POLYNEUROPATHY

                                                          
Chronic Inflammatory Demyelinating Polyneuropathy

Hubertus Köller, M.D., Bernd C. Kieseier, M.D., Sebastian Jander, M.D.,
and Hans-Peter Hartung, M.D.
From the Department of Neurology, Heinrich-
Heine University, Düsseldorf, Germany.
 

Chronic inflammatory demyelinating polyneuropathy is a common,  and potentially treatable disease with an estimated prevalence of about 0.5 per 100,000 children
1 and 1 to 2 per 100,000 adults.
Clinical similarities to the acute variant of inflammatory demyelinating polyneuropathy
(the Guillain–Barré syndrome) and the beneficial effects of immunosuppressive
therapies suggest an immune-mediated pathogenesis. Since the first descriptions of
patients with corticosteroid-responsive chronic polyneuropathies by Austin,
the spectrum of clinical presentation and the diagnostic armamentarium
have enlarged, and further therapeutic options have evolved. The recognition
of this disorder as distinct from other common chronic sensorimotor polyneuropathies
that accompany diabetes, alcoholism, or malnutrition is important. This
review summarizes present knowledge about the clinical features of this condition, diagnostic
criteria and diagnostic procedures involved in assessment, and current management
strategies based on the results of randomized, controlled trials. Current concepts
of immunopathogenesis are also considered.
classic chronic inflammatory demyelinating polyneuropathy
Classic chronic inflammatory demyelinating polyneuropathy is characterized by the
occurrence of symmetrical weakness in both proximal and distal muscles that progressively
increases for more than two months (setting this condition apart from the
Guillain–Barré syndrome, which is self-limited). The condition is associated with impaired
sensation, absent or diminished tendon reflexes, an elevated cerebrospinal fluid
protein level, demyelinating nerve-conduction studies, and signs of demyelination in
nerve-biopsy specimens.

The course can be relapsing or chronic and progressive, the
former being much more common in young adults.
As the disease has become better recognized and clinical trials have been considered,
several groups have proposed clinical definitions of this neuropathy (Table 1).

In all these definitions, the diagnosis is based primarily on clinical features and electrophysiological
studies, whereas the requirement for cerebrospinal fluid examination
and nerve biopsy varies, depending on the level of clinical diagnostic certainty, which
can range from possible to probable to definite. Obtaining both cerebrospinal fluid
and a nerve-biopsy specimen is mandatory to make a definitive diagnosis of the disease,
according to criteria of the American Academy of Neurology,
but not according
to the widely used criteria proposed by Saperstein et al.
and by the Inflammatory Neuropathy
Cause and Treatment
(
INCAT) group.
11
Classic chronic inflammatory demyelinating
polyneuropathy typically responds well to corticosteroid treatment — an obc
clinical presentation

iobservation that may serve to distinguish it from
other forms of acquired demyelinating polyneuropathies.
demyelinating neuropathies distinct
from classic chronic inflammatory
demyelinating polyneuropathy
Refined clinical analysis has defined other forms
of acquired demyelinating polyneuropathies with
presumed autoimmune or dysimmune causes that
differ from classic chronic inflammatory demyelinating
polyneuropathy, both with respect to clinical
presentation and to the response to treatment.
It is not clear whether these conditions are variants
of chronic inflammatory demyelinating polyneuropathy
or distinct diseases.
Distal Acquired Demyelinating Symmetric
Neuropathy
It has been suggested that distal acquired demyelinating
symmetric neuropathy is a distinct acquired
demyelinating polyneuropathy.
16
Features
of the disorder include an increased prevalence in
men and in persons over the age of 50 years, a predominantly
distal sensory loss, a mild distal weakness
(as opposed to the more generalized motor
deficits in classic chronic inflammatory demyelinating
polyneuropathy), and an unsteady gait. IgM
paraproteinemia is present in nearly two thirds of
patients with this condition.
17
IgM-associated distal
demyelinating symmetric neuropathy seems to
respond poorly to immunosuppressive therapy.
17
Multifocal Motor Neuropathy
It is important to differentiate multifocal motor
neuropathy from motor neuron disease. Multifocal
motor neuropathy is characterized by asymmetric
weakness without sensory loss, often starting
in distal arm muscles. A partial motor-conduction
block at multiple sites is a characteristic electrophysiologic
feature, although not all patients have
this finding. The same holds true for the detection
* The criteria are those proposed by the American Academy of Neurology (AAN),
9
Saperstein et al.,
10
and Hughes et al.,
11
for the
Inflammatory
Neuropathy Cause and Treatment (INCAT) group. VDRL denotes Venereal Disease Research Laboratory.
