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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:
Polyneuropathies
Dr Allen serves on Jeffrey A. Allen, MD
the global medical advisory
board of the GBC/CIDP
Foundation International, on
the organizing committee of ABSTRACT
the Inflammatory Neuropathy
Consortium, and as a Purpose of Review: This article reviews the chronic demyelinating neuropathies,
consultant for CSL Behring with a focus on the diagnosis and treatment of immune-mediated neuropathies
and Grifols. Dr Allen receives and the features that can help differentiate immune-mediated neuropathies from
research/grant support from
CSL Behring and has received other chronic demyelinating peripheral nerve conditions.
personal compensation for Recent Findings: Advances in clinical phenotyping and outcomes assessment have
speaking engagements enabled neurologists to improve disease recognition, treatment, and disease monitoring.
from Grifols.
Unlabeled Use of
Our understanding of the immunopathogenesis of demyelinating neuropathies is
Products/Investigational evolving. Identification of new antibodies and recognition that node of Ranvier
Use Disclosure: dysfunction may be an early pathogenic feature may herald further diagnostic and
Dr Allen discusses the
unlabeled/investigational use
treatment advancements.
of alemtuzumab, azathioprine, Summary: The chronic demyelinating polyneuropathies are heterogeneous. The
bevacizumab, chlorambucil, clinical and diagnostic features are sometimes overlapping, and the specific disorders
cyclophosphamide,
cyclosporine, fludarabine,
are variable in pathogenesis, treatment, and prognosis. This heterogeneity underscores
interferon beta-1a, the importance of achieving diagnostic accuracy and implementing disease-specific
lenalidomide, melphalan, treatment approaches.
methotrexate, mycophenolate
mofetil, rituximab,
tacrolimus, and thalidomide Continuum (Minneap Minn) 2017;23(5):1310–1331.
for the treatment of
chronic demyelinating
polyneuropathies.
* 2017 American Academy INTRODUCTION on differentiating immune-mediated
of Neurology.
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

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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- components of cellular and humoral KEY POINTS
logic examination invariably shows immunologic dysfunction.7 Invasion h Chronic inflammatory
reduced or absent muscle stretch re- and delamination of myelin lamellae demyelinating
flexes. Although other symptoms, in- by T cells and macrophages support polyradiculoneuropathy
cluding pain and fatigue, can occur, cellular-mediated demyelination. Immu- is a syndrome with
typical and
they should never be the defining noglobulin and complement deposits
atypical variants.
clinical feature without motor and seen on nerve biopsies, as well as
sensory deficits (Table 5-2). Symp- induction of demyelination in animals h The core clinical
toms evolve over at least 2 months in by sera from patients with CIDP, impli- features of all
chronic inflammatory
a progressive, stepwise, or relapsing cate humoral immunity. Although anti-
demyelinating
course. Up to 16% of patients have an bodies likely play a key role, in most
polyradiculoneuropathy
acute GBS-like presentation.5 The pres- patients no single major target anti- variants are numbness
ence of prominent sensory signs and gen has been identified. Contactin-1 or weakness. Although
the absence of autonomic dysfunction, (CNTN1) and neurofascin-155 (NF155) other symptoms can
facial weakness, preceding infectious IgG4 isotype paranodal protein anti- occur, they should never
illness, or respiratory failure are find- bodies have been found in a minority be the defining feature
ings that raise suspicion for acutely of patients and may provide diagnostic, without the core
presenting CIDP as opposed to GBS.6 prognostic, and therapeutic clarity in clinical features.
