity (Table 5-3).4
younger ages of onset, disabling Unilateral testing of four motor nerves
tremor, sensory ataxia, very high CSF yields a sensitivity of 81.3% and spec-
protein levels, and poor response to IV ificity of 96.1% for definite or probable
immunoglobulin (IVIg). The pheno- CIDP. When five to eight motor nerves
type associated with CNTN1 antibodies are tested, sensitivity improves to
is more variable, with some patients 96.7%, albeit at the cost of specificity
presenting at advanced ages with pre- (79.3%).12 The absence of electro-
dominant motor involvement, rapid physiologic evidence of demyelination
symptom onset, early axonal involve- should prompt exploration for an
ment, and poor response to IVIg, while alternative diagnosis.
others present with clinical features CSF shows albuminocytologic dis-
similar to anti-NF155.9,10 Tests for both sociation in 80% to 95% of those with
antibodies are commercially available typical CIDP. CSF pleocytosis above
and can be obtained in select patients. 10/mm3, and especially above 50/mm3,
While immune-mediated myelin should raise concern for disorders
disruption and eventually axon loss such as human immunodeficiency
are clear pathologic factors that lead virus (HIV), Lyme disease, sarcoidosis,
to disability, the observation that and lymphoma. Albuminocytologic
some patients with CIDP improve dissociation is not pathognomonic
within days of plasma exchange or for CIDP and should be cautiously
IVIg is not consistent with a process interpreted without the characteristic
requiring myelin or axon repair. One clinical and electrophysiologic CIDP
explanation for this clinical observa- findings. MRI in typical CIDP may
October 2017
TABLE 5-3 Electrodiagnostic Criteria for Chronic Inflammatory
Demyelinating Polyradiculoneuropathy According to
2010 European Federation of Neurological Societies/
Peripheral Nerve Society Criteriaa,b

1. Definite, at least one of the following:

a. Motor distal latency prolongation Q50% above ULN in two nerves
(excluding median neuropathy at the wrist), or
b. Reduction of motor conduction velocity Q30% below LLN in two nerves, or
c. Prolongation of F-wave latency Q30% above ULN in two nerves (Q50% if
amplitude of distal negative peak CMAP G80% of LLN values), or
d. Absence of F waves in two nerves if these nerves have distal negative
peak CMAP amplitudes Q20% of LLN plus Q1 other demyelinating
parameterc in Q1 other nerve, or
e. Partial motor conduction blockd: Q50% amplitude reduction of the
proximal negative peak CMAP relative to distal, if distal negative peak
CMAP Q20% of LLN, in two nerves, or in one nerve plus Q1 other
demyelinating parameterc in Q1 other nerve, or
f. Abnormal temporal dispersion (930% duration increase between the
proximal and distal negative peak CMAP) in Q2 nerves, or
g. Distal CMAP duration (interval between onset of the first negative peak
and return to baseline of the last negative peak) increase in Q1 nerve
(median Q6.6 milliseconds, ulnar Q6.7 milliseconds, fibular (peroneal)
Q7.6 milliseconds, tibial Q8.8 milliseconds) plus Q1 other demyelinating
parameterc in Q1 other nerve
2. Probable
Partial motor conduction blockd: Q30% amplitude reduction of the
proximal negative peak CMAP relative to distal, excluding the posterior
tibial nerve, if distal negative peak CMAP Q 20% of LLN, in two nerves, or
in one nerve plus Q1 other demyelinating parameterc in Q1 other nerve
3. Possible
As in 1 but in only one nerve
CMAP = compound muscle action potential; LLN = lower limit of normal values; ULN = upper
limit of normal values.
a
Reprinted with permission from Van den Bergh PY, et al. Eur J Neurol.4 B 2010 The Authors,
European Federation of Neurological Societies and the Peripheral Nerve Society.
onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2009.02930.x/full.
b
To apply criteria, median, ulnar, fibular (peroneal) (stimulated below the fibular head), and
tibial nerves on one side are tested. If criteria are not fulfilled, the same nerves are tested at
the other side, and/or ulnar and median nerves are stimulated at the axilla and Erb point.
Temperatures maintained to Q33-C (91.4-F) palm and Q30-C (86-F) external malleolus.
c
Any nerve meeting any of the criteria (aYg).
d
Conduction block is not considered in the ulnar nerve across the elbow and at least
50% amplitude reduction between Erb point and the wrist is required for probable
conduction block.

show enlarged or enhancing nerve for patients whose disease is diagnos-

roots or plexus elements. Nerve biopsy tically challenging. Segmental demye-
is rarely performed during the routine lination and remyelination, perivascular
diagnostic process but can be helpful T-cell collections, or epineurial and

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 Chronic Demyelinating Polyneuropathies

endoneurial clusters of macrophages and sensory symptoms and signs. It

may be seen.2 Screening for para-
proteins is advised in all with sus-
pected CIDP. Patients found to harbor
a monoclonal gammopathy should
undergo evaluation for lymphopro-
liferative disorders. Select patients may
benefit from more focused testing for
CIDP mimics in appropriate clinical
settings (Table 5-4).
Clinical and Laboratory
Features of Atypical Chronic
Inflammatory Demyelinating
Polyradiculoneuropathy
Like typical CIDP, atypical CIDP is
characterized principally by motor
differs from typical CIDP either by the
pattern of involvement or modality
predominantly affected. Recognized
atypical variants that are still considered
CIDP include distal acquired demyelin-
ating symmetric (DADS) neuropathy,
Lewis-Sumner syndrome (multifocal
acquired demyelinating sensory and
motor neuropathy [MADSAM]), sensory
CIDP, and motor CIDP.
Distal acquired demyelinating sym-
metric neuropathy. DADS is distin-
guished clinically from typical CIDP
by slowly evolving distal sensory
symptoms, sometimes with sensory
ataxia.13 Weakness, if present, is mild

TABLE 5-4 Neuropathies Exclusionary for Chronic Inflammatory

Demyelinating Polyradiculoneuropathy

Investigation in Appropriate
Exclusionary Conditions Clinical Setting
Multifocal motor Anti-GM1 antibody
neuropathy (MMN)
AntiYmyelin-associated Serum/urine immunofixation,
glycoprotein (MAG) anti-MAG antibody, skeletal survey
Polyneuropathy, organomegaly, Serum/urine immunofixation, vascular
endocrinopathy, monoclonal endothelial growth factor, skeletal survey
plasma cell disorder, and skin
changes (POEMS) syndrome
Sarcoidosis Chest and abdominal imaging,
nerve biopsy
Lyme Borrelia burgdorferi serology,
CSF (pleocytosis)
Diphtheria Clinical suspicion, Corynebacterium
diphtheriae by culture
Amyloidosis Serum/urine immunofixation,
TTR genetic testing, nerve or
fat-pad biopsy
Hereditary Appropriate genetic testing
Peripheral nervous Chest and abdominal imaging,
system lymphoma nerve biopsy
Toxic/iatrogenic Thorough medication exposure history
Myelopathy Thorough examination for upper motor
neuron findings, MRI spinal cord
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.