† According to AAN criteria, a partial conduction block is a drop of 20 percent or more in negative peak area or peak-to-peak amplitude and a
change of less than 15 percent in duration between proximal and distal site stimulation. A possible conduction block or temporal dispersion
is a drop of 20 percent or more in negative peak area or peak-to-peak amplitude and a change of more than 15 percent in duration between
proximal and distal site stimulation. A reduced conduction velocity is a velocity of less than 80 percent of the lower limit of the normal range
if the amplitude of the compound muscle action potential (CMAP) is more than 80 percent of the lower limit of the normal range or less than
70 percent of the lower limit if the CMAP amplitude is less than 80 percent of the lower limit. Prolonged distal latency is more than 125 percent
of the upper limit of the normal range if the CMAP amplitude is more than 80 percent of the lower limit of the normal range or more than 150
percent of the upper limit if the CMAP amplitude is less than 80 percent of the lower limit. An absent F wave or F-wave latency is more than
125 percent of the upper limit (INCAT criteria, more than 120 percent) if the CMAP amplitude is more than 80 percent of the lower limit or latency
is more than 150 percent of the upper limit if the CMAP amplitude is less than 80 percent of the lower limit.
Table 1. Diagnostic Criteria.*
Feature AAN Criteria Saperstein Criteria INCAT Criteria
Clinical
involvement
Motor dysfunction, sensory dysfunction
of >1 limb, or both
Major: symmetric proximal
and distal weakness; minor:
exclusively distal weakness
or sensory loss
Progressive or relapsing motor and sensory
dysfunction of more than 1 limb
Time course (mo) ≥2 ≥2 >2
Reflexes Reduced or absent Reduced or absent Reduced or absent
Electrodiagnostic
test results
Any 3 of the following 4 criteria: partial
conduction block of ≥1 motor nerve,
reduced conduction velocity of ≥2 motor
nerves, prolonged distal latency of
≥2 motor nerves, or prolonged F-wave
latencies of ≥2 motor nerves or the absence
of F waves
†
2 of the 4 AAN electrodiagnostic
criteria
Partial conduction block of ≥2 motor nerves
and abnormal conduction velocity or distal
latency or F-wave latency in 1 other
nerve; or, in the absence of partial conduction
block, abnormal conduction velocity,
distal latency, or F-wave latency in 3 motor
nerves; or electrodiagnostic abnormalities
indicating demyelination in 2 nerves
and histologic evidence of demyelination
Cerebrospinal
fluid
White-cell count <10/mm
3
, negative VDRL
test; elevated protein level (supportive)
Protein >45 mg/dl; white-cell
count <10/mm
3
(supportive)
Cerebrospinal fluid analysis recommended
but not mandatory
Biopsy findings Evidence of demyelination and
remyelination
Predominant features of demyelination;
inflammation
(not required)
Not mandatory (except in cases with electrodiagnostic
abnormalities in only 2 motor
nerves)
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of circulating antiganglioside antibodies. Cerebrospinal
fluid protein levels and cell counts are usually
normal. Although corticosteroids and plasmapheresis
are ineffective treatments, multifocal motor
neuropathy improves with immune globulin
18
or
cyclophosphamide
19
therapy.
Multifocal Acquired Demyelinating Sensory
and Motor Neuropathy (the Lewis–Sumner Syndrome)
Multifocal acquired demyelinating sensory and motor
neuropathy (the Lewis–Sumner syndrome) has
similarities to both chronic inflammatory demyelinating
polyneuropathy (i.e., motor and sensory
deficits, an elevated protein content, and abnormal
results on motor-nerve and sensory-nerve conduction
studies) and multifocal motor neuropathy
(i.e., asymmetrical presentation of symptoms, often
starting from the arms and hands, and conduction
block).
20-22
Some patients with the condition have
antibodies to gangliosides,
23
and these patients have
a reasonably good response to treatment with intravenous
immune globulin or cyclophosphamide.
other neuropathies similar to chronic
inflammatory demyelinating
polyneuropathy
A number of other forms of acquired and chronic
polyneuropathy share features with chronic inflammatory
demyelinating polyneuropathy and have
been classified as subgroups. These forms include
axonal chronic inflammatory demyelinating polyneuropathy,
pure sensory chronic inflammatory demyelinating
polyneuropathy,
10
and pure motor and
axonal chronic inflammatory demyelinating polyneuropathy
(which is also termed multifocal acquired
motor axonopathy).
24
Only a small number
of patients within each subgroup have been reported.
Patients with peripheral-nerve demyelination
and a complete or partial response to immunotherapies
are best regarded as having a disorder
that is part of the larger family of chronic acquired
demyelinating polyneuropathies.
10
Depending on
the entire picture, some patients’ condition may also
fit the definition of possible, probable, or definite
chronic inflammatory demyelinating polyneuropathy.
Chronic idiopathic axonal polyneuropathy is
a heterogeneous group of slowly progressing sensorimotor
neuropathies with or without pain, causing
mild-to-moderate disability.
25
concurrent diseases
Chronic inflammatory demyelinating polyneuropathy
may be also associated with concurrent diseases,
such as infection with the human immunodeficiency
virus or hepatitis C, Sjögren’s syndrome, inflammatory
bowel disease, melanoma, lymphoma,
diabetes mellitus,
26,27
and IgM, IgG, or IgA monoclonal
gammopathy of unknown significance.
