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The new england journal of medicine

review article

medical progress

Chronic Inflammatory Demyelinating


Polyneuropathy
Hubertus Kller, M.D., Bernd C. Kieseier, M.D., Sebastian Jander, M.D.,
and Hans-Peter Hartung, M.D.

hronic inflammatory demyelinating polyneuropathy is a com-

c mon, albeit underdiagnosed, and potentially treatable disease with an estimat-


ed prevalence of about 0.5 per 100,000 children1 and 1 to 2 per 100,000 adults.2,3
Clinical similarities to the acute variant of inflammatory demyelinating polyneurop-
athy (the GuillainBarr syndrome) and the beneficial effects of immunosuppressive
From the Department of Neurology, Hein-
rich-Heine University, Dsseldorf, Germany.
Address reprint requests to Dr. Hartung at
the Department of Neurology, Heinrich-
Heine University, Moorenstr. 5, D-40225
Dsseldorf, Germany, or at hans-peter.
hartung@uni-duesseldorf.de.
therapies suggest an immune-mediated pathogenesis. Since the first descriptions of
patients with corticosteroid-responsive chronic polyneuropathies by Austin,4 Thomas N Engl J Med 2005;352:1343-56.
et al.,5 and Dyck et al.,6 the spectrum of clinical presentation and the diagnostic arma- Copyright 2005 Massachusetts Medical Society.

mentarium have enlarged, and further therapeutic options have evolved. The recog-
nition of this disorder as distinct from other common chronic sensorimotor polyneu-
ropathies that accompany diabetes, alcoholism, or malnutrition is important. This
review summarizes present knowledge about the clinical features of this condition, di-
agnostic criteria and diagnostic procedures involved in assessment, and current man-
agement strategies based on the results of randomized, controlled trials. Current con-
cepts of immunopathogenesis are also considered.

clinical presentation
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 pro-
gressively increases for more than two months (setting this condition apart from the
GuillainBarr syndrome, which is self-limited). The condition is associated with im-
paired sensation, absent or diminished tendon reflexes, an elevated cerebrospinal fluid
protein level, demyelinating nerve-conduction studies, and signs of demyelination in
nerve-biopsy specimens.7-9 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 consid-
ered, several groups have proposed clinical definitions of this neuropathy (Table 1).9-15
In all these definitions, the diagnosis is based primarily on clinical features and elec-
trophysiological 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 dis-
ease, according to criteria of the American Academy of Neurology,9 but not according
to the widely used criteria proposed by Saperstein et al.10 and by the Inflammatory Neu-
ropathy Cause and Treatment (INCAT) group.11 Classic chronic inflammatory demye-
linating polyneuropathy typically responds well to corticosteroid treatment an ob-

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Table 1. Diagnostic Criteria.*

Feature AAN Criteria Saperstein Criteria INCAT Criteria


Clinical Motor dysfunction, sensory dysfunction Major: symmetric proximal Progressive or relapsing motor and sensory
involvement of >1 limb, or both and distal weakness; minor: dysfunction of more than 1 limb
exclusively distal weakness
or sensory loss
Time course (mo) 2 2 >2
Reflexes Reduced or absent Reduced or absent Reduced or absent
Electrodiagnos- Any 3 of the following 4 criteria: partial 2 of the 4 AAN electrodiagnos- Partial conduction block of 2 motor nerves
tic test results conduction block of 1 motor nerve, tic criteria and abnormal conduction velocity or dis-
reduced conduction velocity of 2 mo- tal latency or F-wave latency in 1 other
tor nerves, prolonged distal latency of nerve; or, in the absence of partial conduc-
2 motor nerves, or prolonged F-wave tion block, abnormal conduction velocity,
latencies of 2 motor nerves or the ab- distal latency, or F-wave latency in 3 motor
sence of F waves nerves; or electrodiagnostic abnormali-
ties indicating demyelination in 2 nerves
and histologic evidence of demyelination
Cerebrospinal White-cell count <10/mm3, negative VDRL Protein >45 mg/dl; white-cell Cerebrospinal fluid analysis recommended
fluid test; elevated protein level (supportive) count <10/mm3 (supportive) but not mandatory
Biopsy findings Evidence of demyelination and Predominant features of demy- Not mandatory (except in cases with electro-
remyelination elination; inflammation diagnostic abnormalities in only 2 motor
(not required) nerves)

