Chronic Inflammatory REVIEW ARTICLE


Demyelinating C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE

Polyradiculoneuropathy
and Its Variants
By Kelly Gwathmey, MD

ABSTRACT
PURPOSE OF REVIEW: Chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) and its variants comprise a group of
immune-mediated neuropathies with distinctive clinical presentations and
electrodiagnostic features. Prompt recognition of these treatable disorders CITE AS:
is mandatory as delays result in significant disability and morbidity. This CONTINUUM (MINNEAP MINN)
2020;26(5, PERIPHERAL NERVE AND
article highlights the clinical presentation, pathophysiology, diagnostic MOTOR NEURON DISORDERS):
evaluation, and treatment approach of these polyneuropathies. 1205–1223.

Address correspondence to
RECENT FINDINGS: Thespectrum of CIDP is expanding with the recent
Dr Kelly Gwathmey, Department
characterization of neuropathies associated with nodal and paranodal of Neurology, Virginia
antibodies. These neuropathies are distinguished by their unique Commonwealth University,
1101 East Marshall St, PO Box
presentations and are often refractory to IV immunoglobulin (IVIg) therapy. 980599, Richmond, VA 23298,
Subcutaneous immunoglobulins have recently been approved as a Kelly.Gwathmey@vcuhealth.
treatment option for CIDP and join corticosteroids, IVIg, and plasma org.

exchange as first-line treatment. RELATIONSHIP DISCLOSURE:

Dr Gwathmey has served as a
SUMMARY: CIDP is characterized by progressive symmetric proximal and consultant for and received
personal compensation for
distal weakness, large fiber sensory loss, and areflexia, with clinical nadir speaking engagements from
reached more than 8 weeks after symptom onset. Autoimmune Alexion Pharmaceuticals, Inc.
demyelinating neuropathies fall on a continuum, with differences in the UNLABELED USE OF
type of nerve fibers affected and pattern of deficits. Distinguishing PRODUCTS/INVESTIGATIONAL
between typical CIDP and its variants allows for selection of the most USE DISCLOSURE:
Dr Gwathmey discusses the
appropriate treatment. unlabeled/investigational use of
azathioprine, bortezomib,
corticosteroids
(methylprednisolone,
INTRODUCTION prednisone),

I
n 1890, chronic inflammatory demyelinating polyradiculoneuropathy cyclophosphamide,
cyclosporine, methotrexate,
(CIDP) was first described by Eichhorst in a patient with a presentation
mycophenolate mofetil, and
similar to Guillain-Barré syndrome but with a chronic course.1 The term rituximab for the treatment of
chronic inflammatory polyradiculoneuropathy, which summarizes its clinical chronic inflammatory
demyelinating
and pathologic features, was later coined by Dyck and colleagues.2 Although polyradiculoneuropathy and its
CIDP is the most common chronic autoimmune neuropathy, the incidence and variants.
prevalence are quite low across epidemiologic studies. One 2019 meta-analysis
estimated the incidence rate to be 0.33 per 100,000 and the prevalence rate to be © 2020 American Academy
2.81 per 100,000.3 The diagnosis relies on the clinical presentation and of Neurology.

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CIDP AND ITS VARIANTS

electrophysiologic and, in some cases, histopathologic evidence of acquired

demyelination, as well as exclusion of alternative causes of demyelination.

CLINICAL FEATURES
CIDP results in damage predominantly to peripheral nerve myelin, with the
heavily myelinated fibers the most susceptible to injury. Consequently, patients
present with numbness, weakness, and sensory ataxia. Half of patients are
considered to have typical CIDP, which manifests as symmetric proximal and
distal weakness, length-dependent loss of large fiber sensation, and areflexia
(CASE 4-1).4,5 The neuropathy progresses over several months, with clinical nadir
occurring after at least 2 months. The remaining patients have a CIDP variant
(TABLE 4-16–10). The course of CIDP may be monophasic, relapsing and
remitting, or chronically progressive.2,11 In up to 18% of patients, however, the
disease starts acutely, mimicking Guillain-Barré syndrome, and is termed
acute-onset CIDP.6,7 Although clinical nadir is reached within 2 months, patients
have a relapsing or progressive course that differentiates them from those with
Guillain-Barré syndrome.

CASE 4-1 A 65-year-old man presented with 1 year of progressive upper and lower
extremity weakness. He fell frequently and required a cane to ambulate.
He had also noticed a decline in manual dexterity, with difficulty
buttoning shirts and gardening. He denied any dysarthria, dysphagia, or
dyspnea. He had no significant medical comorbidities.
Examination revealed moderate generalized symmetric weakness of
the upper and lower extremities. Pinprick, temperature, and vibratory
sensation and proprioception were diminished in a length-dependent
pattern. Reflexes were diffusely absent. Electrodiagnostic studies
demonstrated a severe generalized primarily demyelinating
polyradiculoneuropathy with secondary axonal loss. CSF analysis
demonstrated a markedly elevated protein of 661 mg/dL with normal
white blood cell count of 1 cell/mm3.
The patient was started on prednisone 60 mg/d. Three months later,
he developed diabetes and had not clinically responded to the
prednisone. He received a loading dose of IV immunoglobulin (IVIg) of
2 g/kg over 5 days followed by 1 g/kg administered every 3 weeks, with
steady improvement in his weakness and sensory deficits.