13,28
The pathogenetic relevance of such concurrent diseases
is unclear. Furthermore, in contrast to distal
acquired demyelinating symmetric neuropathy with
IgM paraproteinemia, the clinical presentation with
both proximal and distal muscle weakness is identical
to that of classic chronic inflammatory polyneuropathy,
and therapeutic guidelines are the same.
The association with diabetes mellitus is of special
interest because, according to some estimates,
chronic inflammatory demyelinating polyneuropathy
occurs more commonly among patients with
diabetes, generating diagnostic and management
challenges.
27
Occasionally, chronic inflammatory
demyelinating polyneuropathy may develop in a
setting of another polyneuropathy, even one with a
hereditary basis, such as Charcot–Marie–Tooth
disease.
29
central nervous system involvement
Magnetic resonance imaging (MRI) of the brain
has revealed demyelinating lesions in the central
nervous system in some patients with chronic inflammatory
demyelinating polyneuropathy, despite
the rarity of cerebral or cerebellar symptoms.
30,31
Demyelination of visual pathways, however, as evidenced
by prolonged latencies of visual evoked potentials,
were identified in nearly half of the patients
with chronic inflammatory demyelinating polyneuropathy
in one study.
30
Symptoms that are related
to cranial-nerve dysfunction are also seen in 5 to
30 percent of patients with the condition.
30,31
Of
interest, clinical symptoms that are based in the central
nervous system as well as brain lesions that are
visualized on MRI may resolve after treatment with
immune globulins.
32
The diagnosis of distal acquired demyelinating
symmetric neuropathy is based mainly on the clinical
presentation and on nerve-conduction findings
that are consistent with demyelination (Table 1).
Elevation of the protein content of the cerebrospinal
fluid, without pleocytosis, and histologic proof
of demyelination and remyelination, often with inflammation,
in nerve-biopsy specimens provide additional
supporting data. When the diagnosis is
not clear, we recommend nerve biopsy, given the
diagnostic approach
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various therapeutic implications and the potentially
serious adverse effects of long-term treatment
with immunomodulatory or immunosuppressive
drugs. A list of the most relevant elements of the
differential diagnosis is provided in Table 2.
electrophysiological diagnostic
procedures
Nerve-conduction studies reveal the cardinal features
of demyelination. An ad hoc committee of the
American Academy of Neurology included mandatory
physiological features as the presence of three
of the following four criteria for demyelination
9
:
partial motor-nerve conduction block (Fig. 1A), reduced
motor-nerve conduction velocity, prolonged
distal motor latencies, and prolonged F-wave latencies.
To define inclusion criteria for clinical
studies, the demyelination criteria have been modified.
10,11
Thaisetthawatkul et al. emphasized the
dispersion of the distal compound muscle action
potential as a very sensitive diagnostic criterion
for chronic inflammatory demyelinating polyneuropathy.
33
Although research criteria for enrollment
in clinical studies need to have a high specificity,
clinical criteria should be more sensitive to
allow the identification of patients who may need
treatment.
14
laboratory examinations
Most experts recommend cerebrospinal fluid analysis
in order to demonstrate the typical findings in
this condition: increased protein and a normal or
only slightly elevated cell count. However, spinal
taps are not mandatory, according to the criteria
of the INCAT group (Table 1). More extended laboratory
testing may also be necessary in some pa-
Table 2. Differential Diagnosis.
Neuropathy Examples Remarks
Guillain–Barré syndrome — Muscular weakness progressing over
a period of ≤1 mo
Inherited neuropathy Hereditary motor and sensory neuropathy; hereditary neuropathy
with susceptibility to pressure palsies
Recessively inherited neuropathies
Family history and DNA analysis
needed
Family history often negative
Metabolic neuropathy Diabetic neuropathy and neuropathy associated with impaired glucose
tolerance; uremic, hepatic, and acromegalic neuropathy;
neuropathy associated with hypothyroidism
Appropriate laboratory testing needed
Paraneoplastic neuropathy Neuropathy associated with lymphoma or carcinoma Workup for underlying cancer needed
Neuropathy associated with
monoclonal gammopathy
Neuropathy associated with osteosclerotic myeloma, with monoclonal
gammopathies of undetermined significance, and with
Waldenström’s macroglobulinemia
Workup for underlying cancer needed
Neuropathy associated with
infectious diseases
Infection with the human immunodeficiency virus
Leprosy
Borreliosis (including Lyme disease)
Diphtheria
Appropriate laboratory testing needed
Typically starts with sensory loss;
minor weakness in later stages
Appropriate laboratory testing needed
Microbiologic culture of isolates
Neuropathy associated with
systemic inflammatory or
immune-mediated diseases
Sarcoidosis; neuropathy associated with acquired amyloidosis; vasculitis,
including polyarteritis nodosa, Churg–Strauss syndrome,
rheumatoid arthritis, Sjögren’s syndrome, Wegener’s
granulomatosis, systemic lupus erythematosus, systemic sclerosis,
giant-cell arteritis, Behçet’s syndrome, cryoglobulinemia,
Castleman’s disease
Nonsystemic vasculitic neuropathy
Appropriate laboratory testing needed
and sural-nerve or muscle biopsy
if condition is suspected
Sural-nerve or muscle biopsy needed
if condition is suspected
Toxic neuropathies Alcohol, industrial agents (e.g., acrylamide), metals (e.g., lead),
drugs (e.g., platinum-based agents, amiodarone, perhexiline,
tacrolimus, chloroquine, and suramin)
Axonal more than demyelinating
Neuropathy due to nutritional
deficiency
Deficiency of vitamin B
1
, B
6
, B
12
, or E Appropriate laboratory testing needed
Porphyria-associated
neuropathy
— Appropriate laboratory testing needed
Polyneuropathy associated
with critical illness
Polyneuropathy associated with sepsis, multiple-organ failure,
or long-term ventilation
—
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tients to search for other causes of a demyelinating
polyneuropathy, as well as concurrent diseases
(Table 2).