* 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 la-
tency is more than 150 percent of the upper limit if the CMAP amplitude is less than 80 percent of the lower limit.

servation that may serve to distinguish it from quired demyelinating polyneuropathy.16 Features
other forms of acquired demyelinating polyneu- of the disorder include an increased prevalence in
ropathies. men and in persons over the age of 50 years, a pre-
dominantly distal sensory loss, a mild distal weak-
demyelinating neuropathies distinct ness (as opposed to the more generalized motor
from classic chronic inflammatory deficits in classic chronic inflammatory demyelin-
demyelinating polyneuropathy ating polyneuropathy), and an unsteady gait. IgM
Refined clinical analysis has defined other forms paraproteinemia is present in nearly two thirds of
of acquired demyelinating polyneuropathies with patients with this condition.17 IgM-associated dis-
presumed autoimmune or dysimmune causes that tal demyelinating symmetric neuropathy seems to
differ from classic chronic inflammatory demye- respond poorly to immunosuppressive therapy.17
linating polyneuropathy, both with respect to clini-
cal presentation and to the response to treatment. Multifocal Motor Neuropathy
It is not clear whether these conditions are variants It is important to differentiate multifocal motor
of chronic inflammatory demyelinating polyneu- neuropathy from motor neuron disease. Multifo-
ropathy or distinct diseases. cal motor neuropathy is characterized by asymmet-
ric weakness without sensory loss, often starting
Distal Acquired Demyelinating Symmetric in distal arm muscles. A partial motor-conduction
Neuropathy block at multiple sites is a characteristic electro-
It has been suggested that distal acquired demye- physiologic feature, although not all patients have
linating symmetric neuropathy is a distinct ac- this finding. The same holds true for the detection

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of circulating antiganglioside antibodies. Cerebro- such as infection with the human immunodefi-
spinal fluid protein levels and cell counts are usu- ciency virus or hepatitis C, Sjgrens syndrome, in-
ally normal. Although corticosteroids and plasma- flammatory bowel disease, melanoma, lymphoma,
pheresis are ineffective treatments, multifocal motor diabetes mellitus,26,27 and IgM, IgG, or IgA mono-
neuropathy improves with immune globulin18 or clonal gammopathy of unknown significance.13,28
cyclophosphamide19 therapy. The pathogenetic relevance of such concurrent dis-
eases is unclear. Furthermore, in contrast to distal
Multifocal Acquired Demyelinating Sensory acquired demyelinating symmetric neuropathy with
and Motor Neuropathy (the LewisSumner Syndrome) IgM paraproteinemia, the clinical presentation with
Multifocal acquired demyelinating sensory and mo- both proximal and distal muscle weakness is identi-
tor neuropathy (the LewisSumner syndrome) has cal to that of classic chronic inflammatory polyneu-
similarities to both chronic inflammatory demye- ropathy, and therapeutic guidelines are the same.
linating polyneuropathy (i.e., motor and sensory The association with diabetes mellitus is of spe-
deficits, an elevated protein content, and abnormal cial interest because, according to some estimates,
results on motor-nerve and sensory-nerve con- chronic inflammatory demyelinating polyneurop-
duction studies) and multifocal motor neuropathy athy occurs more commonly among patients with
(i.e., asymmetrical presentation of symptoms, often diabetes, generating diagnostic and management
starting from the arms and hands, and conduction challenges.27 Occasionally, chronic inflammatory
block).20-22 Some patients with the condition have demyelinating polyneuropathy may develop in a
antibodies to gangliosides,23 and these patients have setting of another polyneuropathy, even one with a
a reasonably good response to treatment with in- hereditary basis, such as CharcotMarieTooth
travenous immune globulin or cyclophosphamide. disease.29