COMMENT This patient’s history, examination, and electrodiagnostic and CSF studies
all support a diagnosis of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP). This case illustrates the importance of
constant appraisal of treatment efficacy and potential side effects. This
patient experienced no improvement with corticosteroids and developed
severe side effects necessitating a change in therapy. For each of the
first-line treatments (immunoglobulins, corticosteroids, and plasma
exchange), only two-thirds of patients will respond. Therefore, changing
CIDP treatment is often necessary.

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 Weakness is the most disabling CIDP symptom and results in impaired KEY POINTS
mobility, falls, and diminished manual dexterity. The presence of proximal
● One-half of patients with
muscle weakness is a diagnostic clue, even if less severe than distal weakness. chronic inflammatory
Postural tremor is a frequent accompanying clinical feature that may be demyelinating
debilitating and poorly responsive to CIDP treatment.12 Unlike in Guillain-Barré polyradiculoneuropathy
syndrome, cranial nerves are usually spared, although involvement of the facial (CIDP) have a typical
presentation of symmetric
and oculomotor nerves has been reported.13 In addition to weakness, most
proximal and distal
patients with CIDP report fatigue.14 Damage to heavily myelinated sensory nerve weakness, length-dependent
fibers results in impaired proprioception and sensory ataxia, whereas small nerve loss of large fiber sensation,
fiber dysfunction causing dysautonomia and neuropathic pain is less common. In and areflexia.
a minority of patients, respiratory impairment (which is much more common in
● Up to 18% of patients with
Guillain-Barré syndrome) has been described.15 CIDP will have an acute
onset that mimics
PATHOPHYSIOLOGY Guillain-Barré syndrome.
In contrast to Guillain-Barré syndrome, antecedent infections are rarely
● CIDP is differentiated
reported in CIDP. Although the exact pathophysiologic mechanisms are from Guillain-Barré
unknown, both cellular and humoral immunity likely play important roles.16 syndrome by a protracted
T cells and macrophages invade and strip the myelin lamellae supporting a time course, absence of
cellular immune response.17 Activation of T cells results in increased autonomic dysfunction, and
absence of respiratory
expression of IL-2 and tumor necrosis factor-α.18,19 Macrophages release toxic
impairment in most patients.
mediators that target peripheral nerves and phagocytose myelin.20 Antibodies
directed against peripheral nerve myelin protein P0 in some patients and ● All patients with
the response of patients to plasma exchange support the role of humoral suspected CIDP should be
immunity.21 screened for a monoclonal
gammopathy.

DIAGNOSTIC EVALUATION ● Albuminocytologic

Basic serum laboratory studies should be performed to exclude alternative or dissociation is expected on
confounding diagnoses, including hemoglobin A1c; complete blood cell count; CSF analysis in CIDP. The
presence of leukocytosis
electrolytes; liver, renal, and thyroid function studies; and vitamin B12 and raises suspicion for other
methylmalonic acid levels. All patients with possible CIDP must be screened conditions, such as
for a monoclonal gammopathy with serum and urine electrophoresis, neurosarcoidosis, human
immunofixation, and free light chains. In the presence of an IgM monoclonal immunodeficiency virus
(HIV), or carcinomatous
gammopathy, myelin-associated glycoprotein (MAG) antibodies should be
meningitis.
obtained. In those with IgG or IgA lambda monoclonal gammopathies, a skeletal
survey should be performed to rule out an osteosclerotic myeloma or ● The sural sparing pattern
plasmacytoma, and vascular endothelial growth factor (VEGF) level should be is an electrophysiologic
obtained to exclude POEMS (polyneuropathy, organomegaly, endocrinopathy, hallmark of CIDP and is
often found in addition to
monoclonal plasma cell disorder, and skin changes). For further discussion of other acquired
paraproteinemic neuropathies, refer to the article “Peripheral Neuropathies demyelinating features.
Associated With Monoclonal Gammopathies” by Elie Naddaf, MD, and Michelle
L. Mauermann, MD, FAAN,22 in this issue of Continuum. In those with poor
response to immunotherapy or with a strong family history, testing for inherited
neuropathies such as Charcot-Marie-Tooth disease and transthyretin familial
amyloidosis may be necessary.23,24
CSF analysis is usually not necessary, but, in certain cases of suspected CIDP,
it may be helpful. When collected, albuminocytologic dissociation (elevated
protein, normal leukocyte count) is anticipated. Elevated CSF protein is
significantly more common in typical and sensory CIDP than in multifocal
CIDP.25 While less than 10% of patients with CIDP may have a mild pleocytosis,
a CSF leukocyte count of greater than 50 cells/mm3 is very unusual and raises

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CIDP AND ITS VARIANTS

concerns of lymphoma, leptomeningeal carcinomatosis, neurosarcoidosis, and

human immunodeficiency virus (HIV).26
Electrophysiologic evidence of acquired demyelination on nerve conduction
studies strongly supports the clinical diagnosis. Expected findings include
slowing of conduction velocities, prolongation of sensory and motor latencies,
prolonged F-wave latencies, partial motor conduction block, abnormal temporal
dispersion, and prolongation of blink reflexes. A unique finding of both acute
and chronic acquired demyelinating neuropathies is the predominant involvement
of the upper extremity sensory nerves with relative sparing of the sural nerve, the
so-called sural sparing pattern. In pure demyelinating neuropathies, EMG may
demonstrate only reduced recruitment of normal morphology motor unit
potentials. With secondary axonal degeneration, active denervation (positive
sharp waves and fibrillation potentials) and reinnervation (high-amplitude
long-duration polyphasic motor unit potentials) may be observed.