nerve biopsy
The diagnostic value of nerve biopsy, usually of the
sural nerve, has been extensively debated during
the past few years. Some experts believe that nerve
biopsy is of no diagnostic value,
34
whereas others
view it as essential for diagnosis and management
in up to 60 percent of patients with chronic inflammatory
demyelinating polyneuropathy.
35
Bosboom
et al.
36
compared signs of demyelination, axonal degeneration,
regeneration, and inflammation in biopsy
specimens from patients with chronic inflammatory
demyelinating polyneuropathy with those
of patients with chronic idiopathic axonal polyneuropathy.
The biopsy specimens from the majority of
patients in both groups had similar or overlapping
abnormalities. In addition, nerve biopsies may have
a low diagnostic yield in chronic inflammatory demyelinating
polyneuropathy, for several reasons.
The most prominent abnormalities may lie in the
proximal segments of the nerves or roots or in motor
nerves, which are areas not accessible to biopsy.
Moreover, concomitant or secondary axonal changes
starting early in the disease processes may over-
B
D
C
F
G
E
A
5 mV
5 msec
Figure 1. Diagnostic Findings in Chronic Inflammatory
Demyelinating Polyneuropathy.
Panel A shows a partial motor-nerve conduction block
and abnormal temporal dispersion in a nerve-conduction
study, with a reduction of compound muscle action potentials
from the abductor digiti minimi muscle after
ulnar nerve stimulation at the elbow (bottom), as compared
with the amplitude after stimulation at the wrist
(top). Axial T
1
-weighted MRI scans of the lower thoracic
spine, shown before the administration of gadolinium in
Panel B and after the administration of gadolinium in
Panel C, reveal strong enhancement of ventral and dorsal
nerve roots (Panel C, arrows). Cross-sections of a sural
nerve in Panels D and E show typical features of chronic
inflammatory demyelinating polyneuropathy, with immunohistochemical
staining mirroring the distribution
pattern of T lymphocytes and macrophages. Invading
CD3+ T cells can primarily be localized to perivascular
infiltrates (Panel D, arrows) in the epineurium and
perineurium, and CD68+ immunoreactive macrophages
(Panel E, arrows) can be seen within the endoneurium.
Panel F shows a semithin section in which the extent of
the inflammatory process is reflected by the loss of myelin
(arrowheads indicate demyelinated axons and arrows
the remains of thinly myelinated fibers) and the invading
macrophages (open arrow). In Panel G, an electron micrograph
shows the onion-bulb formation of Schwann cells
(arrow) around demyelinated axons. (MRI scans were provided
by A. Saleh, Institute for Diagnostic Radiology,
Heinrich-Heine University, Düsseldorf; the semithin section
by E. Neuen-Jacob, Institute of Neuropathology,
University of Düsseldorf; and the electron micrograph by
J. Pollard, University of Sydney.)
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shadow the initial signs of demyelination and inflammation
by the time biopsy is performed.
Despite these limitations, nerve biopsy is still
considered useful by many specialists under certain
conditions (Fig. 1D to 1G). Haq et al. observed that
examination of sural-nerve biopsy specimens had a
higher sensitivity than electrophysiological studies.
37
Likewise, Vallat et al. reported that 8 patients
in a series of 44 had pathological findings indicative
of chronic inflammatory demyelinating polyneuropathy
on biopsy even though they did not have
electrophysiological evidence of demyelination.
38
It is important to note that five of these patients had
a favorable response to therapy.
38
Biopsy is recommended especially for patients
with clinically suspected chronic inflammatory demyelinating
polyneuropathy in whom electrophysiological
proof of demyelination is absent or vasculitis
is suspected. In a series of 100 patients with
chronic inflammatory demyelinating polyneuropathy,
Bouchard et al.
39
observed that axonal loss
on nerve biopsy was the most sensitive prognostic
factor, predicting an unfavorable course of the
disease. They found demyelinating changes in 71
percent of the patients, mixed axonal and demyelinating
changes in 21 percent, and purely axonal
changes in only 5 percent. A diagnostic algorithm
is shown in Figure 2.
mri
MRI may be used to demonstrate gadolinium enhancement
(Fig. 1B and 1C) and enlargement of
proximal nerves or roots, reflecting active inflammation
and demyelination in the cauda equina
40
or
brachial plexus.