other neuropathies similar to chronic central nervous system involvement


inflammatory demyelinating Magnetic resonance imaging (MRI) of the brain
polyneuropathy has revealed demyelinating lesions in the central
A number of other forms of acquired and chronic nervous system in some patients with chronic in-
polyneuropathy share features with chronic inflam- flammatory demyelinating polyneuropathy, despite
matory demyelinating polyneuropathy and have the rarity of cerebral or cerebellar symptoms.30,31
been classified as subgroups. These forms include Demyelination of visual pathways, however, as evi-
axonal chronic inflammatory demyelinating poly- denced by prolonged latencies of visual evoked po-
neuropathy, pure sensory chronic inflammatory de- tentials, were identified in nearly half of the patients
myelinating polyneuropathy,10 and pure motor and with chronic inflammatory demyelinating polyneu-
axonal chronic inflammatory demyelinating poly- ropathy in one study.30 Symptoms that are related
neuropathy (which is also termed multifocal ac- to cranial-nerve dysfunction are also seen in 5 to
quired motor axonopathy).24 Only a small number 30 percent of patients with the condition.30,31 Of
of patients within each subgroup have been report- interest, clinical symptoms that are based in the cen-
ed. Patients with peripheral-nerve demyelination tral nervous system as well as brain lesions that are
and a complete or partial response to immuno- visualized on MRI may resolve after treatment with
therapies are best regarded as having a disorder immune globulins.32
that is part of the larger family of chronic acquired
demyelinating polyneuropathies.10 Depending on diagnostic approach
the entire picture, some patients condition may also
fit the definition of possible, probable, or definiteThe diagnosis of distal acquired demyelinating
chronic inflammatory demyelinating polyneurop- symmetric neuropathy is based mainly on the clin-
athy. Chronic idiopathic axonal polyneuropathy is ical presentation and on nerve-conduction findings
a heterogeneous group of slowly progressing sen- that are consistent with demyelination (Table 1).
sorimotor neuropathies with or without pain, caus- Elevation of the protein content of the cerebrospi-
ing mild-to-moderate disability.25 nal fluid, without pleocytosis, and histologic proof
of demyelination and remyelination, often with in-
concurrent diseases flammation, in nerve-biopsy specimens provide ad-
Chronic inflammatory demyelinating polyneuropa- ditional supporting data. When the diagnosis is
thy may be also associated with concurrent diseases, not clear, we recommend nerve biopsy, given the

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various therapeutic implications and the poten- fied.10,11 Thaisetthawatkul et al. emphasized the
tially serious adverse effects of long-term treatmentdispersion of the distal compound muscle action
with immunomodulatory or immunosuppressive potential as a very sensitive diagnostic criterion
drugs. A list of the most relevant elements of the for chronic inflammatory demyelinating polyneu-
differential diagnosis is provided in Table 2. ropathy.33 Although research criteria for enroll-
ment in clinical studies need to have a high speci-
electrophysiological diagnostic ficity, clinical criteria should be more sensitive to
procedures allow the identification of patients who may need
Nerve-conduction studies reveal the cardinal fea- treatment.14
tures of demyelination. An ad hoc committee of the
American Academy of Neurology included manda- laboratory examinations
tory physiological features as the presence of three Most experts recommend cerebrospinal fluid analy-
of the following four criteria for demyelination9: sis in order to demonstrate the typical findings in
partial motor-nerve conduction block (Fig. 1A), re- this condition: increased protein and a normal or
duced motor-nerve conduction velocity, prolonged only slightly elevated cell count. However, spinal
distal motor latencies, and prolonged F-wave la- taps are not mandatory, according to the criteria
tencies. To define inclusion criteria for clinical of the INCAT group (Table 1). More extended lab-
studies, the demyelination criteria have been modi- oratory testing may also be necessary in some pa-

Table 2. Differential Diagnosis.