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and limited to the distal lower limbs.
Despite minimal weakness, electrophys-
iologic studies demonstrate demyelin-
ation in motor nerves along with
diminished sensory response ampli-
tudes in the lower and sometimes
upper limbs. Motor conduction abnor-
malities are accentuated distally such
that distal latency prolongations are
affected to a greater degree than con-
duction velocity slowing in proximal
segments. CSF protein is often normal
or only mildly elevated. Recognizing the
DADS phenotype has several important
implications. First, DADS may be easily
confused with more common axonal
length-dependent polyneuropathies
(Table 5-5). Second, up to two-thirds
of patients with DADS harbor a mono-
clonal IgM gammopathy (DADS-M), and
at least 50% of those patients express
antiYmyelin-associated glycoprotein
(MAG) antibodies. The presence of a
monoclonal gammopathy has impor-
tant treatment implications (refer to
KEY POINT
the section on anti-MAG neuropathy h Patients with a distal
later in this article). symmetric
Lewis-Sumner syndrome. Lewis- sensory-predominant
Sumner syndrome, also known as neuropathy but
MADSAM, is distinguished from typical demyelinating changes
CIDP by multifocal and asymmetric on nerve conduction
symptom distribution and from multi- studies may have distal
focal motor neuropathy (MMN) by acquired demyelinating
sensory symptomatology.14 Although symmetric neuropathy.
some patients with Lewis-Sumner Recognizing distal
acquired demyelinating
syndrome evolve into having typical
symmetric neuropathy is
CIDP, between 50% and 80% remain
important because it
multifocal. Characteristic electrophysi- may be treatable with
ologic abnormalities include multifocal immunotherapy or
conduction blocks with conduction may be associated
velocity slowing across blocked seg- with monoclonal
ments. Sensory amplitudes are re- gammopathy.
duced unless the blocked segment
is proximal to the site of sensory
nerve stimulation and no wallerian
degeneration has developed. Unlike in
typical CIDP, distal motor latency
prolongation and terminal latency
index reduction are rare.15 These
electrophysiologic features suggest

TABLE 5-5 Features Distinguishing Atypical Chronic Inflammatory Demyelinating

Polyradiculoneuropathy From Length-dependent Axonal Neuropathy

Chronic Inflammatory
Demyelinating
Polyradiculoneuropathy
(CIDP) Type Clinical Features Electrophysiology Other
Distal acquired Sensory ataxia, Prolonged motor CSF protein elevation,
demyelinating symmetric distal large fiber distal latencies IgM gammopathy in
(DADS) neuropathy sensory loss, relatively more than two-thirds (and
spared strength slowed motor myelin-associated
conduction velocity glycoprotein in
two-thirds of those)
Sensory CIDP Sensory ataxia, Normal or small Somatosensory evoked
generalized areflexia, sensory responses; potential prolongations,
rapid upper limb may be non-length MRI root enhancement
involvement, age of dependent or enlargement,
onset 55 years or younger CSF protein elevation
Motor CIDP Proximal and distal Demyelinating MRI nerve root
weakness with features in enhancement or
spared sensation motor nerves; enlargement, CSF
sensory spared protein elevation
CSF = cerebrospinal fluid; IgM = immunoglobulin M; MRI = magnetic resonance imaging.

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 Chronic Demyelinating Polyneuropathies
KEY POINT
h The chronic
immune sensory
polyradiculopathy
variant of chronic
inflammatory
demyelinating
polyradiculoneuropathy
may have normal nerve
conduction studies
because of selective
involvement of the
proximal dorsal sensory
nerve root.
1316 ContinuumJournal.com
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selective involvement of interme-
diate nerve segments rather than the
distal nerve terminal and proximal
trunk lesions that are common in
typical CIDP. CSF albuminocyto-
logic dissociation is less common in
Lewis-Sumner syndrome, occurring in
only 33% to 42%. As in typical CIDP,
MRI of an affected limb may show
enlarged or enhancing nerve seg-
ments or plexus. Although deteriora-
tion after corticosteroid treatment has
been reported, in most patients, re-
sponse to immunotherapy is similar to
typical CIDP.
Sensory chronic inflammatory de-
myelinating polyradiculoneuropathy.
Most pure sensory neuropathies are
axonal without an immune-mediated
basis (Table 5-5). In others, the injury
targets the dorsal root ganglion, rais-
ing concern for a paraneoplastic pro-
cess or Sjögren syndrome. Some
sensory neuropathies show clear evi-
dence of demyelination on motor
nerve conduction studies and are
more appropriately classified as
DADS. Rarely, immune-mediated pro-
cesses preferentially or exclusively
disrupt sensory function, the best
characterized of which is chronic
immune sensory polyradiculopathy
(CISP). CISP is characterized clinically
by progressive numbness and ataxia,
reduced muscle stretch reflexes, and
normal strength.16 Nerve conduction
studies are usually normal, but so-
matosensory evoked potentials be-
come delayed. CSF often shows
elevated protein, and MRI may reveal
enhancing or enlarged nerve roots.
Although nerve biopsy is not part of
the routine diagnostic process, studies
that examined the histopathology of
the sensory nerve root revealed evi-
dence of demyelinating, remyelinating,
and inflammatory change at this site.
These features localize the primary site
of CISP pathology to the dorsal nerve
root. The response to immunotherapy
is similar to typical CIDP.16
Motor chronic inflammatory demy-
elinating polyradiculoneuropathy.
Pure motor CIDP is a rare disorder that
presents clinically with weakness in a
pattern similar to typical CIDP. Unlike
typical CIDP, sensation is clinically and
electrophysiologically spared. Motor
CIDP may be difficult to distinguish from
MMN or motor neuron disease. Unlike
MMN, weakness is not restricted to
individual nerve or plexus segments.
The pattern of weakness (nonsegmen-
tal), absence of bulbar involvement,
demyelinating electrophysiologic abnor-
malities, and response to immunother-
apy distinguish motor CIDP from motor
neuron disease.
Differential Diagnosis
Pitfalls that can lead to the erroneous
diagnosis of CIDP include misinterpre-
tation of axonal electrodiagnostic stud-
ies as demyelinating, overreliance on
mild albuminocytologic dissociation,
and failure to objectify the treatment
response. 17 Even when peripheral
nerve demyelination is well docu-
mented, diagnostic uncertainty may
remain (Table 5-618).
Treatment
Successful CIDP treatment requires
appreciation of two important factors:
the most appropriate treatment agent
and the most effective treatment reg-
imen. While randomized controlled
trial data are available to guide specific
interventions, much remains to be
learned about how best to maximize
therapy in individual patients.
Specific immunotherapies. IVIg,
corticosteroids, and plasma exchange
are effective CIDP treatment options.
Overall, 80% to 90% of patients im-
prove with one of these therapies.19
No consensus exists on which first-line
intervention is best, although several
October 2017
TABLE 5-6 Differential Diagnosis of Chronic Demyelinating Polyneuropathies

Disease Electrophysiology CSF Protein Distinguishing Features

Immune
AIDP F waves prolonged early, Normal or elevated Progressive over
demyelinating features less than 4 weeks
peak 2Y3 weeks
MAG Distally accentuated slowing Elevated DADS phenotype with slow
progression most common
MMN Conduction block in many Normal or elevated Sensation spared,
no UMN abnormalities
POEMS Small motor response Elevated Polyneuropathy, organomegaly,
amplitudes and uniform endocrinopathy, monoclonal
conduction velocity slowing plasma cell disorder, skin changes
Drug-induced May be indistinguishable Normal or elevated Associated with TNF-!
from CIDP antagonists (infliximab,
adalimumab, etanercept),
interferon alfa therapy,
tacrolimus, bortezomib,
pembrolizumab
Metabolic
Diabetic Usually axonal, may Normal or elevated Usually length-dependent
have mild/moderate with small fiber involvement;
demyelination without plexopathy or focal neuropathy
temporal dispersion may have abrupt onset
or conduction block
Uremic Usually axonal, may have Normal or elevated GFR typically G12 mL/min
mild/moderate demyelination
Toxic
Amiodarone Axon loss plus mild to Normal Subacute/chronic, symmetric
moderate conduction sensorimotor, may affect
velocity slowing and proximal muscles, increased
prolonged distal latency risk if exposure longer than 1 year
Ethylene glycol Axon loss predominates Elevated CNS depression, cranial
nerve changes, renal and
cardiac toxicity
Diphtheria May be indistinguishable Elevated Usually evolves over
from CIDP 2Y3 weeks, with or without
CSF pleocytosis; bulbar and
respiratory weakness common
Systemic
Amyloid Typically axonal but Normal or elevated Prominent pain and autonomic
may show CIDP-like dysfunction, cardiac or
demyelination gastrointestinal manifestations
Sarcoid Typically multifocal axonal, or Normal or elevated Pulmonary, skin, ocular, muscle,
length-dependent endocrine, cranial nerve, or
polyneuropathy; rarely CNS involvement
demyelinating with
conduction block
Continued on page 1318

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 Chronic Demyelinating Polyneuropathies