TABLE 4-1 Comparison of Features of Chronic Inflammatory Demyelinating

Polyradiculoneuropathy and Its Variants

Percentage of Chronic
Chronic Inflammatory Inflammatory
Demyelinating Demyelinating
Polyradiculoneuropathy Polyradiculoneuropathy
Variant Clinical Features Cases Treatment Response Notes
4
Typical chronic Symmetric 50% Immunoglobulins, Clinical nadir reached
inflammatory proximal and corticosteroids, plasma after 8 weeks
demyelinating distal weakness, exchange
polyradiculoneuropathy sensory loss,
(CIDP) areflexia

Acute CIDP Symmetric Up to 18%6,7 Immunoglobulins, Clinical nadir reached

proximal and distal corticosteroids, plasma before 8 weeks; may
weakness, sensory exchange mimic Guillain-Barré
loss, areflexia syndrome

Sensory CIDP Symmetric 5–15%5,8 Immunoglobulins, Distinguished from

sensory- corticosteroids, plasma idiopathic sensory
predominant exchange polyneuropathy by
presentation, early ataxia, younger
sensory ataxia, age, early upper
generalized extremity symptoms
hyporeflexia/
areflexia

Chronic immune sensory Sensory ataxia Unknown, very rare Immunoglobulins, Normal nerve
polyradiculopathy corticosteroids conduction studies;
(CISP) diagnosis relies on
somatosensory
evoked potentials,
CSF analysis, and MRI
abnormalities of
lumbar roots

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 MRI studies, although often not performed, may demonstrate enlarged
enhancing nerve roots, plexus, and peripheral nerves.27,28 If concomitant central
nervous system demyelination is a concern, a brain MRI should be obtained.
Nerve ultrasound is emerging as a cost-effective imaging option in CIDP and
may serve as a potential biomarker. In treatment-naïve CIDP, focal enlargement
of the nerves is appreciated, whereas in chronic CIDP, the enlargement becomes
more confluent.29 Unlike axonal neuropathies, nerve enlargement in CIDP
affects primarily the proximal nerve segments (especially the median nerve) and
brachial plexus.30
Nerve biopsy is unnecessary in straightforward cases of CIDP. As CIDP
predominantly affects proximal mixed sensory and motor nerves, high-yield
targeted biopsy would entail greater morbidity than routine biopsy of a
cutaneous sensory nerve. Therefore, biopsy is reserved for those in whom a high
suspicion of an alternative diagnosis exists. When performed, biopsy often shows

CONTINUED FROM PAGE 1208

Percentage of Chronic
Chronic Inflammatory Inflammatory
Demyelinating Demyelinating
Polyradiculoneuropathy Polyradiculoneuropathy
Variant Clinical Features Cases Treatment Response Notes
4,8,9
Motor CIDP Symmetric 4–10% Immunoglobulins; avoid May have
proximal and corticosteroids electrophysiologic
distal motor evidence of sensory
deficits involvement

Multifocal acquired Asymmetric distal 8–15%5,9 Immunoglobulins, May evolve into

demyelinating sensory
and motor neuropathy
(MADSAM)
more than corticosteroids, plasma typical CIDP
proximal sensory exchange
and motor
deficits; affects
upper more than
lower extremities

Distal acquired Symmetric distal 2–10%9,10 With myelin-associated May be associated

demyelinating and
symmetric (DADS)
neuropathy
more than glycoprotein (MAG) with an IgM
proximal, sensory antibodies, treatment monoclonal
more than motor ineffective although gammopathy; may
deficits; affects rituximab response have MAG antibodies;
lower more than reported in some series; considered
upper extremities without MAG antibodies, DADS-CIDP in the
response to absence of
immunoglobulins, monoclonal
corticosteroids, plasma gammopathy and
exchange MAG antibodies

CSF = cerebrospinal fluid; IgM = immunoglobulin M; MRI = magnetic resonance imaging.

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CIDP AND ITS VARIANTS

histopathologic evidence of inflammatory cells infiltrating the endoneurium,

epineurium, and perivascular regions. With repeated demyelination and
remyelination, Schwann cell cytoplasmic processes stack, resulting in the typical
onion bulb formation.
Numerous recent publications have drawn attention to the high rate of
CIDP misdiagnosis.31 These diagnostic errors result in long-term use of
inappropriate treatments with extraordinary risk of adverse effects and cost to
the health care system. The source of these errors results primarily from
misinterpretation of electrodiagnostic studies and overinterpretation of
subjective response to IVIg infusions (TABLE 4-232). To prevent diagnostic
mistakes, particular attention should be paid to the clinical presentation and
adherence to published electrodiagnostic criteria for CIDP, the most widely
accepted of which is the European Federation of Neurological Societies/Peripheral
Nerve Society criteria (TABLE 4-333,34).35 With more than 15 different
published electrodiagnostic criteria for CIDP, the lack of a single universally
accepted criteria likely also contributes to diagnostic errors.36 Whereas nerve
conduction studies are an essential part of the diagnostic evaluation of CIDP, not
all patients meet formal criteria for CIDP; the presence of symmetric weakness
of all four limbs and proximal weakness in at least one limb in a patient with
possible CIDP has equivalent diagnostic sensitivity and specificity to nerve
conduction criteria.37