Neuropathy Examples Remarks


GuillainBarr syndrome Muscular weakness progressing over
a period of 1 mo
Inherited neuropathy Hereditary motor and sensory neuropathy; hereditary neuropathy Family history and DNA analysis
with susceptibility to pressure palsies needed
Recessively inherited neuropathies Family history often negative
Metabolic neuropathy Diabetic neuropathy and neuropathy associated with impaired glu- Appropriate laboratory testing needed
cose tolerance; uremic, hepatic, and acromegalic neuropathy;
neuropathy associated with hypothyroidism
Paraneoplastic neuropathy Neuropathy associated with lymphoma or carcinoma Workup for underlying cancer needed
Neuropathy associated with Neuropathy associated with osteosclerotic myeloma, with mono- Workup for underlying cancer needed
monoclonal gammopathy clonal gammopathies of undetermined significance, and with
Waldenstrms macroglobulinemia
Neuropathy associated with Infection with the human immunodeficiency virus Appropriate laboratory testing needed
infectious diseases Leprosy Typically starts with sensory loss;
minor weakness in later stages
Borreliosis (including Lyme disease) Appropriate laboratory testing needed
Diphtheria Microbiologic culture of isolates
Neuropathy associated with Sarcoidosis; neuropathy associated with acquired amyloidosis; vas- Appropriate laboratory testing needed
systemic inflammatory or culitis, including polyarteritis nodosa, ChurgStrauss syn- and sural-nerve or muscle biopsy
immune-mediated diseases drome, rheumatoid arthritis, Sjgrens syndrome, Wegeners if condition is suspected
granulomatosis, systemic lupus erythematosus, systemic scle-
rosis, giant-cell arteritis, Behets syndrome, cryoglobulinemia,
Castlemans disease
Nonsystemic vasculitic neuropathy Sural-nerve or muscle biopsy needed
if condition is suspected
Toxic neuropathies Alcohol, industrial agents (e.g., acrylamide), metals (e.g., lead), Axonal more than demyelinating
drugs (e.g., platinum-based agents, amiodarone, perhexiline,
tacrolimus, chloroquine, and suramin)
Neuropathy due to nutritional Deficiency of vitamin B1, B6, B12, or E Appropriate laboratory testing needed
deficiency
Porphyria-associated Appropriate laboratory testing needed
neuropathy
Polyneuropathy associated Polyneuropathy associated with sepsis, multiple-organ failure,
with critical illness or long-term ventilation

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tients to search for other causes of a demyelinating myelinating polyneuropathy, for several reasons.
polyneuropathy, as well as concurrent diseases The most prominent abnormalities may lie in the
(Table 2). proximal segments of the nerves or roots or in mo-
tor nerves, which are areas not accessible to biopsy.
nerve biopsy Moreover, concomitant or secondary axonal chang-
The diagnostic value of nerve biopsy, usually of the es starting early in the disease processes may over-
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
A
view it as essential for diagnosis and management
in up to 60 percent of patients with chronic inflam- 5 mV
35
matory demyelinating polyneuropathy. Bosboom
5 msec
et al.36 compared signs of demyelination, axonal de-
generation, regeneration, and inflammation in bi-
opsy specimens from patients with chronic inflam-
matory demyelinating polyneuropathy with those
of patients with chronic idiopathic axonal polyneu-
ropathy. 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 de-
B C

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 po-
tentials from the abductor digiti minimi muscle after
ulnar nerve stimulation at the elbow (bottom), as com-
pared with the amplitude after stimulation at the wrist
(top). Axial T1-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 D E
nerve in Panels D and E show typical features of chronic
inflammatory demyelinating polyneuropathy, with im-
munohistochemical 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 mye- F
lin (arrowheads indicate demyelinated axons and arrows
the remains of thinly myelinated fibers) and the invading
macrophages (open arrow). In Panel G, an electron micro-
graph shows the onion-bulb formation of Schwann cells
(arrow) around demyelinated axons. (MRI scans were pro-
vided by A. Saleh, Institute for Diagnostic Radiology,
Heinrich-Heine University, Dsseldorf; the semithin sec-
G
tion by E. Neuen-Jacob, Institute of Neuropathology,
University of Dsseldorf; and the electron micrograph by
J. Pollard, University of Sydney.)