TABLE 5-6 Differential Diagnosis of Chronic Demyelinating Polyneuropathies

Continued from page 1317

Disease Electrophysiology CSF Protein Distinguishing Features

Inherited
HNPP Mild conduction velocity Normal Symptoms triggered by mild
slowing accentuated at trauma or compression
compressible sites
CMT1 Uniform conduction Normal or Onset variable but often early in life;
velocity slowing typically mildly elevated motor symptoms often predominant
without conduction block despite clear sensory signs on
or temporal dispersion examination; very slowly progressive;
family history often presenta
Fabry disease Slow conduction Normal or elevated X-linked; onset childhood or
velocity and increased adolescence; pain, angiokeratomas,
distal latency; may be premature atherosclerosis
normal early in disease
Refsum disease Demyelinating with Elevated Autosomal recessive; onset usually
severe conduction infancy or early adult; retinitis
velocity slowing pigmentosa, cerebellar ataxia, hearing
loss, cardiac conduction disease
MLD Conduction velocity Elevated Autosomal recessive; arylsulfatase
slowing without A mutation; onset most often
conduction block late infancy, although presentation
in adolescence and even adulthood
can occur; multiple CNS deficits
Krabbe disease Slow conduction Elevated Autosomal recessive;
velocity, occasionally galactosylceramide
with conduction block $-galactosidase mutation; onset in
infancy, adolescence, adulthood;
multiple CNS deficits
Mitochondrial
MNGIE Demyelinating with Elevated Onset childhood or adolescence;
conduction velocity slowing. myopathy, external ophthalmoplegia,
Conduction block and neuropathy, episodic gastrointestinal
temporal dispersion pseudo-obstruction and
in some patients gastroparesis, encephalopathy
AIDP = acute inflammatory demyelinating polyradiculoneuropathy; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy;
CMT1= Charcot-Marie-Tooth disease type 1; CNS = central nervous system; CSF = cerebrospinal fluid; DADS = distal acquired demyelinating
symmetric neuropathy; GFR = glomerular filtration rate; HNPP = hereditary neuropathy with liability to pressure palsies; MAG =
myelin-associated glycoprotein; MLD = metachromatic leukodystrophy; MMN = multifocal motor neuropathy; MNGIE = mitochondrial
neurogastrointestinal encephalomyopathy; POEMS = polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder,
and skin changes; TNF-! = tumor necrosis factor !; UMN = upper motor neuron.
a
For more information, refer to the article ‘‘Charcot-Marie-Tooth Disease and Other Genetic Polyneuropathies’’ by Sindhu Ramchandren,
MD, MS,18 in this issue of Continuum.

factors restrict plasma exchange to placebo-controlled CIDP trial, the

patients who are severely affected Immune Globulin Intravenous for
or have treatment-refractory disease. Chronic Inflammatory Demyelinating
IVIg efficacy was established, in Polyneuropathy (ICE) study.20 The
part, based upon a large randomized percentage of patients with improved

1318 ContinuumJournal.com October 2017

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 KEY POINTS
6-month disability was significantly first-line therapies, patients are often h No consensus exists on
greater in the IVIg group (54%) com- poorly responsive to these standard which first-line therapy
pared to placebo (21%). Corticoste- interventions. B-cell depletion therapy is best for chronic
roids were evaluated in one unblinded with rituximab has been associated inflammatory
randomized trial of 28 patients com- with meaningful beneficial responses in demyelinating
paring no treatment to prednisone other IgG4-mediated diseases, suggest- polyradiculoneuropathy.
tapering from 120 mg every other ing that it could be an effective option in IV immunoglobulin is
day.21 Patients treated with predni- patients with anti-CNTN1 and NF155 better tolerated and
sone improved over 3 months, while antibodies.27 perhaps more effective,
untreated patients worsened. A ran- Patients chronically dependent on but sustained drug-free
remission may be
domized controlled trial comparing IVIg or corticosteroids are sometimes
more likely after
IVIg to methylprednisolone showed treated with other medications in
corticosteroids.
that IVIg was better tolerated and hopes of reducing the first-line ther-
perhaps more effective than corticoste- apy. Randomized controlled trials of h Although the ideal IV
immunoglobulin
roids, but patients treated with cortico- azathioprine, methotrexate, and inter-
treatment regimen has
steroids less frequently relapsed within feron beta-1a failed to show treatment
not been determined,
6 months of treatment.22 Although the efficacy,28 although none of the trials dosing based on the
long-term relapse rate was similar (IVIg could exclude a small benefit. Data from Immune Globulin
87%, corticosteroids 79%), the median uncontrolled or retrospective series Intravenous for
time to deterioration was longer after dis- suggest that some patients may benefit Chronic Inflammatory
continuing corticosteroids (14 months) from cyclosporine, cyclophosphamide, Demyelinating
than IVIg (4.5 months).23 rituximab, alemtuzumab, mycopheno- Polyneuropathy trial
The ideal doses of IVIg and cortico- late mofetil, tacrolimus, and autologous (2 g/kg loading dose
steroids have not been defined. IVIg is hematopoietic stem cell transplanta- divided over 2 to
usually administered as a 2 g/kg loading tion. However, in the absence of pro- 5 consecutive days,
dose divided over 2 to 5 consecutive spective data from randomized studies, 1 g/kg every 3 weeks or
equivalent maintenance)
days. Based on the ICE trial,20 initial the role of aggressive immunosuppres-
is recommended for
maintenance of 1 g/kg every 3 weeks sion in CIDP is undefined; individual
therapy induction.
or equivalent is recommended. The disease severity, previous treatments
generally accepted induction dosage attempted, and risk analysis should be h Most patients with
chronic inflammatory
for prednisone is 60 mg/d. Patients taken into account.
demyelinating
refractory to the initial choice should Optimizing immunotherapy. Most
polyradiculoneuropathy
be switched to the other therapy patients who respond to IVIg do so by respond to treatment
unless a medical contraindication exists. the third maintenance infusion.20 Corti- within 3 months.
Although no trials have been dedicated costeroids may need up to 12 weeks
h Once maximum benefit
to atypical CIDP variants, treatment before benefit is appreciated.4 In either
is reached, IV
is similar to typical CIDP with a few case, if a clear treatment response is not immunoglobulin and
exceptions. Patients with DADS with documented by 3 to 6 months, reconsi- prednisone taper trials
only slowly progressive symptoms dering the treatment drug, treatment are recommended to
and minimal disability may be followed dose, or diagnosis is advisable. Re- assess the need for
clinically without immunotherapy. Pa- sponding patients may continue therapy ongoing therapy and
tients with motor CIDP and possibly until the maximum benefit is reached. optimize therapy to
Lewis-Sumner syndrome should be of- However, it has been noted that many individual patient needs.
fered IVIg over corticosteroids because patients require only brief courses of
of potential corticosteroid-induced wor- immunotherapy and that overtreatment
sening.24Y26 Special note is also needed of CIDP is common. It is imperative that
on patients harboring IgG4 anti-CNTN1 once maximum benefit is achieved,
and NF155 antibodies. Although IVIg structured dose reduction or optimiza-
and corticosteroids are still considered tion trials be attempted.4
Continuum (Minneap Minn) 2017;23(5):1310–1331 ContinuumJournal.com 1319
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Chronic Demyelinating Polyneuropathies
KEY POINTS
h Measures of disability The strategy to best taper or optimize
and strength can be treatment is unknown. One challenge is
helpful adjuncts to objective documentation of treatment
the examination response or relapse. Incorporation of
to document disease-focused disability assessments
treatment efficacy and with the Rasch-built Overall Disability
identify relapse. Scale (RODS)29 and strength measure-
h Although all patients ment with a grip strength dynamome-
with chronic ter30 may enhance traditional outcome
inflammatory assessments and raise confidence in treat-
demyelinating ment efficacy determinations (Case 5-1).
polyradiculoneuropathy Immunotherapy tapering often carries
should be screened concern for irreversible disability accu-
for a monoclonal mulation in the event of relapse. Using
gammopathy, in
the tools discussed combined with sub-
most patients with
jective patient experience may provide a
neuropathy and
reasonable management approach that
monoclonal
balances risk of early relapse with the
gammopathy of
undetermined need to avoid overtreatment.
significance, the
pathologic significance DEMYELINATING
is unknown. NEUROPATHIES ASSOCIATED
WITH MONOCLONAL
GAMMOPATHY
Paraprotein-associated neuropathies
are clinically and electrophysiologically
heterogeneous, and, in most cases, the
pathogenic significance of the para-
protein is uncertain. Approximately
3% of individuals older than 50 years
of age and 7.5% older than 85 years of
age harbor a monoclonal paraprotein,
of which 8% to 36% develop a symp-
tomatic polyneuropathy.32 Although
the majority (75%) are benign (mono-
clonal gammopathy of undetermined
significance [MGUS]), a 1% risk per
year of progression to hematologic
malignancy exists.
Neuropathy Associated
With IgG and IgA Monoclonal
Gammopathy of
Undetermined Significance
The pathoimmunologic relationship be-
tween neuropathy and IgG and IgA
MGUS is uncertain.33 IgG and IgA
paraproteins may be uncovered in
patients with chronic progressive or
1320 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
relapsing demyelinating polyneu-
ropathy clinically and electrophysio-
logically indistinguishable from CIDP
as well as in patients with distal axonal
sensory or sensorimotor polyneurop-
athy.34 The therapeutic approach to
IgG/IgA paraprotein-associated neu-
ropathy is guided by the phenotype;
patients presenting as CIDP are treated
similarly to those with CIDP without
gammopathy.33 At present, no compel-
ling evidence supports the use of im-
munotherapy in those with distal axonal
IgG/IgA MGUSYassociated neuropathies.
Neuropathy Associated With
IgM Monoclonal Gammopathy
of Undetermined Significance
IgM paraprotein represents only 20% of
monoclonal gammopathies,35 but up to
50% of patients with paraprotein and
neuropathy harbor the IgM type.36
Evaluation for IgM-secreting lympho-
proliferative diseases, particularly
Waldenström macroglobulinemia or
lymphoma, is prudent. Most patients
develop a DADS phenotype with dis-
tally accentuated motor nerve demye-
lination on nerve conduction studies.13
At least two-thirds of patients demon-
strate IgM antibody reactivity to neural
antigens, the most common of which
is MAG.
Neuropathy With AntiYMyelin-
Associated Glycoprotein
Antibodies
Polyneuropathy associated with anti-
MAG antibodies has unique clinical and
electrophysiologic features that can
help distinguish it from other chronic
demyelinating polyneuropathies. Dif-
ferentiation is important as prognosis,
immunopathogenesis, and treatment
response are different than in CIDP.
Clinical and diagnostic features of
antiYmyelin-associated glycoprotein
neuropathy. Anti-MAG neuropathy
typically presents in the sixth or
October 2017
 KEY POINT