41-43
Abnormalities of the brachial
plexus with irregular swelling and increased signal
intensity on T
2
-weighted images were detected in
about 50 percent of patients with chronic inflammatory
demyelinating polyneuropathy.
34
Of interest,
these changes have also been noted in patients
with distal demyelinating polyneuropathy associated
with IgM monoclonal gammopathy,
42
pointing
to similarly widespread nerve disease in the latter
condition.
A normal, well-balanced network of immunocompetent
cells and soluble factors meticulously regulates
the immune system within the local tissue
compartment of the peripheral nerves, sustaining
its integrity. Protection against immune responses
to autoantigens is key for the maintenance of selftolerance.
In chronic inflammatory demyelinating
polyneuropathy, self-tolerance breaks down, and
autoreactive T cells and B cells, which are part of
the normal immune repertoire, become activated,
causing the organ-specific damage characteristic of
autoimmune disease.
44
The concept of molecular
mimicry may hold special relevance to the breakdown
in tolerance associated with autoimmune
neuropathies. Molecular mimicry refers to a process
in which the host generates an immune response
to an inciting factor, most frequently an infectious
organism that shares epitopes with the host’s affected
tissue. However, in chronic inflammatory demyelinating
polyneuropathy, specific targets for such
a response have been convincingly identified only
in rare instances.
Although chronic inflammatory demyelinating
polyneuropathy occurs rarely in the context of cancer,
an association with melanoma is of great interest,
since both melanoma and Schwann cells derive
from neural crest tissues and share antigens. Several
cases of chronic inflammatory demyelinating
polyneuropathy have been reported in association
with melanoma; several carbohydrate epitopes
shared by the myelin sheath and the tumor have
been implicated as target antigens.
45,46
Nevertheless,
the hypothesis of molecular mimicry cannot
explain the entire immunopathologic and laboratory
spectrum of this complex disorder. On the
basis of current data, chronic inflammatory demyelinating
polyneuropathy appears to be an organ-specific,
immune-mediated disorder emerging from a
synergistic interaction of cell-mediated and humoral
immune responses directed against incompletely
characterized peripheral nerve antigens (Fig. 3).
cellular immune response
Evidence of T-cell activation in the systemic immune
compartment in patients with chronic inflammatory
demyelinating polyneuropathy exists,
although antigen specificity remains largely unknown.
47-49
From studies of nerve-biopsy specimens
and animal models, it is known that activated
T lymphocytes can invade peripheral-nerve
tissue. The T-cell populations that have been identified
are heterogeneous, belonging to both the CD4
and CD8 subgroups.
50-54
In order to generate inflammatory
lesions in nerves, activated T cells must
cross the blood–nerve barrier, a complex process
that includes homing, adhesion, and transmigration.
55
Derangement of the blood–nerve barrier has
pathogenesis
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been shown by demonstrating that the tight-junction
proteins claudin-5 and ZO-1 are down-regulated
in sural-nerve biopsy specimens.
56
Elevated
levels of soluble adhesion molecules,
57,58
chemokines,
59,60
and matrix metalloproteinases
61,62
can
be detected in serum, cerebrospinal fluid, or both
— findings that are indicative of active T-cell migration
across the blood–nerve barrier.
Once within the peripheral nervous system, these
T cells may undergo clonal expansion after encountering
an antigen presented in the context of appropriate
major-histocompatibility-complex molecules
and costimulatory signals. Such T cells then express
and secrete cytokines such as tumor necrosis factor
a
, interferong
, and interleukin-2.
55,63
T cells
thereby activate resident endoneurial or passenger
macrophages, which then discharge an array of
neurotoxic and immunopotentiating molecules
(i.e., oxygen radicals, nitric oxide metabolites, arachidonic
acid metabolites, proteases, and complement
components)
64,65
or engage in increased
phagocytic and cytotoxic activity against myelin or
Schwann cells. On the other hand, specialized subpopulations
of T cells may terminate the acute immunoinflammatory
process by secreting down-regulatory
cytokines (e.g., transforming growth factor
Figure 2. Algorithm of Diagnostic Procedures.
If a patient presents with a history of symptoms suggestive of chronic inflammatory demyelinating polyneuropathy of two months’ duration
or more, we perform nerve-conduction studies for signs of demyelination — including partial conduction block, reduced motor-nerve conduction
velocity, prolonged distal latency of the motor nerve, and the absence of F waves or a prolonged F-wave latency — to differentiate between
predominantly demyelinating or axonal disease of peripheral nerves. We also use laboratory tests — including cell-count and protein
studies of cerebrospinal fluid (CSF) — to evaluate supportive criteria and to rule out other causes. If these causes have been ruled out and
electrodiagnostic and supportive CSF criteria are fulfilled, patients may begin long-term antiinflammatory and immunosuppressive therapy.
To confirm the diagnosis, we recommend sural-nerve biopsy.