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shadow the initial signs of demyelination and in- to autoantigens is key for the maintenance of self-
flammation by the time biopsy is performed. tolerance. In chronic inflammatory demyelinating
Despite these limitations, nerve biopsy is still polyneuropathy, self-tolerance breaks down, and
considered useful by many specialists under certain autoreactive T cells and B cells, which are part of
conditions (Fig. 1D to 1G). Haq et al. observed that the normal immune repertoire, become activated,
examination of sural-nerve biopsy specimens had a causing the organ-specific damage characteristic of
higher sensitivity than electrophysiological stud- autoimmune disease.44 The concept of molecular
ies.37 Likewise, Vallat et al. reported that 8 patients mimicry may hold special relevance to the break-
in a series of 44 had pathological findings indicative down in tolerance associated with autoimmune
of chronic inflammatory demyelinating polyneu- neuropathies. Molecular mimicry refers to a process
ropathy on biopsy even though they did not have in which the host generates an immune response
electrophysiological evidence of demyelination.38 to an inciting factor, most frequently an infectious
It is important to note that five of these patients had organism that shares epitopes with the hosts affect-
a favorable response to therapy.38 ed tissue. However, in chronic inflammatory demy-
Biopsy is recommended especially for patients elinating polyneuropathy, specific targets for such
with clinically suspected chronic inflammatory de- a response have been convincingly identified only
myelinating polyneuropathy in whom electrophys- in rare instances.
iological proof of demyelination is absent or vascu- Although chronic inflammatory demyelinating
litis is suspected. In a series of 100 patients with polyneuropathy occurs rarely in the context of can-
chronic inflammatory demyelinating polyneurop- cer, an association with melanoma is of great inter-
athy, Bouchard et al.39 observed that axonal loss est, since both melanoma and Schwann cells derive
on nerve biopsy was the most sensitive prognos- from neural crest tissues and share antigens. Sev-
tic factor, predicting an unfavorable course of the eral cases of chronic inflammatory demyelinat-
disease. They found demyelinating changes in 71 ing polyneuropathy have been reported in associa-
percent of the patients, mixed axonal and demye- tion with melanoma; several carbohydrate epitopes
linating changes in 21 percent, and purely axonal shared by the myelin sheath and the tumor have
changes in only 5 percent. A diagnostic algorithm been implicated as target antigens.45,46 Neverthe-
is shown in Figure 2. less, the hypothesis of molecular mimicry cannot
explain the entire immunopathologic and labo-
mri ratory spectrum of this complex disorder. On the
MRI may be used to demonstrate gadolinium en- basis of current data, chronic inflammatory demye-
hancement (Fig. 1B and 1C) and enlargement of linating polyneuropathy appears to be an organ-spe-
proximal nerves or roots, reflecting active inflam- cific, immune-mediated disorder emerging from a
mation and demyelination in the cauda equina40 or synergistic interaction of cell-mediated and humor-
brachial plexus.41-43 Abnormalities of the brachial al immune responses directed against incomplete-
plexus with irregular swelling and increased signal ly characterized peripheral nerve antigens (Fig. 3).
intensity on T2-weighted images were detected in
about 50 percent of patients with chronic inflam- cellular immune response
matory demyelinating polyneuropathy.34 Of inter- Evidence of T-cell activation in the systemic im-
est, these changes have also been noted in patients mune compartment in patients with chronic in-
with distal demyelinating polyneuropathy associ- flammatory demyelinating polyneuropathy exists,
ated with IgM monoclonal gammopathy,42 point- although antigen specificity remains largely un-
ing to similarly widespread nerve disease in the lat- known.47-49 From studies of nerve-biopsy speci-
ter condition. mens and animal models, it is known that acti-
vated T lymphocytes can invade peripheral-nerve
pathogenesis tissue. The T-cell populations that have been iden-
tified are heterogeneous, belonging to both the CD4
A normal, well-balanced network of immunocom- and CD8 subgroups.50-54 In order to generate in-
petent cells and soluble factors meticulously reg- flammatory lesions in nerves, activated T cells must
ulates the immune system within the local tissue cross the bloodnerve barrier, a complex process
compartment of the peripheral nerves, sustaining that includes homing, adhesion, and transmigra-
its integrity. Protection against immune responses tion.55 Derangement of the bloodnerve barrier has

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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 Electrophysiological examination Laboratory examination Other family members with


examination may be for signs of demyelination (including CSF analysis) similar symptoms
negative in the first
12 wk

Electrodiagnostic and CSF criteria


Electrodiagnostic and supportive
fulfilled and no evidence of another
CSF criteria not fulfilled
cause of polyneuropathy

Signs of demyelination in sural-nerve


biopsy specimen and no evidence
of other cause of polyneuropathy

Consider GuillainBarr Start treatment for chronic inflammatory Consider hereditary motor
syndrome demyelinating polyneuropathy and sensory neuropathy

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 con-
duction velocity, prolonged distal latency of the motor nerve, and the absence of F waves or a prolonged F-wave latency to differentiate be-
tween 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.

been shown by demonstrating that the tight-junc- and secrete cytokines such as tumor necrosis fac-
tion proteins claudin-5 and ZO-1 are down-regu- tor a, interferon-g, and interleukin-2.55,63 T cells
lated in sural-nerve biopsy specimens.56 Elevated thereby activate resident endoneurial or passenger
levels of soluble adhesion molecules,57,58 chemo- macrophages, which then discharge an array of
kines,59,60 and matrix metalloproteinases61,62 can neurotoxic and immunopotentiating molecules
be detected in serum, cerebrospinal fluid, or both (i.e., oxygen radicals, nitric oxide metabolites, ar-
findings that are indicative of active T-cell mi- achidonic acid metabolites, proteases, and comple-
gration across the bloodnerve barrier. ment components)64,65 or engage in increased
Once within the peripheral nervous system, these phagocytic and cytotoxic activity against myelin or
T cells may undergo clonal expansion after encoun- Schwann cells. On the other hand, specialized sub-
tering an antigen presented in the context of appro- populations of T cells may terminate the acute im-
priate major-histocompatibility-complex molecules munoinflammatory process by secreting down-reg-
and costimulatory signals. Such T cells then express ulatory cytokines (e.g., transforming growth factor