Case 5-1 h The typical course of

antiYmyelin-associated
A 63-year-old woman presented with a 6-month history of numbness
glycoprotein related
and paresthesia bilaterally in her feet and hands. She reported that within
neuropathy is slow
3 months of sensory symptom onset she was having trouble turning keys in
progression with or
a lock and started to frequently trip during walking. Five months after
without immunotherapy.
onset, rising from the floor was difficult. She had a history of fibromyalgia
and chronic joint pain and fatigue.
Examination revealed bilateral and symmetric weakness in the proximal
and distal lower limbs and distal upper limbs, reduced vibration sensation
in the feet and toes, and diffusely reduced or absent deep tendon reflexes.
Grip strength measured by hand dynamometer was 21 lb on the right
and 16 lb on the left. Disability as measured by the Rasch-built Overall
Disability Scale (RODS) was 26 out of 48.
Nerve conduction studies revealed unequivocal evidence of peripheral
nerve demyelination in the form of motor conduction velocity slowing
greater than 30% below the lower limit of normal in more than two nerves.
CSF demonstrated albuminocytologic dissociation (protein 98 mg/dL).
The patient was diagnosed with chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) and treated with IV immunoglobulin (IVIg)
2 g/kg loading dose (divided over a 3-day course) followed by 1 g/kg
maintenance on a single day every 3 weeks. Three months after treatment
initiation, she reported residual paresthesia in the distal lower limbs and
persistent chronic joint pain but otherwise had normal strength and sensation.
Manual muscle strength confirmed the subjective improvements, and grip
strength was 50 lb on both sides. RODS disability improved to 44 out of 48.
Maintenance IVIg was continued at 1g/kg every 3 weeks for another 3 months
and then slowly tapered by extending the treatment interval by 1 week every
infusion cycle. When the treatment interval exceeded 6 weeks, IVIg was
stopped. During the taper process, she reported worsening fatigue, anxiety
about relapse, and transient heightened joint pain but no change in strength
and sensation. Neurologic examinations, grip strength dynamometer, and
RODS disability scales at 3 and 6 months post-IVIg withdrawal were stable.
Comment. This patient’s symptoms and signs, electrophysiology, and CSF
profile are classic for typical CIDP. She was treated with evidence-based IVIg
dosing; 2 g/kg loading dose followed by 1 g/kg every 3 weeks. Early
initiation of immunotherapy is critically important to prevent accumulating
disability in CIDP. Equally as important is recognition that in some patients
CIDP follows a monophasic course and prolonged immunotherapy is not
needed. Although the best strategy to taper IVIg is unknown, some attempt
should be made to reduce or optimize treatment after a patient has
achieved a predetermined level of improvement and stability. This can be
challenging, especially in patients with preexisting conditions (such as
fibromyalgia, as in this patient) that have symptoms that may be difficult to
differentiate from CIDP. Collection of grip strength31 and RODS disability
score29 can be helpful additions to the routine neurologic examination to
document treatment response and monitor for disease relapse.

seventh decades of life and affects men athy similar to DADS with distally
more often than women. Most patients accentuated demyelination on nerve
develop a slowly progressive, distal, conduction studies. Electrophysiologic
sensory-predominant, ataxic neurop- abnormalities often appear more severe

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 Chronic Demyelinating Polyneuropathies

KEY POINT
h At present, no than the degree of clinical impairment.
immunotherapy has Although the prognosis is generally
proven efficacy for favorable, functional impairment due
the treatment of to tremor and gait ataxia may accumu-
antiYmyelin-associated late over time.37 Less commonly, pro-
glycoprotein gression is rapid or relapsing with
neuropathy. severe gait ataxia or proximal weakness.
Pathogenesis of antiYmyelin-associ-
ated glycoprotein neuropathy. MAG is
a transmembrane glycoprotein concen-
trated in noncompacted periaxonal
myelin regions. IgM deposits and wid-
ening of outer myelin lamellae may be
seen on nerve biopsy. Passive trans-
fer of human IgM anti-MAG antibodies
to animals results in a neuropathy
with clinical and morphologic features
similar to humans.38 These findings
provide evidence that the anti-MAG
antibody is pathogenic.
Treatment of antiYmyelin-associated
glycoprotein neuropathy. Although
anti-MAG antibody reduction would
seem to be an effective treatment strat-
egy, at present, no therapy has proven
efficacy. Randomized controlled trials of
rituximab failed to meet prespecified
primary outcome measures, although
the primary end points and method of
administration (single course) may have
limited the sensitivity to detect benefit.39
Improvement following antibody inhibi-
tion with IVIg and removal with plasma
exchange have been reported in small
numbers of patients, but the effects are
temporary at best.40 The use of cyto-
toxic agents (eg, cyclophosphamide,
fludarabine, chlorambucil) to reduce
antibody synthesis may be beneficial in
some patients but is limited by toxicity.
Immunotherapy for anti-MAG neu-
ropathy should be individualized
(Case 5-2). Patients without significant
disability can be reassured of the
often-favorable prognosis and offered
symptomatic treatment for tremor
and paresthesia. If deterioration is
rapid, a course of IVIg or plasma
exchange might be tried. Biologic or
cytotoxic agents can be considered
in those with significant chronic or
progressive disability, although all

Case 5-2
A 63-year-old woman presented with 3 years of slowly worsening
numbness and paresthesia in her feet and hands. Her gait was unsteady,
but she was able to walk independently without falls. Examination
revealed loss of vibration sensation and proprioception in her feet and
fingers, mild ataxia with finger-nose-finger testing, preserved strength
with the exception of toe extension (grade 4/5), absent ankle reflexes, and
hypoactive knee and upper limb reflexes. Nerve conduction studies were
remarkable for prolonged distal motor latencies and reduced sensory
response amplitudes. Serum immunofixation showed an IgM monoclonal
gammopathy. AntiYmyelin-associated glycoprotein (MAG) antibodies were
present. At her visit, the patient asked if her neuropathy could be treated.
Comment. The decision to treat anti-MAGYassociated neuropathy is not
straightforward. Given the natural history of most anti-MAG neuropathies
and the absence of treatment efficacy data, a conservative management
strategy with physical therapy for balance and symptomatic medications
for uncomfortable positive sensory symptoms is a reasonable course of
action. Patients with a more aggressive pattern or those with marked
disability could be offered immunotherapy, but all are unproven and have
risks that must be weighed against unknown benefits. Regardless, periodic
surveillance for plasma cell proliferative disorders is important for all
patients with a monoclonal gammopathy.