some subsets of patients that are more
Pathogenesis broadly referred to as having CIDP.8
The immunopathogenesis of CIDP has Although the literature pertaining to
yet to be well characterized but has CNTN1 and NF155 antibodies is limited
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Chronic Demyelinating Polyneuropathies

KEY POINTS
h No reliable biomarker tion may be treatment-induced rever-
TABLE 5-2 Chronic
exists by which to Inflammatory sal of antibody-mediated ion channel
diagnose chronic Demyelinating alterations at the nodes of Ranvier.11
inflammatory Polyradiculoneuropathy
demyelinating Symptoms Other Than Laboratory Testing
polyradiculoneuropathy. Weakness and Numbness Other than the clinical characteristics,
h Chronic inflammatory documentation of demyelination on
Symptom Frequency
demyelinating nerve conduction studies is the most
polyradiculoneuropathy Pain, usually in 33% important feature that differentiates
electrodiagnostic distal extremities CIDP from other acquired chronic
criteria, such as those Fatigue, Up to 75% polyneuropathies. Classic demyelinat-
proposed by the occasionally severe ing abnormalities include slowed mo-
European Federation of Tremor 50% tor conduction velocity, prolonged
Neurological Societies distal motor latency and F waves,
Autonomic 25%
and the Peripheral
dysfunction, temporal dispersion of compound
Nerve Society, are
usually mild muscle action potential (CMAP) con-
valuable resources
when diagnosing the Cranial nerve 5Y20% figurations, and motor conduction
disease. The absence dysfunction, blocks. Especially when demyelinating
most often changes are equivocal or accompanied
of demyelination on
facial nerve
nerve conduction with axon loss, referencing one of the
studies should prompt Respiratory failure Very rare many electrodiagnostic criteria sets is
exploration for an encouraged. The European Federa-
alternative diagnosis. tion of Neurological Societies (EFNS)/
h Although 80% to 95% to case reports and small case series, Peripheral Nerve Society (PNS) criteria
of patients with typical most have observed that patients have the most favorable balance of
chronic inflammatory harboring anti-NF155 antibodies have sensitivity and specificity (Table 5-3).4
demyelinating younger ages of onset, disabling Unilateral testing of four motor nerves
polyradiculoneuropathy tremor, sensory ataxia, very high CSF yields a sensitivity of 81.3% and spec-
show CSF protein levels, and poor response to IV ificity of 96.1% for definite or probable
albuminocytologic immunoglobulin (IVIg). The pheno- CIDP. When five to eight motor nerves
dissociation, it is a
type associated with CNTN1 antibodies are tested, sensitivity improves to
nonspecific abnormality.
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
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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- differs from typical CIDP either by the
proteins is advised in all with sus- pattern of involvement or modality
pected CIDP. Patients found to harbor predominantly affected. Recognized
a monoclonal gammopathy should atypical variants that are still considered
undergo evaluation for lymphopro- CIDP include distal acquired demyelin-
liferative disorders. Select patients may ating symmetric (DADS) neuropathy,
benefit from more focused testing for Lewis-Sumner syndrome (multifocal
CIDP mimics in appropriate clinical acquired demyelinating sensory and
settings (Table 5-4). motor neuropathy [MADSAM]), sensory
CIDP, and motor CIDP.
Clinical and Laboratory Distal acquired demyelinating sym-
Features of Atypical Chronic metric neuropathy. DADS is distin-
Inflammatory Demyelinating guished clinically from typical CIDP
Polyradiculoneuropathy by slowly evolving distal sensory
Like typical CIDP, atypical CIDP is symptoms, sometimes with sensory
characterized principally by motor 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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KEY POINT
and limited to the distal lower limbs. the section on anti-MAG neuropathy h Patients with a distal
Despite minimal weakness, electrophys- later in this article). symmetric
iologic studies demonstrate demyelin- Lewis-Sumner syndrome. Lewis- sensory-predominant
ation in motor nerves along with Sumner syndrome, also known as neuropathy but
diminished sensory response ampli- MADSAM, is distinguished from typical demyelinating changes
tudes in the lower and sometimes CIDP by multifocal and asymmetric on nerve conduction
upper limbs. Motor conduction abnor- symptom distribution and from multi- studies may have distal
malities are accentuated distally such focal motor neuropathy (MMN) by acquired demyelinating
that distal latency prolongations are sensory symptomatology.14 Although symmetric neuropathy.