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Systemic Immune Peripheral Nervous System


Compartment
Nerve cell

Macrophage Apoptosis

Antigen-presenting
cell Schwann cell
Autoreactive Lytic
Autoreactive T cell membrane-attack
T cell complex
Tumor necrosis
Macrophage factor a C5b-9
Adhesion Chemokines Reactivation
and expansion Reactive oxygen and
molecules Interferon-g nitric oxide
Type 1 Tumor necrosis Complement
factor a Proteases
helper T cell
Activated
T cells

Matrix
metalloproteinases Interleukin-10
Transforming
growth factor b
Autoantibodies
Interleukin-4 Type 2 Plasma cell Autoantibodies
Interleukin-6 helper T cell
Compact Myelin Noncompact Myelin
Myelin protein zero Myelin basic Ganglioside
protein
Plasma cell
Axon

Myelin-
Bloodnerve associated
Myelin protein 2 glycoprotein Connexin 32
barrier

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 spe-
cific 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 bloodnerve 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 interferon-
g. Autoantibodies crossing the bloodnerve barrier or locally produced by plasma cells contribute to demyelination and axonal damage. Au-
toantibodies 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 mem-
brane-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 pro-
teins, such as myelin protein zero, which account for more than 50 percent of the total membrane protein in human peripheral nervous sys-
tem 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.

b) or other molecules. It is important to note that neuropathy, a finding that is underscored by the
the local immune environment of the peripheral observed expression of major-histocompatibility-
nerves appears to facilitate the apoptosis of invad- complex class II molecules and the class Ilike mol-
ing autoaggressive T cells,66 a process augmented ecule CD1a in nerve-biopsy specimens.68 Costimu-
by therapeutically administered corticosteroids.67 latory molecules B7-1 and B7-2 are essential for
Macrophages also serve as antigen-presenting effective antigen presentation and may determine
cells in chronic inflammatory demyelinating poly- the differentiation of T lymphocytes into a pheno-