TREATMENT
CIDP treatment is initiated with one of three first-line therapies: immunoglobulins
(including IV and subcutaneous routes of administration), corticosteroids, or
plasma exchange; 50% to 70% of patients respond to one of these therapies.38 The
choice of treatment is tailored to the patient’s medical comorbidities, dosing
schedule, and, at times, availability of the product. The treatment approach
consists of induction therapy followed by maintenance therapy.
IVIg therapy was approved by the US Food and Drug Administration (FDA)
for treatment of CIDP in 2008. The initial dose, typically 2 g/kg, is divided over
2 to 5 days and followed by maintenance dosing of 1 g/kg administered every
3 weeks.33 Treatment for 6 weeks is recommended to assess for response before
switching to another therapy,39 and up to 12 weeks of treatment are necessary for

TABLE 4-2 Electrophysiologic Pitfalls Resulting in a Misdiagnosis of Chronic

Inflammatory Demyelinating Polyradiculoneuropathya

◆ Equivocal degrees of conduction velocity slowing in the axonal polyneuropathies

◆ Prolonged fibular (peroneal) nerve distal motor latency in the setting of reduced amplitude
◆ Mild conduction velocity slowing observed in motor neuron disease
◆ Conduction velocity slowing limited to sites of compression
◆ Slowing of sensory responses and amplitude-independent slowing in the context of diabetes
◆ Conduction velocity slowing and prolongation of distal latencies due to cold limb
temperatures

a
Data from Allen JA, et al, Muscle Nerve31 and Allen JA, Lewis RA, Neurology.32

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maximal benefit.40 Treatment response should be constantly assessed with the
goal to reduce the dose and frequency of the treatments and, if possible, taper the
IVIg entirely. Compared to the maintenance dose of 1 g/kg used in the ICE
(Immune Globulin Intravenous for Chronic Inflammatory Demyelinating
Polyneuropathy) trial, tailoring the regimen to the individual is noninferior
and more cost-effective.40,41 A phase 3 study of three different IVIg regimens
(0.5 g/kg, 1 g/kg, and 2 g/kg) every 3 weeks is ongoing; it is hoped that it will
establish the optimal maintenance dosing.42
Subcutaneous immunoglobulin (SCIg) therapy, approved by the FDA in
March 2018 for treatment of CIDP, is an appealing alternative to maintenance
IVIg for many patients given its lower incidence of systemic side effects. As it is
self-administered, patients also appreciate more autonomy. The PATH (Chronic

European Federation of Neurological Societies/Peripheral Nerve Society TABLE 4-3

Electrodiagnostic Criteria for Chronic Inflammatory Demyelinating
Polyradiculoneuropathya,b

Definite (at least one of the following):

◆ Motor distal latency prolongation ≥50% above upper limit of normal values (ULN) in two
nerves (excluding median neuropathy at the wrist from carpal tunnel syndrome), OR
◆ Reduction of motor conduction velocity ≥30% below lower limit of normal values (LLN) in two
nerves, OR
◆ Prolongation of F-wave latency ≥30% above ULN in two nerves (≥50% if amplitude of distal
negative peak compound muscle action potential [CMAP] <80% of LLN values), OR
◆ Absence of F waves in two nerves if the nerves have distal negative peak CMAP amplitudes
≥20% of LLN + ≥1 other demyelinating parameterc in ≥1 other nerve, OR
◆ Partial motor conduction block: ≥50% amplitude reduction of the proximal negative peak
CMAP relative to distal, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one
nerve + ≥1 other demyelinating parameterc in ≥1 other nerve, OR
◆ Abnormal temporal dispersion (>30% duration increase between the proximal and distal
negative peak CMAP) in ≥2 nerves, OR
◆ Distal CMAP duration (interval between onset of the first negative peak and return to
baseline of the last negative peak) increase in ≥1 nerve (median ≥6.6 ms, ulnar ≥6.7 ms,
peroneal ≥7.6 ms, tibial ≥8.8 ms)34 + ≥1 other demyelinating parameterc in ≥1 other nerve
Probable
◆ ≥30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding
the posterior tibial nerve, if distal negative peak CMAP ≥20% of LLN, in two nerves, or in one
nerve + ≥1 other demyelinating parameterc in ≥1 other nerve
Possible
◆ As in definite but in only one nerve

a
Modified with permission from Van den Bergh PYK, et al, Eur J Neurol.33 © 2010 The Authors. Journal
compilation © 2010 EFNS and Peripheral Nerve Society.
b
To apply these criteria, the median, ulnar (stimulated below the elbow), fibular (peroneal) (stimulate 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 the ulnar and median nerves are stimulated bilaterally at the axilla and at
Erb’s point. Motor conduction block is not considered in the ulnar nerve across the elbow, and at least 50%
amplitude reduction between Erb’s point and the wrist is required for probable conduction block.
Temperatures should be maintained to at least 33°C (91.4°F) at the palm and 30°C (86°F) at the external
malleolus (good practice points).
c
Any nerve meeting any of the criteria (1 through 7).