Progressive or relapsing proximal paresis, distal
paresis, or both, with or without hypoesthesia
and reduced or no tendon reflexes
Duration <2 mo Duration ≥2 mo
Electrophysiological
examination may be
negative in the first
1–2 wk
Consider Guillain–Barré
syndrome
Laboratory examination
(including CSF analysis)
Electrophysiological examination
for signs of demyelination
Other family members with
similar symptoms
Electrodiagnostic and CSF criteria
fulfilled and no evidence of another
cause of polyneuropathy
Electrodiagnostic and supportive
CSF criteria not fulfilled
Consider hereditary motor
and sensory neuropathy
Start treatment for chronic inflammatory
demyelinating polyneuropathy
Signs of demyelination in sural-nerve
biopsy specimen and no evidence
of other cause of polyneuropathy
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b
) or other molecules. It is important to note that
the local immune environment of the peripheral
nerves appears to facilitate the apoptosis of invading
autoaggressive T cells,
66
a process augmented
by therapeutically administered corticosteroids.
67
Macrophages also serve as antigen-presenting
cells in chronic inflammatory demyelinating polyneuropathy,
a finding that is underscored by the
observed expression of major-histocompatibilitycomplex
class II molecules and the class I–like molecule
CD1a in nerve-biopsy specimens.
68
Costimulatory
molecules B7-1 and B7-2 are essential for
effective antigen presentation and may determine
the differentiation of T lymphocytes into a pheno-
Figure 3. Immunopathogenesis of Chronic Inflammatory Demyelinating Neuropathy.
A schematic illustration of the basic principles of the cellular and humoral immune responses shows that autoreactive T cells recognize a specific
autoantigen in the context of major histocompatibility complex class II and costimulatory molecules on the surface of antigen-presenting
cells (macrophages) in the systemic immune compartment. An infection might trigger this event through molecular mimicry, a cross-reaction
toward epitopes shared between the microbial agent and nerve antigens. These activated T lymphocytes can cross the blood–nerve barrier in
a process involving cellular adhesion molecules, matrix metalloproteinases, and chemokines. Within the peripheral nervous system, T cells
activate macrophages that enhance phagocytic activity, the production of cytokines, and the release of toxic mediators, including nitric oxide,
reactive oxygen intermediates, matrix metalloproteinases, and proinflammatory cytokines, including tumor necrosis factor
a
and interferong
. Autoantibodies crossing the blood–nerve barrier or locally produced by plasma cells contribute to demyelination and axonal damage. Autoantibodies
can mediate demyelination by antibody-dependent cellular cytotoxicity, potentially block epitopes that are functionally relevant
for nerve conduction, and activate the complement system by the classic pathway, yielding proinflammatory mediators and the lytic membrane-
attack complex C5b-9. Termination of the inflammatory response occurs through the induction of T-cell apoptosis and the release of
antiinflammatory cytokines, including interleukin-10 and transforming growth factor
b
. The myelin sheath (inset) is composed of various proteins,
such as myelin protein zero, which account for more than 50 percent of the total membrane protein in human peripheral nervous system
myelin; myelin protein 2; myelin basic protein; myelin-associated glycoprotein; connexin 32; and gangliosides and related glycolipids.
These molecules have been identified as target antigens for antibody responses with varying frequencies in patients with this disease.
Systemic Immune
Compartment
Peripheral Nervous System
Antigen-presenting
cell
Blood–nerve
barrier
Autoreactive
T cell
Autoreactive
T cell
Reactivation
and expansion
Activated
T cells
Autoantibodies
Autoantibodies
Chemokines Adhesion
molecules
Macrophage
Macrophage
Apoptosis
Compact Myelin Noncompact Myelin
Nerve cell
Axon
Lytic
membrane-attack
complex
C5b-9
Schwann cell
Plasma cell
Plasma cell Interleukin-4
Interleukin-6
Myelin basic
protein
Myelin protein 2
Myelin protein zero Ganglioside
Connexin 32
Myelinassociated
glycoprotein
Interleukin-10
Transforming
growth factor b
Tumor necrosis
factor a
Reactive oxygen and
nitric oxide
Complement
Proteases
Interferon-g
Tumor necrosis
factor a
Matrix
metalloproteinases
Type 1
helper T cell
Type 2
helper T cell
type of type 1 or type 2 helper cells, thus modulating
the local immune response and the clinical course
of the disease. A spontaneous immune neuropathy
with clinical, electrophysiological, and morphologic
similarities to chronic inflammatory demyelinating
polyneuropathy in humans develops in autoimmune
nonobese diabetic mice that are deficient
in B7-2 costimulation.
69
The cellular immune response within the peripheral
nervous system is tightly regulated at the
transcriptional level. One of its key regulators, the
transcription factor nuclear factork
B, is up-regulated
predominantly in macrophages in chronic inflammatory
demyelinating polyneuropathy.