affected to a greater degree than con- some patients with Lewis-Sumner Recognizing distal
acquired demyelinating
duction velocity slowing in proximal syndrome evolve into having typical
symmetric neuropathy is
segments. CSF protein is often normal CIDP, between 50% and 80% remain
important because it
or only mildly elevated. Recognizing the multifocal. Characteristic electrophysi- may be treatable with
DADS phenotype has several important ologic abnormalities include multifocal immunotherapy or
implications. First, DADS may be easily conduction blocks with conduction may be associated
confused with more common axonal velocity slowing across blocked seg- with monoclonal
length-dependent polyneuropathies ments. Sensory amplitudes are re- gammopathy.
(Table 5-5). Second, up to two-thirds duced unless the blocked segment
of patients with DADS harbor a mono- is proximal to the site of sensory
clonal IgM gammopathy (DADS-M), and nerve stimulation and no wallerian
at least 50% of those patients express degeneration has developed. Unlike in
antiYmyelin-associated glycoprotein typical CIDP, distal motor latency
(MAG) antibodies. The presence of a prolongation and terminal latency
monoclonal gammopathy has impor- index reduction are rare.15 These
tant treatment implications (refer to 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 selective involvement of interme- root. The response to immunotherapy
immune sensory diate nerve segments rather than the is similar to typical CIDP.16
polyradiculopathy distal nerve terminal and proximal Motor chronic inflammatory demy-
variant of chronic trunk lesions that are common in elinating polyradiculoneuropathy.
inflammatory typical CIDP. CSF albuminocyto- Pure motor CIDP is a rare disorder that
demyelinating logic dissociation is less common in presents clinically with weakness in a
polyradiculoneuropathy Lewis-Sumner syndrome, occurring in pattern similar to typical CIDP. Unlike
may have normal nerve only 33% to 42%. As in typical CIDP, typical CIDP, sensation is clinically and
conduction studies MRI of an affected limb may show electrophysiologically spared. Motor
because of selective enlarged or enhancing nerve seg- CIDP may be difficult to distinguish from
involvement of the
ments or plexus. Although deteriora- MMN or motor neuron disease. Unlike
proximal dorsal sensory
tion after corticosteroid treatment has MMN, weakness is not restricted to
nerve root.
been reported, in most patients, re- individual nerve or plexus segments.
sponse to immunotherapy is similar to The pattern of weakness (nonsegmen-
typical CIDP. tal), absence of bulbar involvement,
Sensory chronic inflammatory de- demyelinating electrophysiologic abnor-
myelinating polyradiculoneuropathy. malities, and response to immunother-
Most pure sensory neuropathies are apy distinguish motor CIDP from motor
axonal without an immune-mediated neuron disease.
basis (Table 5-5). In others, the injury
targets the dorsal root ganglion, rais- Differential Diagnosis
ing concern for a paraneoplastic pro- Pitfalls that can lead to the erroneous
cess or Sjögren syndrome. Some diagnosis of CIDP include misinterpre-
sensory neuropathies show clear evi- tation of axonal electrodiagnostic stud-
dence of demyelination on motor ies as demyelinating, overreliance on
nerve conduction studies and are mild albuminocytologic dissociation,
more appropriately classified as and failure to objectify the treatment
DADS. Rarely, immune-mediated pro- response. 17 Even when peripheral
cesses preferentially or exclusively nerve demyelination is well docu-
disrupt sensory function, the best mented, diagnostic uncertainty may
characterized of which is chronic remain (Table 5-618).
immune sensory polyradiculopathy
(CISP). CISP is characterized clinically Treatment
by progressive numbness and ataxia, Successful CIDP treatment requires
reduced muscle stretch reflexes, and appreciation of two important factors:
normal strength.16 Nerve conduction the most appropriate treatment agent
studies are usually normal, but so- and the most effective treatment reg-
matosensory evoked potentials be- imen. While randomized controlled
come delayed. CSF often shows trial data are available to guide specific
elevated protein, and MRI may reveal interventions, much remains to be
enhancing or enlarged nerve roots. learned about how best to maximize
Although nerve biopsy is not part of therapy in individual patients.