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CIDP AND ITS VARIANTS

Inflammatory Demyelinating Polyneuropathy and Treatment With

Subcutaneous Immunoglobulin) clinical trial was the pivotal phase 3 study that
randomly assigned patients with CIDP who were IVIg dependent to placebo,
0.2 g/kg 20% SCIg weekly, or 0.4 g/kg 20% SCIg weekly.43 The primary outcome
was the proportion of CIDP relapses or withdrawals from the study in each group
over the 24-week duration of the trial. Of the trial participants, 63% in the
placebo arm, 39% in the 0.2 g/kg arm, and 33% in the 0.4 g/kg arm met the
primary outcome (P=.0007). Both doses of SCIg were found to be efficacious and
well tolerated, supporting the use of SCIg as maintenance therapy in CIDP. A
small study of patients with CIDP who were treatment naïve compared SCIg to
IVIg and found them equally efficacious in terms of isokinetic muscle strength;
notably, improvement was earlier in the IVIg group at 2 weeks in contrast to
5 weeks in the SCIg group.44
Several corticosteroid regimens are used for induction therapy, including oral
prednisone (1 g/kg/d to 1.5 g/kg/d or alternate-day equivalent dose), dexamethasone
40 mg/d for 4 days every 4 weeks, or IV methylprednisolone 0.5 g one day each
week or for 4 consecutive days monthly.45 Comparison of these three regimens in
125 patients who were treatment naïve demonstrated that 60% of patients
improved and 61% of responders achieved remission; no differences between
treatments were seen in safety and efficacy.46 A large randomized controlled trial
investigating the additional benefit of IV methylprednisolone in combination
with IVIg for induction therapy is under way.47
Plasma exchange significantly improves clinical impairment and disability in
CIDP, but the benefit is short-lived. Five to ten exchanges of 50 mL/kg plasma
volume on alternate days are initiated within 2 to 4 weeks as induction therapy,
followed by one to two sessions every 3 to 4 weeks as maintenance therapy.
Given the logistic challenges of plasma exchange as maintenance therapy, it is
often considered for patients with CIDP refractory to IVIg and corticosteroids.
Many steroid-sparing immunosuppressant medications have been used in
CIDP, including mycophenolate mofetil,48 azathioprine, cyclophosphamide,
methotrexate, and cyclosporine. The data supporting the use of these drugs are
limited, as the existing trials were underpowered to demonstrate a significant
benefit.49 However, it is common clinical practice to use azathioprine or
mycophenolate mofetil in addition to corticosteroids to facilitate successful
tapering of the steroid dose, and pulse IV cyclophosphamide 1 g/m2 may be used
for patients with CIDP refractory to standard therapy.48,50 A 2018 study of
fingolimod failed to demonstrate efficacy.51 No clear guidance is available
regarding the treatment approach in refractory CIDP. Case reports and small
series exist that have used immunoadsorption, rituximab, and bortezomib in
refractory cases.52–54 Consideration of an alternative diagnosis is mandatory in
those with seemingly refractory disease.23
The treatment strategy in CIDP must be tailored to disease activity. The
Chronic Inflammatory Demyelinating Polyneuropathy Disease Activity Status
Tool (CDAS) allows for easy and reproducible classification of patients with
CIDP according to disease activity and treatment status. Among 106 patients
with CIDP followed for an average of 6.4 years, 11% were classified as
“cured,” 20% as in remission (defined as being stable off treatment for
<5 years), 44% had stable active disease that required ongoing treatment,
7% were improving on treatment following recent diagnosis, and 18% had
“unstable active disease” (either treatment refractory or treatment naïve).55

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Those with active disease may require dose escalation or switching therapies, KEY POINTS
whereas treatment tapering may be considered in those with inactive disease.
● Patients with suspected
Incorporation of validated clinical outcome measures should inform treatment CIDP do not require a
decisions. The standard outcome measures include manual muscle testing, the nerve biopsy if the
Inflammatory Neuropathy Cause and Treatment Disability Score (INCAT), electrodiagnostic findings
and handgrip strength.56 A newer instrument, the Inflammatory Rasch-built and clinical features are
consistent with an
Overall Disability Scale (I-RODS), demonstrates excellent responsiveness and
acquired demyelinating
correlates with objective measures of strength.57,58 Several disease-specific polyradiculoneuropathy.
validated quality-of-life instruments, such as the Inflammatory Neuropathy
Quality of Life Instrument (IN-QoL) and the Chronic Acquired Polyneuropathy ● More than 15 sets of
Patient-Reported Index (CAPPRI), can provide additional value to clinical diagnostic criteria for CIDP
have been published; the
assessments.59,60 most widely accepted is the
European Federation of
CIDP VARIANTS Neurological Sciences/
In contrast to “typical” CIDP, the CIDP variants do not conform to the expected Peripheral Nerve Society
criteria.
pattern of symmetric generalized weakness with length-dependent sensory
deficits. These polyneuropathies are characterized by sensory predominance ● The first-line treatments
(eg, sensory CIDP), motor predominance (eg, motor CIDP or multifocal motor for CIDP include
neuropathy [MMN]), asymmetry (eg, multifocal acquired demyelinating immunoglobulins (IV
and subcutaneous),
sensory and motor neuropathy [MADSAM]), or distal predominance (eg, distal
corticosteroids, and plasma
acquired demyelinating symmetric [DADS] neuropathy). exchange. Given the need for
long-term venous access and
Sensory CIDP limited facilities capable of
outpatient plasma exchange,
Approximately 5% to 15% of patients
in practice, plasma exchange
with CIDP have a pure sensory clinical is considered second- or
presentation but with electrophysiologic third-line treatment by many
evidence of demyelination on motor experts.
nerve conduction studies.61 Some of these
● Clinical trials suggest IV
patients will evolve into typical CIDP immunoglobulin (IVIg) can be
and develop weakness. Very few patients discontinued successfully
will have clinical and electrophysiologic without relapse in
involvement strictly isolated to the approximately 50% of
patients. The treating
sensory nerves. Sensory CIDP is physician should work
characterized by early ataxia, early toward reducing or
upper extremity involvement, diffuse discontinuing the IVIg if
hyporeflexia, cranial nerve involvement, possible.
and onset before the age of 55.62
● Use of clinically
Chronic immune sensory appropriate outcome
polyradiculopathy (CISP) represents a measures, such as disability
rare subtype of sensory CIDP. Patients scales and quality-of-life
present with prominent sensory ataxia. instruments, helps to inform
medical decision making in
The subtype was first reported in 2004; CIDP.
patients have sensory symptoms with
normal nerve conduction studies.63
Elevated CSF protein, enlarged and
enhancing nerve roots on lumbar MRI FIGURE 4-1
(FIGURE 4-1), and delayed somatosensory Sagittal postcontrast T1-weighted MRI
shows lumbar nerve root enhancement
evoked potentials are hallmarks. Patients (arrows) in a patient with chronic
with CISP may be treated successfully inflammatory sensory
with corticosteroids or IVIg. polyradiculoneuropathy.