1322 ContinuumJournal.com October 2017

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have risks that must be balanced against pathic features can sometimes mimic
unknown benefits. CIDP, clinical and electrophysiologic
clues can assist with early diagnosis.
Polyneuropathy, Organomegaly, Therapies that are beneficial in CIDP
Endocrinopathy, Monoclonal are typically not effective in POEMS.
Plasma Cell Disorder, and Skin The unique POEMS features should be
Changes (POEMS) Syndrome closely sought in patients with pre-
The acronym POEMS refers to the five sumed CIDP that is treatment refractory,
symptoms and signs that tend to as a POEMS diagnosis has important
predominate in POEMS syndrome prognostic and treatment implications.
(Table 5-7).41 Although the neuro- Clinical and Diagnostic Features
of POEMS. In up to 50% of patients,
polyneuropathy is the presenting
TABLE 5-7 Diagnostic Criteria POEMS symptom. Clinical and electro-
for POEMS physiologic features are similar to
Syndromea,b
typical CIDP, although severe pain is
common and nerve conduction stud-
b Mandatory Criteria
ies are more likely to show axon loss
Polyneuropathy and uniform conduction velocity
Monoclonal plasma cell slowing without conduction block.42
proliferative disorder CSF protein level and serum vascular
(almost always lambda) endothelial growth factor (VEGF)
b Major Criteria levels are often markedly elevated.
Castleman disease Pathogenesis of POEMS. POEMS
Sclerotic bone lesions
is a paraneoplastic syndrome asso-
ciated with neoplastic plasma cells.
Vascular endothelial
The pathogenesis likely involves
growth factor
(VEGF) elevation overproduction of VEGF by mono-
clonal plasma cells with resulting in-
b Minor Criteria
creased vascular permeability and
Organomegaly neovascularization. Plasma VEGF levels
Extravascular volume are not only diagnostically helpful but
overload also correlate with clinical improve-
Endocrinopathy ment after treatment.
Skin changes Treatment of POEMS. POEMS treat-
ment involves targeting the underlying
Papilledema
plasma cell disorder. Isolated osteo-
Thrombocytosis/polycythemia sclerotic plasmocytomas may be irradi-
POEMS = polyneuropathy, organ- ated or surgically excised. Diffuse lesions
omegaly, endocrinopathy, monoclonal or disseminated bone marrow involve-
plasma cell disorder, and skin changes.
a
Modified with permission from
ment requires systemic therapy. High-
Dispenzieri A, Am J Hematol.41 dose melphalan supplemented by
B 2014 Wiley Periodicals, Inc. autologous peripheral blood stem cell
onlinelibrary.wiley.com/doi/
10.1002/ajh.23644/full. transplantation is considered the most
b
A POEMS diagnosis can be made effective intervention.43 Lenalidomide/
when three major criteria, two of
which must include polyneuropathy thalidomide, bevacizumab (anti-VEGF
and plasma cell disorder, and at least monoclonal antibody), and chemother-
one minor criterion are present.
apy with melphalan or cyclophospha-
mide may also be treatment options.
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 Chronic Demyelinating Polyneuropathies
KEY POINTS
h Multifocal motor
neuropathy most
commonly presents
with weakness in the
distal upper limbs.
h Antibody-induced
dysfunction at the
nodes of Ranvier may
be an early pathologic
process in multifocal
motor neuropathy.
1324 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
MULTIFOCAL MOTOR
NEUROPATHY
MMN is an acquired, chronic, autoim-
mune, asymmetric motor neuropathy.
The pattern of motor involvement,
spared sensation, electrophysiologic
characteristics, immunopathogenesis,
and treatment response distinguish
MMN from other chronic demyelinat-
ing polyneuropathies.
Clinical Features
MMN is a rare condition that affects
fewer than 1 per 100,000. The mean age
of onset is around 40 years, with a male
to female ratio of 3:1. The condition is
characterized clinically by asymmetric
weakness in the distribution of mono-
neuropathies and electrophysiologically
by multifocal conduction blocks.44 In
80% of patients, weakness first develops
in the upper limbs, and in 90%, distal
muscles are preferentially affected.45
Cramps and fasciculations are common.
Mild sensory loss limited to the distal
lower limbs can be seen in up to 20% of
patients. Muscle stretch reflexes are
reduced in affected limbs but may be
intact in areas without weakness.
Pathogenesis
The precise immunopathogenesis of
MMN is uncertain. Although traditionally
considered a demyelinating disorder
with secondary axonal degeneration,
several lines of evidence implicate early
pathology at the nodes of Ranvier. IgM
anti-GM1 antibodies are frequently
detected in those with MMN. Although
ubiquitously expressed in both motor
and sensory nerves, GM1 is most abun-
dantly localized to nodes of Ranvier and
adjacent paranodes of peripheral motor
nerves.46 Human sera containing anti-
GM1 antibodies induces conduction
block, immunoglobulin deposits at the
nodes of Ranvier, and nodal widening
in animal nerve.47 When in the pres-
ence of complement, anti-GM1 anti-
bodies may reduce sodium currents
sufficient to block action potential gen-
eration.48 In humans with MMN, motor
axon excitability studies have shown
axonal hyperpolarization at sites distal
to areas of conduction block.49 As in
MMN, antiganglioside antibodies ap-
pear to play a prominent pathophysio-
logic role in the acute motor axonal
neuropathy (AMAN) variant of Guillain-
Barré syndrome. Antibodies against
GM1, GM1b, GD1a, and GalNAc-GD1a
are frequently detected in patients with
AMAN, albeit of the IgG rather than
IgM type.50 Also as in MMN, autoanti-
body binding to GM1 gangliosides at
the nodes of Ranvier, complement
activation, and sodium channel dysfunc-
tion may be pathophysiologically im-
portant in AMAN.51,52 Taken together,
these observations imply that nodal
depolarization due to antibody-induced
complement-mediated injury at the
nodes of Ranvier and adjacent axo-
lemma hyperpolarization due to reac-
tive increased sodium/potassium pump
activity are pathophysiologic processes
that mediate conduction block and
muscular weakness.53 The observation
that both MMN and AMAN may rapidly
improve following treatment with IVIg
further supports reversal of antibody-
mediated nodal membrane dysfunc-
tion, rather than restoration of myelin
structural damage.11 This concept has
yet to be confirmed.
Laboratory Features
The defining electrophysiologic char-
acteristic of MMN is conduction block
(Table 5-8), with normal sensory re-
sponses even across sites of motor
block. Conduction block in upper limb
nerves at the midforearm level is most
common. Proposed MMN diagnostic
criteria suggest that a diagnosis of MMN
can be reliably concluded when weak-
ness and electrophysiologic conduction
block are present in two or more nerves,
October 2017
 KEY POINTS