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type of type 1 or type 2 helper cells, thus modulating various antibodies and separate mechanisms are
the local immune response and the clinical course involved in individual patients.
of the disease. A spontaneous immune neuropathy
with clinical, electrophysiological, and morpholog- axonal loss
ic similarities to chronic inflammatory demyelinat- Chronic inflammatory demyelinating polyneurop-
ing polyneuropathy in humans develops in auto- athy, though a demyelinating polyneuropathy, is
immune nonobese diabetic mice that are deficient associated with a concomitant axonal loss attri-
in B7-2 costimulation.69 buted to the primary demyelinating process.39,48
The cellular immune response within the pe- This finding appears to be important, since the long-
ripheral nervous system is tightly regulated at the term prognosis in chronic inflammatory demyelin-
transcriptional level. One of its key regulators, the ating polyneuropathy depends on the magnitude
transcription factor nuclear factor-kB, is up-regu- of axonal loss rather than on demyelination. There
lated predominantly in macrophages in chronic in- are questions as to whether the release of neuro-
flammatory demyelinating polyneuropathy.70 toxic cytokines (e.g., tumor necrosis factor a) and
noxious mediators (e.g., nitric oxide and metallo-
humoral immune response proteinases) enhances axonal destruction, but it
The contribution of autoantibodies to the patho- has become clear that early, effective therapy mini-
genesis of chronic inflammatory demyelinating mizes axonal loss.
polyneuropathy was suggested more than 20 years
ago on the basis of immunoglobulin and comple- current treatment
ment deposition on myelinated nerve fibers71 and
the presence of oligoclonal IgG bands in the cere- In general, therapies are directed at blocking im-
brospinal fluid.72 Passive transfer experiments have mune processes to arrest inflammation and demy-
demonstrated that serum or purified IgG from pa- elination and to prevent secondary axonal degen-
tients with chronic inflammatory demyelinating eration. In patients who have a response, treatment
polyneuropathy induces conduction block and de- must be continued until maximum improvement
myelination in rat nerves.73 In these experiments, or stabilization occurs; thereafter, maintenance
the 28-kD myelin protein zero was identified as one therapy is required and must be tailored to the indi-
of the putative target antigens.74 vidual patient, with the goal of preventing or dimin-
Gangliosides and related glycolipids may also ishing the frequency of relapses or disease progres-
be target antigens (Fig. 3, inset). In a few patients sion. A positive response to therapy is determined
with chronic inflammatory demyelinating polyneu- by a measurable improvement in strength and sen-
ropathy, there is serologic evidence of recent in- sation and the patients ability to perform activi-
fection with Campylobacter jejuni. Given the shared ties of daily living. It is important to be aware that
expression of carbohydrate epitopes in nerve gly- infections and febrile conditions may also affect de-
colipids and microbial lipopolysaccharides, this myelination and thereby worsen the clinical symp-
finding may hint at molecular mimicry as the un- toms of chronic inflammatory demyelinating poly-
derlying cause of chronic inflammatory demyelin- neuropathy. Concomitant use of neurotoxic drugs
ating polyneuropathy in rare instances.75 GM1 an- or the presence of systemic conditions known to
tiserum from a patient with chronic inflammatory cause neuropathies may also theoretically influence
demyelinating polyneuropathy substantially sup- the clinical symptoms of the condition.
pressed sodium currents in single myelinated nerve The most widely used treatments for chronic
fibers from rats.76 Serum reactivity against presum- inflammatory demyelinating polyneuropathy (Ta-
ably nonmyelin antigens on Schwann cells has re- ble 3) consist of intravenous immune globu-
cently been reported in 12 of 46 patients studied.77 lin,11,80,81,84-86 plasma exchange,78,79 and corti-
Demyelination and conduction block may also costeroids.11,87,88 Therapy should be initiated early
result from serum constituents other than mye- in the course of the disease to prevent continuing
lin-directed antibodies, such as cytokines, comple- demyelination and secondary axonal loss leading
ments, or other inflammatory mediators (e.g., ni- to permanent disability. According to published
tric oxide). The low frequency of specific antibodies data, there appears to be no difference in efficacy
that is observed in patients with chronic inflam- among these three main therapies.28,85,87 The de-
matory demyelinating polyneuropathy suggests that cision to choose one of them is usually made on

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Table 3. Current Therapy Based on the Results of Randomized, Controlled Studies.*

No. of
Reference Year Therapy Patients Duration Design Result
Dyck et al.78 1994 Plasma exchange vs. intrave- 15 42 days Randomized, observer- No significant
nous immune globulin blinded, crossover difference
Hahn et al.79 1996 Plasma exchange 15 28 days Double-blind, sham- Improvement in
controlled, crossover 80% of patients
Hahn et al.80 1996 Intravenous immune 30 28 days Double-blind, placebo- Improvement in
globulin controlled, crossover 63% of patients
Mendell et al.81 2001 Intravenous immune 53 42 days Double-blind, randomized, Improvement in
globulin placebo-controlled 76% of patients
Hughes et al.11 2001 Intravenous immune globu- 32 14 days Double-blind, randomized, No significant
lin vs. oral prednisolone crossover difference
Dyck et al.82 1985 Azathioprine in combination 30 9 mo Open, parallel-group, No significant
with prednisone vs. pred- randomized difference
nisone alone
Hadden et al.83 1999 Interferon beta-1a in treat- 20 28 wk Double-blind, randomized, No significant
ment-resistant disease placebo-controlled, benefit of
crossover treatment

* 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.