70
humoral immune response
The contribution of autoantibodies to the pathogenesis
of chronic inflammatory demyelinating
polyneuropathy was suggested more than 20 years
ago on the basis of immunoglobulin and complement
deposition on myelinated nerve fibers
71 and
the presence of oligoclonal IgG bands in the cerebrospinal
fluid.72 Passive transfer experiments have
demonstrated that serum or purified IgG from patients
with chronic inflammatory demyelinating
polyneuropathy induces conduction block and demyelination
in rat nerves.73 In these experiments,
the 28-kD myelin protein zero was identified as one
of the putative target antigens.74
Gangliosides and related glycolipids may also
be target antigens (Fig. 3, inset). In a few patients
with chronic inflammatory demyelinating polyneuropathy,
there is serologic evidence of recent infection
with Campylobacter jejuni. Given the shared
expression of carbohydrate epitopes in nerve glycolipids
and microbial lipopolysaccharides, this
finding may hint at molecular mimicry as the underlying
cause of chronic inflammatory demyelinating
polyneuropathy in rare instances.75 GM1 antiserum
from a patient with chronic inflammatory
demyelinating polyneuropathy substantially suppressed
sodium currents in single myelinated nerve
fibers from rats.76 Serum reactivity against presumably
nonmyelin antigens on Schwann cells has recently
been reported in 12 of 46 patients studied.77
Demyelination and conduction block may also
result from serum constituents other than myelin-
directed antibodies, such as cytokines, complements,
or other inflammatory mediators (e.g., nitric
oxide). The low frequency of specific antibodies
that is observed in patients with chronic inflammatory
demyelinating polyneuropathy suggests that
various antibodies and separate mechanisms are
involved in individual patients.
axonal loss
Chronic inflammatory demyelinating polyneuropathy,
though a demyelinating polyneuropathy, is
associated with a concomitant axonal loss attributed
to the primary demyelinating process.39,48
This finding appears to be important, since the longterm
prognosis in chronic inflammatory demyelinating
polyneuropathy depends on the magnitude
of axonal loss rather than on demyelination. There
are questions as to whether the release of neurotoxic
cytokines (e.g., tumor necrosis factor a) and
noxious mediators (e.g., nitric oxide and metalloproteinases)
enhances axonal destruction, but it
has become clear that early, effective therapy minimizes
axonal loss.
In general, therapies are directed at blocking immune
processes to arrest inflammation and demyelination
and to prevent secondary axonal degeneration.
In patients who have a response, treatment
must be continued until maximum improvement
or stabilization occurs; thereafter, maintenance
therapy is required and must be tailored to the individual
patient, with the goal of preventing or diminishing
the frequency of relapses or disease progression.
A positive response to therapy is determined
by a measurable improvement in strength and sensation
and the patient’s ability to perform activities
of daily living. It is important to be aware that
infections and febrile conditions may also affect demyelination
and thereby worsen the clinical symptoms
of chronic inflammatory demyelinating polyneuropathy.
Concomitant use of neurotoxic drugs
or the presence of systemic conditions known to
cause neuropathies may also theoretically influence
the clinical symptoms of the condition.
The most widely used treatments for chronic
inflammatory demyelinating polyneuropathy (Table
3) consist of intravenous immune globulin,
11,80,81,84-86 plasma exchange,78,79 and corticosteroids.
11,87,88 Therapy should be initiated early
in the course of the disease to prevent continuing
demyelination and secondary axonal loss leading
to permanent disability. According to published
data, there appears to be no difference in efficacy
among these three main therapies.28,85,87 The decision
to choose one of them is usually made on
current treatment
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The new england journal of medicine
1352
the basis of cost, availability (e.g., plasmapheresis
and venous access), and side effects (most important,
the serious long-term side effects of corticosteroids).
87 All these factors should be considered
when cost–utility analyses are performed.89 In some
60 to 80 percent of patients with classic chronic inflammatory
demyelinating polyneuropathy, the condition
improves while they are receiving one of the
three therapies, but the long-term prognosis appears
to vary according to the time at which therapy
is initiated and the degree of associated axonal
loss. Azathioprine,82 cyclophosphamide, and cyclosporine
have long been used mainly as secondary
agents in the therapy of chronic inflammatory demyelinating
polyneuropathy, but reliable data on
their efficacy from randomized, controlled trials are
not available.90 For unknown reasons, the efficacy
of these latter treatments is clearly less favorable in
patients who have a neuropathy accompanied by
antibodies to myelin-associated glycoprotein.91,92
Given the presumed autoimmune cause of this
condition and its suggested pathogenetic similarities
to multiple sclerosis, immunomodulatory therapies
that are considered effective in that disorder
have been investigated. Twenty patients with treatment-
resistant chronic inflammatory demyelinating
polyneuropathy were enrolled in a prospective,
multicenter, open-label study that evaluated intramuscular
interferon beta-1a at a dose of 30 µg once
a week for six months.93 Thirty-five percent of the
patients had an improvement, and the disease stabilized
in 50 percent, prompting the authors to
recommend a larger, placebo-controlled trial. However,
another study, in which four patients with
chronic inflammatory demyelinating polyneuropathy
were treated, showed that treatment with interferon
beta-1a was effective only in combination
with intravenous immune globulin.94 Furthermore,
a small, randomized, double-blind, placebo-controlled,
crossover study involving 10 patients with
treatment-resistant chronic inflammatory demyelinating
polyneuropathy and evaluating interferon
beta-1a (3 million IU for 2 weeks and 6 million IU
for 10 weeks, administered subcutaneously three
times per week) failed to show a significant treatment
effect.83 The role of interferon alfa in the condition
is also uncertain. Some case reports95,96 and
an open-label prospective pilot study97 suggested
that interferon alfa was effective.