TABLE 5-8 Electrophysiologic Criteria for Conduction Blocka h Conduction block is not
an essential finding in
Conduction multifocal motor
Block Definition Qualifier neuropathy provided
b other characteristic
Definite Q50% negative compound muscle Negative CMAP amplitude
action potential (CMAP) area 920% lower limit of normal clinical features
reduction on proximal versus (LLN) and 91 mV are present.
distal stimulation of median, h Anti-GM1 antibodies
ulnar, or fibular (peroneal) nerve Increase of proximal
negative peak CMAP are present in many,
duration e30% but not all, patients
with multifocal motor
Probableb,c Q30% negative CMAP area Negative CMAP amplitude
neuropathy. Conversely,
reduction on proximal versus 920% LLN and 91 mV
anti-GM1 antibodies
distal stimulation of upper
limb nerve Increase of proximal in low titers may be
negative peak CMAP identified in disorders
duration e30% other than multifocal
Probableb,c Q50% negative CMAP area Negative CMAP amplitude motor neuropathy.
reduction on proximal versus 920% LLN and 91 mV h IV immunoglobulin is
distal stimulation of median, the only therapy with
Increase of proximal
ulnar, or fibular (peroneal) nerve
negative peak CMAP proven efficacy for
duration 930% multifocal motor
a
Modified with permission from Joint Task Force of the EFNS and the PNS, J Peripher Nerv Syst.44 neuropathy.
B 2010 Peripheral Nerve Society. onlinelibrary.wiley.com/doi/10.1111/j.1529-8027.2010.00290.x/abstract.
b
Evidence for conduction block must be found at sites distinct from common entrapment or
compression syndromes.
c
‘‘Probable’’ criteria for conduction block may be satisfied if there is a Q30% area reduction and
duration changes by e30% OR there is a Q50% area reduction and duration changes by >30%.

provided sensation is spared and no Differential Diagnosis

upper motor neuron findings are pres-
ent.44 Even so, conduction block may
not be identified in all patients with
MMN. The absence of conduction
block may be because of the activity-
dependent nature of the blocks or
because the blocks are located at sites
that are inaccessible with nerve conduc-
tion studies. Widespread evidence of
demyelination may be seen in some,
but not all, patients.
Up to 60% of patients with MMN
have elevated IgM anti-GM1 antibodies.
Patients with anti-GM1 antibodies tend
to have more severe weakness, dis-
ability, and eventual axon loss compared
with seronegative patients.54 CSF protein
is often normal or only mildly elevated.
The diagnostic role of imaging is limited,
but it may show nerve enlargement,
particularly in the brachial plexus.
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Astute attention to the pattern and type
of symptoms, electrophysiology, and lab-
oratory data can help differentiate MMN
from other motor nerve disorders
(Table 5-9). Anti-GM1 antibodies are
occasionally present in other lower motor
neuron conditions, including amyotrophic
lateral sclerosis. Absence of anti-GM1
antibodies does not exclude MMN, and a
positive test can create diagnostic con-
fusion in the wrong clinical context. The
pattern of pure axon loss on nerve con-
duction studies and EMG and absence of
anti-GM1 antibodies has been described
as multifocal acquired motor axonopathy
(Case 5-3).56 Treatment for this condi-
tion is similar to that for MMN.57
Treatment
IVIg is the first-line treatment for MMN.
Efficacy has been well documented in
ContinuumJournal.com 1325
 1326
ContinuumJournal.com
TABLE 5-9 Differential Diagnosis of Multifocal Motor Neuropathy

Clinical Presentation Electrophysiology Laboratory

Deep Tendon Nerve Conduction Anti-GM1
Disease Pattern Motor Sensory Reflexes Course Studies CSF Protein Antibody
MMN Asymmetric, Abnormal Normal Reduced Slow, Often conduction Normal or Up to 60%
nerve or plexus relapsing, block, with or without mildly
progressive other demyelinating elevated
features, normal
sensory nerve
action potentials
CIDP Generalized Abnormal Abnormal Reduced Relapsing, Demyelinating Elevated in Rare
progressive 80Y95%
of patients
LSS Asymmetric, Abnormal Abnormal Reduced Relapsing, Demyelinating, with Elevated in Rare
nerve or plexus progressive or without conduction 33Y42%
block, abnormal of patients
sensory nerve
action potentials
ALS Asymmetric, Abnormal Normal Increased Rapid or slow, Axonal Normal Rare
segmental progressive

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

HNPP Asymmetric, Abnormal Abnormal Reduced Relapsing Demyelinating, Normal Absent
nerve accentuated at
compressible sites
ALS = amyotrophic lateral sclerosis; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CSF = cerebrospinal fluid; HNPP = hereditary neuropathy with liability
Chronic Demyelinating Polyneuropathies

to pressure palsies; LSS = Lewis-Sumner syndrome; MMN = multifocal motor neuropathy.

October 2017
 Case 5-3
A 44-year-old man developed distal weakness in the right upper
limb. Over the following years, weakness slowly worsened; by age 47,
he had developed a left wristdrop. Cramps and fasciculations affected
both limbs. Examination revealed right first dorsal interosseous and
abductor pollicis brevis weakness and atrophy. On the left, only wrist
and finger extension were weak. Muscle stretch reflexes were reduced
in the upper limbs and normal in the legs. He had no sensory deficits
or cranial nerve abnormalities. Grip strength measured by hand
dynamometer was 17 lb on the right and 38 lb on the left. His
Rasch-built Overall Disability Scale for Multifocal Motor Neuropathy
(RODS-MMN)55 score was 41 out of 50. Electrophysiologic studies
showed no conduction block or other demyelinating features. On EMG,
fibrillation potentials were limited to right median and ulnar innervated
and left radial innervated muscles. CSF protein was normal. Anti-GM1
antibodies were absent. A diagnosis of multifocal motor neuropathy
(MMN) was considered. The patient was offered treatment with IV
immunoglobulin (IVIg).
Comment. This case illustrates several MMN challenges. First, the clinical
phenotype of weakness limited to individual nerves rather than myotomes
is critically important to distinguish MMN from amyotrophic lateral
sclerosis. The absence of bulbar and upper motor neuron deficits is helpful
as well. Second, conduction block and anti-GM1 antibodies are not present
in all patients with MMN. If the clinical hallmarks of MMN are present, a
treatment trial with IVIg is reasonable. This patient might fall into the
so-called multifocal acquired motor axonopathy category. Third, serial
collection of grip strength and RODS disability scores can be useful
additions to the routine neurologic examination, especially in patients
with an uncertain diagnosis. These can be especially helpful for
documenting treatment benefit, monitoring relapse, and optimizing
therapy in chronically treatment dependent patients.