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CIDP AND ITS VARIANTS

Pure Motor CIDP

Pure motor CIDP appears to be a rare variant reported in only a few series,64 and
some patients have sensory nerve involvement on electrodiagnostic studies. In its
purest form, motor CIDP clinically and electrophysiologically spares the sensory
nerves, perhaps consistent with an expanded spectrum of MMN. Further
supporting this possibility, some patients with motor CIDP decompensate when
treated with corticosteroids, similar to in MMN.9

Multifocal Motor Neuropathy

MMN is a distinct chronic immune-mediated motor polyneuropathy that falls
outside of the CIDP rubric. Although historically categorized as a demyelinating
polyneuropathy, emerging evidence indicates that the characteristic partial
motor conduction block is due to anti-GM1 antibody–mediated conduction
failure at the node of Ranvier, suggesting MMN should be classified as a
nodopathy rather than a demyelinating syndrome.65 The immune-mediated
attack on the motor fibers of at least two peripheral nerves results in a multifocal
pattern. MMN typically presents with asymmetric distal upper extremity
weakness, with cramps and fasciculations manifesting in affected peripheral
nerve territories (CASE 4-2). In the differential diagnosis of motor neuron
diseases with the progressive painless weakness, patients with MMN lack upper
motor neuron signs. Cold paresis (increased weakness during cold) is also a
clinical hallmark (although this finding is common in other motor neuropathies,
such as monomelic amyotrophy). Conduction block of motor nerves causes
weakness without atrophy unless secondary axonal degeneration is present.
The electrophysiologic hallmark of MMN is demonstration of partial motor
conduction block at noncompressible sites. This is often difficult to demonstrate
on routine electrodiagnostic testing; alternative techniques, including
transcutaneous cervical root stimulation, transcranial magnetic stimulation, and
triple stimulation (which estimates the percentage of motor units discharged by

CASE 4-2 A 54-year-old man presented with progressive painless weakness of his
distal right arm, followed by his left foot. He denied any ocular, bulbar, or
sensory symptoms.
On examination, he had marked weakness of his right wrist and finger
extension and left foot dorsiflexion and eversion. Motor nerve
conduction studies demonstrated conduction block in several motor
nerves, with completely normal sensory responses. His CSF analysis
demonstrated a normal protein level. Anti-GM1 antibodies were negative.

COMMENT This patient’s multifocal weakness with electrophysiologic evidence of an

acquired demyelinating motor neuropathy is diagnostic of multifocal motor
neuropathy (MMN). Approximately 50% of patients with this pure motor
neuropathy lack the characteristic anti-GM1 antibodies. Also, unlike in
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), CSF
protein is often normal. This patient was started on IV immunoglobulin
(IVIg) with complete resolution of his neurologic deficits.

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transcranial electrical stimulation through electrical stimulation at three sites,
including the scalp, Erb’s point, and peripheral nerve), may be used.66
Significant titers of IgM antibodies directed toward GM1, a ganglioside on the
motor nerve axolemma at the node and Schwann cell paranode, are found in
40% to 60% of patients with MMN.66 Testing of GM1/galactocerebroside
complexes may increase the sensitivity to 70%.67 On MRI, T2 hyperintensity
and contrast enhancement of the brachial plexus is a common feature.68 Nerve
ultrasound demonstrating increased cross-sectional area of the median and
ulnar nerves may be more sensitive than MRI.69
The first-line treatment of MMN is IVIg, and most patients require long-term
treatment.70 For many patients, the effectiveness of IVIg declines several years
after initiation, usually in the setting of axonal degeneration.71 SCIgs are likely an
alternative in some patient populations.72 Most patients fail to respond to steroids
and may even deteriorate clinically.73 IV cyclophosphamide (1 g/m2 monthly for
six doses), with or without associated plasma exchange, may be an effective
strategy in some patients with IVIg-refractory MMN. Small uncontrolled studies
suggest individual patients may respond to B-cell depletion with rituximab,
although randomized clinical trials have not been performed.73