Of concern, chronic inflammatory demyelinating
polyneuropathy has been reported to develop
during treatment with interferon alfa98-100 or interferon
beta.101 Furthermore, interferon was ineffective
in patients with IgM monoclonal gammopathy102
and the Guillain–Barré syndrome.103 These
disturbing observations raise the provocative question
of whether interferons are causally related to
the onset of chronic inflammatory demyelinating
* Most of the clinical trials in chronic inflammatory demyelinating polyneuropathy have been limited to several weeks,
which is a rather short time period for a disease that typically spans months or years.
Table 3. Current Therapy Based on the Results of Randomized, Controlled Studies.*
Reference Year Therapy
No. of
Patients Duration Design Result
Dyck et al.78 1994 Plasma exchange vs. intravenous
immune globulin
15 42 days Randomized, observerblinded,
crossover
No significant
difference
Hahn et al.79 1996 Plasma exchange 15 28 days Double-blind, shamcontrolled,
crossover
Improvement in
80% of patients
Hahn et al.80 1996 Intravenous immune
globulin
30 28 days Double-blind, placebocontrolled,
crossover
Improvement in
63% of patients
Mendell et al.81 2001 Intravenous immune
globulin
53 42 days Double-blind, randomized,
placebo-controlled
Improvement in
76% of patients
Hughes et al.11 2001 Intravenous immune globulin
vs. oral prednisolone
32 14 days Double-blind, randomized,
crossover
No significant
difference
Dyck et al.82 1985 Azathioprine in combination
with prednisone vs. prednisone
alone
30 9 mo Open, parallel-group,
randomized
No significant
difference
Hadden et al.83 1999 Interferon beta-1a in treatment-
resistant disease
20 28 wk Double-blind, randomized,
placebo-controlled,
crossover
No significant
benefit of
treatment
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medical progress
1353
polyneuropathy, as opposed to being capable of
suppressing the disease.104 Hughes et al. concluded
that there is currently no adequate evidence to
decide whether interferons are beneficial in the
treatment of this condition.90
Other forms of treatment have been tested in
open-label studies with a small number of patients
or in individual patients. Beneficial effects in patients
with previously treatment-resistant chronic
inflammatory demyelinating polyneuropathy were
reported for the combination of plasmapheresis
and intravenous immune globulin,105 mycophenolate
mofetil,106-108 cyclosporine,109-111 etanercept,
112 cyclophosphamide,113,114 and autologous
hematopoietic stem-cell transplantation.115 In patients
with multifocal motor neuropathy or chronic
inflammatory demyelinating polyneuropathy, the
combination of intravenous immune globulin and
mycophenolate mofetil may permit a reduction in
the dose of immune globulin or corticosteroids, a
finding that was recently suggested by an openlabel
study of 6 patients116 and a retrospective
analysis of the efficacy of mycophenolate mofetil
in 21 patients with chronic inflammatory demyelinating
polyneuropathy.108 Two recent open-label
studies involving 30 patients found improvement
in those with IgM-associated demyelinating polyneuropathy
who were receiving treatment with
rituximab, a chimeric humanized monoclonal antibody
against CD20 antigen that reduces B-lymphocyte
counts.117,118 However, no data that have
been collected on the basis of randomized, controlled
studies with a sufficient number of patients
are available to allow conclusive recommendations
about treatment with any of these agents. Furthermore,
controlled trials providing long-term data are
lacking. The evidence concerning the efficacy of
plasma exchange, intravenous immune globulin,
and corticosteroids derives only from short-term
studies. Plasma exchange and intravenous immune
globulin are expensive therapies and must be continued
over the long term to maintain benefit. Anecdotal
experience suggests that the use of immunosuppressive
agents may allow therapy with plasma
exchange or intravenous immune globulin to be administered
less frequently or even phased out, with
subsequent substantial financial savings. There is
clearly a need for controlled studies to assess this
long-term aspect of therapy for chronic inflammatory
demyelinating polyneuropathy.
It is important to recognize chronic inflammatory
demyelinating polyneuropathy in a patient with
a chronic progressive or chronic relapsing neuropathy,
since therapies that are at least partially
effective — including corticosteroids, intravenous
immune globulin, plasma exchange, and immunosuppressants
— are available for this crippling disease.
Sets of diagnostic criteria have been developed.
The disorder appears to be heterogeneous in
terms of clinical presentation and immunopathogenesis.
Further research should provide further
insight into the underlying mechanisms of nerve
damage and may facilitate the development of more
effective treatments.
We are indebted to Marinos C. Dalakas, of Bethesda, Md., David
R. Cornblath, of Baltimore, and John Pollard, of Sydney, for their
critical review of the manuscript and many helpful suggestions.
conclusions
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