multiple randomized controlled trials.58
Younger patients, early treatment initia-
tion, predominantly demyelinating
features, and fewer affected limbs pre-
dict favorable treatment outcome.59
Elevated anti-GM1 antibodies and con-
duction block were correlated with a
favorable response in one retrospective
study,60 but other studies have not
made the same correlation.61 Mainte-
nance IVIg dose and frequency should
be optimized to individual needs. In
some, the beneficial effect lessens
over time. Although dose escalation
may restore short-term IVIg efficacy,
gradual worsening with progressive
reduction of strength despite contin-
ued therapy may occur. As in CIDP,
monitoring with grip strength and dis-
ability outcomes55 may help objectify
the treatment response and facilitate
avoidance of IVIg overtreatment or
undertreatment.
Unlike other immune-mediated neu-
ropathies, corticosteroids and plasma
exchange are usually not effective.44
Almost 20% of patients worsen with
corticosteroid treatment. Favorable re-
sponses to rituximab have been re-
ported by some, but an open-label
trial showed no change in IVIg dose,
strength, or disability in patients with
MMN treated with rituximab.62 Although
benefit with cyclophosphamide has
been described in small series, potential
toxicity restricts its wide use.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Chronic Demyelinating Polyneuropathies
CONCLUSION
While ostensibly similar, the chronic
demyelinating polyneuropathies have
variable clinical presentations and di-
agnostic features. Categorization as
discussed within this article provides
a rationale for development of treat-
ment approaches based on the clini-
cal, electrophysiologic, and diagnostic
data. Our evolving understanding of
the immunologic underpinnings of
these neuropathies may offer diagnos-
tic clarity in the future and, by exten-
sion, improved treatment approaches.
REFERENCES
1. Eichhorst. Correspondenz-blatt fur Schweizer
Ärzte. 1890;20:559.
2. Dyck PJ, Lais AC, Ohta M, et al. Chronic
inflammatory polyradiculoneuropathy.
Mayo Clin Proc 1975;50(11):621Y637.
3. Lunn MP, Manji H, Choudhary PP, et al.
Chronic inflammatory demyelinating
polyradiculoneuropathy: a prevalence study
in south east England. J Neurol Neurosurg
Psychiatry 1999;66(5):677Y680. doi:10.1136/
jnnp.66.5.677.
4. Van den Bergh PY, Hadden RD, Bouche P,
et al. European Federation of Neurological
Societies/Peripheral Nerve Society guideline
on management of chronic inflammatory
demyelinating polyradiculoneuropathy:
report of a joint task force of the European
Federation of Neurological Societies and the
Peripheral Nerve SocietyVfirst revision. Eur J
Neurol 2010;17(3):356Y363. doi:10.1111/
j.1468-1331.2009.02930.x.
5. McCombe PA, Pollard JD, McLeod JG.
Chronic inflammatory demyelinating
polyradiculoneuropathy: a clinical and
electrophysiological study of 92 cases.
Brain 1987;110(6):1617Y1630. doi:10.1093/
brain/110.6.1617.
6. Dionne A, Nicolle MW, Hahn AF. Clinical and
electrophysiologic parameters distinguishing
acute-onset chronic inflammatory demyelinating
polyneuropathy from acute inflammatory
demyelinating polyneuropathy. Muscle Nerve
2010;41(2):202Y207. doi:10.1002/mus.21480.
7. Dalakas MC. Pathogenesis of
immune-mediated neuropathies. Biochim
Biophys Acta 2015;1852(4):658Y666.
doi:10.1016/j.bbadis.2014.06.013.
8. Querol L, Illa I. Paranodal and other
autoantibodies in chronic inflammatory
neuropathies. Curr Opin Neurol
1328 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
2015;28(5):474Y479. doi:10.1097/
WCO.0000000000000233.
9. Devaux JJ, Miura Y, Fukami Y, et al.
Neurofascin-155 IgG4 in chronic inflammatory
demyelinating polyneuropathy. Neurology
2016;86(9):800Y807 doi:10.1212/
WNL.0000000000002418.
10. Querol L, Nogales-Gadea G, Rojas-Garcia R,
et al. Antibodies to contactin-1 in chronic
inflammatory demyelinating polyneuropathy.
Ann Neurol 2013;73(3):370Y380. doi:0.1002/
ana.23794.
11. Berger M, Allen JA. Optimizing IgG therapy
in chronic autoimmune neuropathies: a
hypothesis driven approach. Muscle Nerve
2015;51(3):315Y326. doi:10.1002/mus.24526.
12. Rajabally YA, Nicolas G, Piéret F, et al.
Validity of diagnostic criteria for chronic
inflammatory demyelinating polyneuropathy:
a multicentre European study. J Neurol
Neurosurg Psychiatry 2009;80(12):1364Y1368.
doi:10.1136/jnnp.2009.179358.
13. Katz JS, Saperstein DS, Gronseth G, et al.
Distal acquired demyelinating symmetric
neuropathy. Neurology 2000;54(3):615Y620.
doi:10.1212/WNL.54.3.615.
14. Lewis RA, Sumner AJ, Brown MJ, Asbury AK.
Multifocal demyelinating neuropathy with
persistent conduction block. Neurology
1982;32(9):958Y964. doi:10.1212/
WNL.32.9.958.
15. Kuwabara S, Isose S, Mori M, et al. Different
electrophysiological profiles and treatment
response in ‘typical’ and ‘atypical’ chronic
inflammatory demyelinating polyneuropathy.
J Neurol Neurosurg Psychiatry 2015;86(10):
1054Y1059. doi:10.1136/jnnp-2014-308452.
16. Sinnreich M, Klein CJ, Daube JR, et al.
Chronic immune sensory polyradiculopathy:
a possibly treatable sensory ataxia. Neurology
2004;63(9):1662Y1669. doi:10.1212/
01.WNL.0000142507.12763.58.
17. Allen JA, Lewis RA. CIDP diagnostic pitfalls
and perception of treatment benefit.
Neurology 2015;85(6):498Y504. doi:10.1212/
WNL.0000000000001833.
18. Ramchandren S. Charcot-Marie-Tooth
Disease and other genetic polyneuropathies.
Continuum (Minneap Minn) 2017;23
(5 Peripheral Nerve and Motor Neuron
Disorders):1360Y1377.
19. Cocito D, Paolasso I, Antonini G, et al. A
nationwide retrospective analysis on the
effect of immune therapies in patients with
chronic inflammatory demyelinating
polyradiculoneuropathy. Eur J Neurol
2010;17(2):289Y294. doi:10.1111/
j.1468Y1331.2009.02802.x.
October 2017
20. Hughes RA, Donofrio P, Bril V, et al.
Intravenous immune globulin (10%
caprylate-chromatography purified) for
the treatment of chronic inflammatory
demyelinating polyradiculoneuropathy
(ICE study): a randomised placebo-controlled
trial. Lancet Neurol 2008;7(2):136Y144.
doi:10.1016/S1474-4422(07)70329-0.
21. Dyck PJ, O’Brien PC, Oviatt KF, et al.
Prednisone improves chronic inflammatory
demyelinating polyradiculoneuropathy
more than no treatment. Ann Neurol
1982;11(2):136Y114. doi:10.1002/
ana.410110205.
22. Nobile-Orazio E, Cocito D, Jann S, et al.
Intravenous immunoglobulin versus
intravenous methylprednisolone for
chronic inflammatory demyelinating
polyradiculoneuropathy: a randomised
controlled trial. Lancet Neurol
2012;11(6):493Y502. doi:10.1016/
S1474-4422(12)70093-5.
23. Nobile-Orazio E, Cocito D, Jann S, et al.
Frequency and time to relapse after
therapy discontinuation in CIDP patients
treated for six months with IVIg or IV
methylprednisolone (IMC study follow-up).
J Peripher Nerv Sys 2013;18:S80YS81.
24. Donaghy M, Mills KR, Boniface SJ, et al.
Pure motor demyelinating neuropathy:
deterioration after steroid treatment
and improvement with intravenous
immunoglobulin. J Neurol Neurosurg
Psychiatry 1994;57(7):778Y783. doi:10.1136/
jnnp.57.7.778.
25. Eftimov F, Liesdek MH, Verhamme C,
et al. Deterioration after corticosteroids in
CIDP may be associated with pure focal
demyelination pattern. BMC Neurol
2014;14:72. doi:10.1186/1471-2377-14-72.
26. Attarian S, Verschueren A, Franques J,
et al. Response to treatment in patients
with Lewis-Sumner syndrome. Muscle
Nerve 2011;44(2):179Y184. doi:10.1002/
mus.22024.
27. Querol L, Rojas-Garc<a R, Diaz-Manera J,
et al. Rituximab in treatment-resistant CIDP
with antibodies against paranodal proteins.
Neurol Neuroimmunol Neuroinflamm
2015;2(5):e149. doi:10.1212/
NXI.0000000000000149.
28. Mahdi-Rogers M, van Doorn PA, Hughes RA.
Immunomodulatory treatment other
than corticosteroids, immunoglobulin and
plasma exchange for chronic inflammatory