Multifocal Acquired Demyelinating Sensory and Motor Neuropathy

MADSAM (ie, Lewis-Sumner syndrome or multifocal CIDP) is another variant
of CIDP that is differentiated from MMN by the involvement of sensory fibers.
Patients develop an insidious onset of gradually progressive, asymmetric, upper

A 72-year-old man had presented 4 years earlier with symmetric CASE 4-3
numbness and “heaviness” of both feet. Over time, this sensation had
ascended to the level of his knees. He also gradually developed
weakness affecting his distal upper and lower extremities and gait ataxia.
His electrodiagnostic studies at initial presentation revealed absent
sensory responses, extremely prolonged distal motor latencies (eg,
26.2 milliseconds for the right tibial compound muscle action potential
[CMAP]), and severely slowed conduction velocities without evidence of
conduction block. During initial evaluation of his neuropathy, an IgM
lambda monoclonal gammopathy and positive anti–myelin-associated
glycoprotein antibodies were identified.
Over the subsequent years, he was treated with IV immunoglobulin
(IVIg), plasma exchange, mycophenolate mofetil, and azathioprine.
Despite these treatments, he continued to gradually decline.

This patient’s diagnosis is distal acquired demyelinating symmetric (DADS) COMMENT

neuropathy with anti-MAG antibodies. He was initially misdiagnosed with
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP),
resulting in use of numerous therapies without clinical response. This is the
expected outcome as DADS with anti-MAG antibodies is classically
treatment refractory. Earlier recognition of his diagnosis would have
prevented years of expensive and futile treatments.

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CIDP AND ITS VARIANTS

extremity weakness and numbness.74 Nearly half of patients with MADSAM

progress to typical CIDP. Cranial nerve involvement may occur, affecting the
optic, oculomotor, trigeminal, and facial nerves. Electrophysiologic and
histopathologic features resemble CIDP, and, similarly, three-fourths of patients
will have albuminocytologic dissociation on CSF analysis.75 Unlike MMN,
MADSAM is responsive to both corticosteroids and IVIg.

Distal Acquired Demyelinating Symmetric Neuropathy

DADS neuropathy is a CIDP variant causing symmetric distal-predominant
sensory or sensorimotor deficits resulting in ataxia. Weakness, if present, affects
the distal lower extremities. Action tremor may also be a feature. IgM
monoclonal gammopathy and MAG or sulfated glucuronyl paragloboside
antibodies are present in many patients with DADS.
Electrodiagnostic studies demonstrate acquired demyelination with extremely
prolonged distal motor and sensory latencies. In contrast to typical CIDP,
patients have disproportionate slowing of distal motor conductions with a
terminal latency index (distal nerve conduction distance/[proximal motor
conduction velocity  distal motor latency]) ≤0.25, absence of conduction block,

TABLE 4-4 Nodo-Paranodopathies

Antibody
Target Clinical Features
Neurofascin Subacute onset,
155 (NF155) symmetric motor more
than sensory, sensory
ataxia, tremor (also of
head/voice), distal-
predominant; cranial
neuropathies reported
Percentage of
Chronic Inflammatory
Demyelinating
Polyradiculoneuropathy
Casesa Target Treatment Response
5–10% Paranodal transmembrane Good response to
cell adhesion molecule rituximab and plasma
located on Schwann cell exchange; partial
membrane response to
corticosteroids; IV
immunoglobulin (IVIg)
refractory

Neurofascin Subacute onset, 2% Axonal membrane protein Good response to

140 (NF140)/ symmetric sensory and involved in clustering of rituximab; partial
neurofascin motor, sensory ataxia, sodium channels located at response to IVIg and
186 (NF186) cranial neuropathies; the nodes of Ranvier; corticosteroids
nephrotic syndrome interacts with gliomedin
reported and neuronal cell molecules

Contactin-1 Subacute onset, 5% Paranodal, axonal cell Good response to

(CNTN1) symmetric motor more adhesion molecule rituximab; partial
than sensory, sensory response to
ataxia; nephrotic corticosteroids; IVIg
syndrome reported refractory

Contactin- Subacute onset, <1% Paranodal, axonal cell Good response to

associated symmetric distal- adhesion molecule rituximab; IVIg refractory
protein 1 predominant, severe
(CASPR1) neuropathic pain

a
Percentages of nodal and paranodal antibodies in CIDP taken from Pascual-Goñi E, et al, Curr Opin Neurol.79

1216 OCTOBER 2020

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and absence of sural response.76 Histopathologic evidence of segmental
demyelination with IgM and complement deposits in the myelin sheaths and
widened outer myelin lamellae is seen. The response to immunotherapy in DADS
with anti-MAG antibodies remains suboptimal (CASE 4-3). Up to 50% of patients
with anti-MAG neuropathies have been reported to respond to rituximab in
some series, although no consensus exists on its use.77 Patients with DADS who
lack anti-MAG antibodies, however, may respond to IVIg, corticosteroids, and
plasma exchange.78