the routine diagnostic process, studies Specific immunotherapies. IVIg,
that examined the histopathology of corticosteroids, and plasma exchange
the sensory nerve root revealed evi- are effective CIDP treatment options.
dence of demyelinating, remyelinating, Overall, 80% to 90% of patients im-
and inflammatory change at this site. prove with one of these therapies.19
These features localize the primary site No consensus exists on which first-line
of CISP pathology to the dorsal nerve intervention is best, although several
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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
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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

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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
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Chronic Demyelinating Polyneuropathies

KEY POINTS
h Measures of disability The strategy to best taper or optimize relapsing demyelinating polyneu-
and strength can be treatment is unknown. One challenge is ropathy clinically and electrophysio-
helpful adjuncts to objective documentation of treatment logically indistinguishable from CIDP
the examination response or relapse. Incorporation of as well as in patients with distal axonal
to document disease-focused disability assessments sensory or sensorimotor polyneurop-
treatment efficacy and with the Rasch-built Overall Disability athy.34 The therapeutic approach to
identify relapse. Scale (RODS)29 and strength measure- IgG/IgA paraprotein-associated neu-
h Although all patients ment with a grip strength dynamome- ropathy is guided by the phenotype;
with chronic ter30 may enhance traditional outcome patients presenting as CIDP are treated
inflammatory assessments and raise confidence in treat- similarly to those with CIDP without
demyelinating ment efficacy determinations (Case 5-1). gammopathy.33 At present, no compel-
polyradiculoneuropathy Immunotherapy tapering often carries ling evidence supports the use of im-
should be screened concern for irreversible disability accu- munotherapy in those with distal axonal
for a monoclonal mulation in the event of relapse. Using IgG/IgA MGUSYassociated neuropathies.
gammopathy, in
the tools discussed combined with sub-
most patients with Neuropathy Associated With
jective patient experience may provide a
neuropathy and
reasonable management approach that IgM Monoclonal Gammopathy
monoclonal
balances risk of early relapse with the of Undetermined Significance
gammopathy of
undetermined need to avoid overtreatment. IgM paraprotein represents only 20% of
significance, the monoclonal gammopathies,35 but up to
pathologic significance DEMYELINATING 50% of patients with paraprotein and
is unknown. NEUROPATHIES ASSOCIATED neuropathy harbor the IgM type.36
WITH MONOCLONAL Evaluation for IgM-secreting lympho-
GAMMOPATHY proliferative diseases, particularly
Paraprotein-associated neuropathies Waldenström macroglobulinemia or
are clinically and electrophysiologically lymphoma, is prudent. Most patients
heterogeneous, and, in most cases, the develop a DADS phenotype with dis-
pathogenic significance of the para- tally accentuated motor nerve demye-
protein is uncertain. Approximately lination on nerve conduction studies.13
3% of individuals older than 50 years At least two-thirds of patients demon-
of age and 7.5% older than 85 years of strate IgM antibody reactivity to neural
age harbor a monoclonal paraprotein, antigens, the most common of which
of which 8% to 36% develop a symp- is MAG.
tomatic polyneuropathy.32 Although
the majority (75%) are benign (mono- Neuropathy With AntiYMyelin-
clonal gammopathy of undetermined Associated Glycoprotein
significance [MGUS]), a 1% risk per Antibodies
year of progression to hematologic Polyneuropathy associated with anti-
malignancy exists. MAG antibodies has unique clinical and
electrophysiologic features that can
Neuropathy Associated help distinguish it from other chronic
With IgG and IgA Monoclonal demyelinating polyneuropathies. Dif-
Gammopathy of ferentiation is important as prognosis,
Undetermined Significance immunopathogenesis, and treatment
The pathoimmunologic relationship be- response are different than in CIDP.