demyelinating polyradiculoneuropathy.
Cochrane Database Syst Rev
2013;(6):CD003280. doi:10.1002/
14651858.CD003280.pub4.
Continuum (Minneap Minn) 2017;23(5):1310–1331
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
29. van Nes SI, Vanhoutte EK, van Doorn PA,
et al. Rasch-built Overall Disability Scale
(R-ODS) for immune-mediated peripheral
neuropathies. Neurology 2011;76(4):
337Y345. doi:10.1212/WNL.0b013e318208824b.
30. Draak TH, Pruppers MH, van Nes SI,
et al. Grip strength comparison in
immune-mediated neuropathies:
Vigorimeter vs. Jamar. J Peripher Nerv Syst
2015;20(3):269Y276. doi:10.1111/jns.12126.
31. Vanhoutte EK, Latov N, Deng C, et al.
Vigorimeter grip strength in CIDP: a responsive
tool that rapidly measures the effect of
IVIGVthe ICE study. Eur J Neurol 2013;20(5):
748Y755. doi:10.1111/j.1468-1331.2012.03851.x.
32. Nobile-Orazio E, Barbieri S, Baldini L, et al.
Peripheral neuropathy in monoclonal
gammopathy of undetermined significance:
prevalence and immunopathogenetic
studies. Acta Neurol Scand 1992;85(6):383Y390.
doi:10.1111/j.1600-0404.1992.tb06033.x.
33. Joint Task Force of the EFNS and the PNS.
European Federation of Neurological Societies/
Peripheral Nerve Society Guideline on
management of paraproteinemic
demyelinating neuropathies. Report of a Joint
Task Force of the European Federation of
Neurological Societies and the Peripheral
Nerve SocietyVfirst revision. J Peripher Nerv
Syst 2010;15(3):185Y195. doi:10.1111/
j.1529-8027.2010.00278.x.
34. Magy L, Chassande B, Maisonobe T, et al.
Polyneuropathy associated with IgG/IgA
monoclonal gammopathy: a clinical and
electrophysiological study of 15 cases. Eur J
Neurol 2003;10(6):677Y685. doi:10.1046/
j.1468-1331.2003.00687.x.
35. Kyle RA, Therneau TM, Rajkumar SV, et al.
Prevalence of monoclonal gammopathy of
undetermined significance. N Engl J Med
2006;354(13):1362Y1369. doi:10.1056/
NEJMoa054494.
36. Gosselin S, Kyle RA, Dyck PJ. Neuropathy
associated with monoclonal gammopathies
of undetermined significance. Ann Neurol
1991;30(1):54Y61. doi:10.1002/
ana.410300111.
37. Nobile-Orazio E, Meucci N, Baldini L, et al.
Long-term prognosis of neuropathy
associated with anti-MAG IgM M-proteins
and its relationship to immune therapies.
Brain 2000;123(pt 4):710Y717. doi:10.1111/
j.1529-8027.2000.22-14.x.
38. Tatum AH. Experimental paraprotein
neuropathy, demyelination by passive
transfer of human IgM anti-myelin-associated
glycoprotein. Ann Neurol 1993;33(5):502Y506.
doi:10.1002/ana.410330514.
ContinuumJournal.com 1329
 Chronic Demyelinating Polyneuropathies
39. Léger JM, Viala K, Nicolas G, et al.
Placebo-controlled trial of rituximab in IgM
anti-myelin-associated glycoprotein
neuropathy. Neurology 2013;80(24):
2217Y2225. doi:10.1212/
WNL.0b013e318296e92b.
40. Lunn MP, Nobile-Orazio E. Immunotherapy
for IgM anti-myelin-associated glycoprotein
paraprotein-associated peripheral neuropathies.
Cochrane Database Syst Rev 2016;10:CD002827.
doi:10.1002/14651858.CD002827.pub4.
41. Dispenzieri A. POEMS syndrome: 2014
update on diagnosis, risk-stratification, and
management. Am J Hematol 2014;89(2):
214Y223. doi:10.1002/ajh.23644.
42. Mauermann ML, Sorenson EJ, Dispenzieri A,
et al. Uniform demyelination and more
severe axonal loss distinguish POEMS syndrome
from CIDP. J Neurol Neurosurg Psychiatry 2012;
83(5):480Y486. doi:10.1136/jnnp-2011-301472.
43. Kuwabara S, Dispenzieri A, Arimura K, et al.
Treatment for POEMS (polyneuropathy,
organomegaly, endocrinopathy, M-protein,
and skin changes) syndrome. Cochrane
Database Syst Rev 2012;(6):CD006828.
doi:10.1002/14651858.CD006828.pub3.
44. Joint Task Force of the EFNS and the PNS.
European Federation of Neurological
Societies/Peripheral Nerve Society guideline
on management of multifocal motor
neuropathy. Report of a joint task force of
the European Federation of Neurological
Societies and the Peripheral Nerve
SocietyVfirst revision. J Peripher Nerv Syst
2010;15(4):295Y301. doi:10.1111/j.1529-8027.
2010.00290.x.
45. Nobile-Orazio E. Multifocal motor neuropathy.
J Neuroimmunol 2001;115(1Y2):4Y18.
doi:10.1016/S0165-5728(01)00266-1.
46. Willison HJ, Yuki N. Peripheral neuropathies
and anti-glycolipid antibodies. Brain
2002;125(pt 12):2591Y2625. doi:10.1093/
brain/awf272.
47. Uncini A, Santoro M, Corbo M, et al.
Conduction abnormalities induced by sera of
patients with multifocal motor neuropathy
and anti-GM1 antibodies. Muscle Nerve
1993;16(6):610Y615. doi:10.1002/
mus.880160606.
48. Takigawa T, Yasuda H, Kikkawa R, et al.
Antibodies against GM1 ganglioside affect
K+ and Na+ currents in isolated rat
myelinated nerve fibers. Ann Neurol
1995;37(4):436Y442. doi:10.1002/
ana.410370405.
49. Kiernan MC, Guglielmi JM, Kaji R,
et al. Evidence for axonal membrane
1330 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
hyperpolarization in multifocal motor
neuropathy with conduction block.
Brain 2002;125(pt 3):664Y675. doi:10.1093/
brain/awf041.
50. Ogawara K, Kuwabara S, Mori M, et al.
Axonal Guillain-Barré syndrome: relation
to anti-ganglioside antibodies and
Campylobacter jejuni infection in Japan.
Ann Neurol 2000:48(4);624Y631. doi:0.1002/
1531-8249(200010)48:4G624::AID-ANA99
3.0.CO;2-O.
51. Kuwabara S, Bostock H, Ogawara K, et al.
The refractory period of transmission is
impaired in axonal Guillain-Barré syndrome.
Muscle Nerve 2003:28(6);683Y689.
doi:10.1002/mus.10488.
52. Kuwabara S, Ogawara K, Sung JY, et al.
Differences in membrane properties of
axonal and demyelinating Guillain-Barré
syndromes. Ann Neurol 2002;52(2):180Y187.
doi:10.1002/ana.10275.
53. Uncini A, Kuwabara S. Nodopathies of the
peripheral nerve: an emerging concept. J
Neurol Neurosurg Psychiatry 2015;86(11):
1186Y1195. doi:10.1136/jnnp-2014-310097.
54. Cats EA, Jacobs BC, Yuki N, et al. Multifocal
motor neuropathy: association of anti-GM1
IgM antibodies with clinical features.
Neurology 2010;75(22):1961Y1967.
doi:10.1212/WNL.0b013e3181ff94c2.
55. Vanhoutte EK, Faber CG, van Nes SI,
et al. Rasch-built Overall Disability Scale
for Multifocal motor neuropathy
(MMN-RODS(B)). J Peripher Nerv Syst
2015;20(3):296Y305. doi:10.1111/jns.12141.
56. Katz JS, Barohn RJ, Kojan S, et al. Axonal
multifocal motor neuropathy without
conduction block or other features
of demyelination. Neurology
2002;58(4):615Y620. doi:10.1212/
WNL.58.4.615.
57. Fisher D, Grothe C, Schmidt S, Schröder R.
On the early diagnosis of IVIg-responsive
chronic multifocal acquired motor
axonopathy. J Neurol 2004;251(10):
1204Y1207. doi:10.1007/s00415-004-0507-z.
58. van Schaik IN, van den Berg LH, de Haan R,
Vermeulen M. Intravenous immunoglobulin
for multifocal motor neuropathy. Cochrane
Database Syst Rev 2005;(2):CD004429.
doi:10.1002/14651858.CD004429.pub2.
59. Van den Berg-Vos, Franssen H, Visser J,
et al. Disease severity in multifocal motor
neuropathy and its association with the
response to immunoglobulin treatment. J
Neurol 2002;249(3):330Y336. doi:10.1046/
j.1529-8027.2002.02032_4.x.
October 2017
60. Van den Berg-Vos RM, Franssen H, Wokke
JH, et al. Multifocal motor neuropathy:
diagnostic criteria that predict the response
to immunoglobulin treatment. Ann Neurol
2000;48(6):919Y926. doi:10.1002/
1531-8249(200012)48:6G919::
62. Chaudhry V, Cornblath DR. An open-label
AID-ANA1393.0.CO;2-J.
61. Léger JM, Viala K, Cancalon F, et al.
Intravenous immunoglobulin as short- and
long-term therapy of multifocal motor
neuropathy: a retrospective study of
response to IVIg and of its predictive criteria
in 40 patients. J Neurol Neurosurg Psychiatry
2008;79(1):93Y96. doi:10.1136/
jnnp.2007.121756.
trial of rituximab (RituxanA) in multifocal
motor neuropathy. J Peripher Nerv Syst
2010;15(3):196Y201. doi:10.1111/
j.1529-8027.2010.00270.x.

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