Nodopathies and Paranodopathies

Approximately 10% of patients with CIDP have autoantibodies directed to
paranodal or nodal antigens that represent a distinct entity classified as
nodo-paranodopathies.10 Testing for these pathogenic autoantibodies is
indicated in the context of unique clinical presentations (eg, subacute onset,
predominant tremor, distal predominant presentation, or sensory ataxia) and
often treatment-refractory polyneuropathy (TABLE 4-4,79 CASE 4-4).81
The targets of these autoantibodies in the paranodal region are three cell adhesion
molecules: contactin 1 (CNTN1) and contactin-associated protein 1 (CASPR1) in

A 40-year-old man presented to the hospital with a 3-week history of CASE 4-4
generalized weakness and distal-predominant sensory loss. His
examination was remarkable for weakness of most muscle groups in the 4/5
range, with a length-dependent loss of large fiber–mediated sensation. His
reflexes were unobtainable. His electrodiagnostic studies demonstrated
prolonged and absent F waves, multiple areas of partial motor conduction
block, and a sural sparing pattern on sensory nerve conduction studies. He
was diagnosed with Guillain-Barré syndrome and treated with 2 g/kg IV
immunoglobulin (IVIg). Despite this therapy, he continued to decline and
subsequently received plasma exchange before being discharged to a
rehabilitation hospital.
He was readmitted 1 week later with significant worsening and
had become quadriplegic and areflexic. Given his atypical course,
nodal and paranodal autoantibodies were tested, and an anti-neurofascin
155 (NF155) antibody was identified. He was started on rituximab, with
significant improvement in his function and only mild residual proximal
muscle weakness in his upper and lower extremities 3 months later.

This case of chronic inflammatory demyelinating polyradiculoneuropathy COMMENT

(CIDP) associated with the paranodal antibody NF155 illustrates an
important point. These rare forms of CIDP should be considered in the
setting of recurrent failures of first-line treatments such as plasma
exchange and IVIg. Additionally, nodo-paranodopathies often have a
subacute onset mimicking Guillain-Barré syndrome and must remain in the
differential if the patient’s course is atypical. This patient did not respond
adequately until treated with rituximab, a distinction that has recently been
highlighted in the literature.80

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CIDP AND ITS VARIANTS

the axons and neurofascin 155 (NF155) in the myelin. These proteins form a
complex that assembles nodal voltage-gated sodium channels and juxtaparanodal
voltage-gated potassium channels (FIGURE 4-2).81 At the node of Ranvier,
autoantibodies target neurofascin isoforms 140 and 186 (NF140 and NF186).
These paranodal and nodal autoantibodies are of the IgG4 isotype.
Immunoglobulin response is achieved in only 40% of patients, and other
treatment considerations include rituximab, plasma exchange, and corticosteroids.

PROGNOSIS
The CIDP disease course varies dramatically from person to person. Over half of
patients will experience significant disability during their course, necessitating
either assistive devices to ambulate or becoming wheelchair dependent.82,83
Approximately 10% of patients will develop permanent disability or even

FIGURE 4-2
The node of Ranvier. This figure demonstrates the molecular components of the node of
Ranvier, paranode, and juxtaparanode. In the paranodal region, the cell adhesion molecules
contactin 1 (CNTN1), contactin-associated protein 1 (CASPR1), and neurofascin 155 (NF155)
may be targeted in some forms of chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP). At the node of Ranvier, neurofascin 186 (NF186) may be a target. Multiple other
important components of nodal and paranodal function are displayed that are relevant to
the pathophysiology and treatment of other autoimmune neuropathies, including
myelin-associated glycoprotein (MAG) in distal acquired demyelinating symmetric
(DADS) neuropathy and GM1 in multifocal motor neuropathy (MMN).
CASPR2 = contactin-associated protein 2; CNTN2 = contactin 2; Kv = voltage-gated potassium channel;
Nav = voltage-gated sodium channel; NrCAM = neuronal cell adhesion molecule.
Figure reprinted with permission from Querol L, et al, Nat Rev Neurol.81 © 2017 Wolters Kluwer Health, Inc.

1218 OCTOBER 2020

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die,82–84 whereas up to 25% of patients may attain complete remission.84 Recent KEY POINTS
studies suggest that initial disability, older age at onset, F-wave latency, and
● Multifocal motor
reduced distal compound muscle action potential (CMAP) duration predict poor neuropathy may mimic
long-term outcome.85,86 amyotrophic lateral
sclerosis given its painless
progressive weakness, but it
is differentiated by its lack
CONCLUSION
of upper motor neuron signs
CIDP is the most common chronic autoimmune polyneuropathy, and its and electrophysiologic
diagnosis depends not only on a thorough examination but also on evidence of conduction
high-quality electrodiagnostic studies demonstrating unequivocal evidence of block on motor nerve
conduction studies.
acquired demyelination. Classically associated with gradually progressive
generalized weakness and sensory ataxia, nearly one-half of patients with ● Distal acquired
CIDP will have an atypical presentation, with the disease classified as a demyelinating symmetric
variant. Knowledge of these variants and their defining clinical and (DADS) neuropathy is often
electrodiagnostic characteristics enables clinicians to select the most associated with IgM
monoclonal gammopathy
appropriate treatment. Despite recent therapeutic advances, much remains and myelin-associated
unknown regarding the optimal treatment strategy. glycoprotein antibodies.
Patients with DADS are often
refractory to treatment.
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