tween neuropathy and IgG and IgA Clinical and diagnostic features of
MGUS is uncertain.33 IgG and IgA antiYmyelin-associated glycoprotein
paraproteins may be uncovered in neuropathy. Anti-MAG neuropathy
patients with chronic progressive or typically presents in the sixth or
1320 ContinuumJournal.com October 2017

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

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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 MULTIFOCAL MOTOR bodies may reduce sodium currents
neuropathy most NEUROPATHY sufficient to block action potential gen-
commonly presents MMN is an acquired, chronic, autoim- eration.48 In humans with MMN, motor
with weakness in the mune, asymmetric motor neuropathy. axon excitability studies have shown
distal upper limbs. The pattern of motor involvement, axonal hyperpolarization at sites distal
h Antibody-induced spared sensation, electrophysiologic to areas of conduction block.49 As in
dysfunction at the characteristics, immunopathogenesis, MMN, antiganglioside antibodies ap-
nodes of Ranvier may and treatment response distinguish pear to play a prominent pathophysio-
be an early pathologic MMN from other chronic demyelinat- logic role in the acute motor axonal
process in multifocal ing polyneuropathies. neuropathy (AMAN) variant of Guillain-
motor neuropathy. Barré syndrome. Antibodies against
Clinical Features GM1, GM1b, GD1a, and GalNAc-GD1a
MMN is a rare condition that affects are frequently detected in patients with
fewer than 1 per 100,000. The mean age AMAN, albeit of the IgG rather than
of onset is around 40 years, with a male IgM type.50 Also as in MMN, autoanti-
to female ratio of 3:1. The condition is body binding to GM1 gangliosides at
characterized clinically by asymmetric the nodes of Ranvier, complement
weakness in the distribution of mono- activation, and sodium channel dysfunc-
neuropathies and electrophysiologically tion may be pathophysiologically im-
by multifocal conduction blocks.44 In portant in AMAN.51,52 Taken together,
80% of patients, weakness first develops these observations imply that nodal
in the upper limbs, and in 90%, distal depolarization due to antibody-induced
muscles are preferentially affected.45 complement-mediated injury at the
Cramps and fasciculations are common. nodes of Ranvier and adjacent axo-
Mild sensory loss limited to the distal lemma hyperpolarization due to reac-
lower limbs can be seen in up to 20% of tive increased sodium/potassium pump
patients. Muscle stretch reflexes are activity are pathophysiologic processes
reduced in affected limbs but may be that mediate conduction block and
intact in areas without weakness. muscular weakness.53 The observation
that both MMN and AMAN may rapidly
Pathogenesis improve following treatment with IVIg
The precise immunopathogenesis of further supports reversal of antibody-
MMN is uncertain. Although traditionally mediated nodal membrane dysfunc-
considered a demyelinating disorder tion, rather than restoration of myelin
with secondary axonal degeneration, structural damage.11 This concept has
several lines of evidence implicate early yet to be confirmed.
pathology at the nodes of Ranvier. IgM
anti-GM1 antibodies are frequently Laboratory Features
detected in those with MMN. Although The defining electrophysiologic char-
ubiquitously expressed in both motor acteristic of MMN is conduction block
and sensory nerves, GM1 is most abun- (Table 5-8), with normal sensory re-
dantly localized to nodes of Ranvier and sponses even across sites of motor
adjacent paranodes of peripheral motor block. Conduction block in upper limb
nerves.46 Human sera containing anti- nerves at the midforearm level is most
GM1 antibodies induces conduction common. Proposed MMN diagnostic
block, immunoglobulin deposits at the criteria suggest that a diagnosis of MMN
nodes of Ranvier, and nodal widening can be reliably concluded when weak-
in animal nerve.47 When in the pres- ness and electrophysiologic conduction
ence of complement, anti-GM1 anti- block are present in two or more nerves,
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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- Astute attention to the pattern and type
ent.44 Even so, conduction block may of symptoms, electrophysiology, and lab-
not be identified in all patients with oratory data can help differentiate MMN
MMN. The absence of conduction from other motor nerve disorders
block may be because of the activity- (Table 5-9). Anti-GM1 antibodies are
dependent nature of the blocks or occasionally present in other lower motor
because the blocks are located at sites neuron conditions, including amyotrophic
that are inaccessible with nerve conduc- lateral sclerosis. Absence of anti-GM1
tion studies. Widespread evidence of antibodies does not exclude MMN, and a
demyelination may be seen in some, positive test can create diagnostic con-
but not all, patients. fusion in the wrong clinical context. The
Up to 60% of patients with MMN pattern of pure axon loss on nerve con-
have elevated IgM anti-GM1 antibodies. duction studies and EMG and absence of
Patients with anti-GM1 antibodies tend anti-GM1 antibodies has been described
to have more severe weakness, dis- as multifocal acquired motor axonopathy
ability, and eventual axon loss compared (Case 5-3).56 Treatment for this condi-
with seronegative patients.54 CSF protein tion is similar to that for MMN.57
is often normal or only mildly elevated.
The diagnostic role of imaging is limited, Treatment
but it may show nerve enlargement, IVIg is the first-line treatment for MMN.
particularly in the brachial plexus. Efficacy has been well documented in
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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 monitoring with grip strength and dis-
Younger patients, early treatment initia- ability outcomes55 may help objectify
tion, predominantly demyelinating the treatment response and facilitate
features, and fewer affected limbs pre- avoidance of IVIg overtreatment or
dict favorable treatment outcome.59 undertreatment.
Elevated anti-GM1 antibodies and con- Unlike other immune-mediated neu-
duction block were correlated with a ropathies, corticosteroids and plasma
favorable response in one retrospective exchange are usually not effective.44
study,60 but other studies have not Almost 20% of patients worsen with
made the same correlation.61 Mainte- corticosteroid treatment. Favorable re-
nance IVIg dose and frequency should sponses to rituximab have been re-
be optimized to individual needs. In ported by some, but an open-label
some, the beneficial effect lessens trial showed no change in IVIg dose,
over time. Although dose escalation strength, or disability in patients with
may restore short-term IVIg efficacy, MMN treated with rituximab.62 Although
gradual worsening with progressive benefit with cyclophosphamide has
reduction of strength despite contin- been described in small series, potential
ued therapy may occur. As in CIDP, toxicity restricts its wide use.

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Chronic Demyelinating Polyneuropathies

CONCLUSION 2015;28(5):474Y479. doi:10.1097/


WCO.0000000000000233.
While ostensibly similar, the chronic 9. Devaux JJ, Miura Y, Fukami Y, et al.
demyelinating polyneuropathies have Neurofascin-155 IgG4 in chronic inflammatory
variable clinical presentations and di- demyelinating polyneuropathy. Neurology
agnostic features. Categorization as 2016;86(9):800Y807 doi:10.1212/
WNL.0000000000002418.
discussed within this article provides
10. Querol L, Nogales-Gadea G, Rojas-Garcia R,
a rationale for development of treat- et al. Antibodies to contactin-1 in chronic
ment approaches based on the clini- inflammatory demyelinating polyneuropathy.
cal, electrophysiologic, and diagnostic Ann Neurol 2013;73(3):370Y380. doi:0.1002/
ana.23794.
data. Our evolving understanding of
11. Berger M, Allen JA. Optimizing IgG therapy
the immunologic underpinnings of in chronic autoimmune neuropathies: a
these neuropathies may offer diagnos- hypothesis driven approach. Muscle Nerve
tic clarity in the future and, by exten- 2015;51(3):315Y326. doi:10.1002/mus.24526.
sion, improved treatment approaches. 12. Rajabally YA, Nicolas G, Piéret F, et al.
Validity of diagnostic criteria for chronic
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