the basis of cost, availability (e.g., plasmapheresis a week for six months.93 Thirty-five percent of the
and venous access), and side effects (most impor- patients had an improvement, and the disease sta-
tant, the serious long-term side effects of cortico- bilized in 50 percent, prompting the authors to
steroids).87 All these factors should be considered recommend a larger, placebo-controlled trial. How-
when costutility analyses are performed.89 In some ever, another study, in which four patients with
60 to 80 percent of patients with classic chronic in- chronic inflammatory demyelinating polyneurop-
flammatory demyelinating polyneuropathy, the con- athy were treated, showed that treatment with in-
dition improves while they are receiving one of the terferon beta-1a was effective only in combination
three therapies, but the long-term prognosis ap- with intravenous immune globulin.94 Furthermore,
pears to vary according to the time at which therapy a small, randomized, double-blind, placebo-con-
is initiated and the degree of associated axonal trolled, crossover study involving 10 patients with
loss. Azathioprine,82 cyclophosphamide, and cyclo- treatment-resistant chronic inflammatory demy-
sporine have long been used mainly as secondary elinating polyneuropathy and evaluating interfer-
agents in the therapy of chronic inflammatory de- on beta-1a (3 million IU for 2 weeks and 6 million IU
myelinating polyneuropathy, but reliable data on for 10 weeks, administered subcutaneously three
their efficacy from randomized, controlled trials are times per week) failed to show a significant treat-
not available.90 For unknown reasons, the efficacy ment effect.83 The role of interferon alfa in the con-
of these latter treatments is clearly less favorable in dition is also uncertain. Some case reports95,96 and
patients who have a neuropathy accompanied by an open-label prospective pilot study97 suggested
antibodies to myelin-associated glycoprotein.91,92 that interferon alfa was effective.
Given the presumed autoimmune cause of this Of concern, chronic inflammatory demyelinat-
condition and its suggested pathogenetic similari- ing polyneuropathy has been reported to develop
ties to multiple sclerosis, immunomodulatory ther- during treatment with interferon alfa98-100 or inter-
apies that are considered effective in that disorder feron beta.101 Furthermore, interferon was ineffec-
have been investigated. Twenty patients with treat- tive in patients with IgM monoclonal gammop-
ment-resistant chronic inflammatory demyelinat- athy102 and the GuillainBarr syndrome.103 These
ing polyneuropathy were enrolled in a prospective, disturbing observations raise the provocative ques-
multicenter, open-label study that evaluated intra- tion of whether interferons are causally related to
muscular interferon beta-1a at a dose of 30 g once the onset of chronic inflammatory demyelinating

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medical progress

polyneuropathy, as opposed to being capable of more, controlled trials providing long-term data are
suppressing the disease.104 Hughes et al. conclud- lacking. The evidence concerning the efficacy of
ed that there is currently no adequate evidence to plasma exchange, intravenous immune globulin,
decide whether interferons are beneficial in the and corticosteroids derives only from short-term
treatment of this condition.90 studies. Plasma exchange and intravenous immune
Other forms of treatment have been tested in globulin are expensive therapies and must be con-
open-label studies with a small number of patients tinued over the long term to maintain benefit. Anec-
or in individual patients. Beneficial effects in pa- dotal experience suggests that the use of immuno-
tients with previously treatment-resistant chronic suppressive agents may allow therapy with plasma
inflammatory demyelinating polyneuropathy were exchange or intravenous immune globulin to be ad-
reported for the combination of plasmapheresis ministered less frequently or even phased out, with
and intravenous immune globulin,105 mycophen- subsequent substantial financial savings. There is
olate mofetil,106-108 cyclosporine,109-111 etaner- clearly a need for controlled studies to assess this
cept,112 cyclophosphamide,113,114 and autologous long-term aspect of therapy for chronic inflamma-
hematopoietic stem-cell transplantation.115 In pa- tory demyelinating polyneuropathy.
tients with multifocal motor neuropathy or chronic
inflammatory demyelinating polyneuropathy, the conclusions
combination of intravenous immune globulin and
mycophenolate mofetil may permit a reduction in It is important to recognize chronic inflammato-
the dose of immune globulin or corticosteroids, a ry demyelinating polyneuropathy in a patient with
finding that was recently suggested by an open- a chronic progressive or chronic relapsing neu-
label study of 6 patients116 and a retrospective ropathy, since therapies that are at least partially
analysis of the efficacy of mycophenolate mofetil effective including corticosteroids, intravenous
in 21 patients with chronic inflammatory demye- immune globulin, plasma exchange, and immuno-
linating polyneuropathy.108 Two recent open-label suppressants are available for this crippling dis-
studies involving 30 patients found improvement ease. Sets of diagnostic criteria have been devel-
in those with IgM-associated demyelinating poly- oped. The disorder appears to be heterogeneous in
neuropathy who were receiving treatment with terms of clinical presentation and immunopatho-
rituximab, a chimeric humanized monoclonal an- genesis. Further research should provide further
tibody against CD20 antigen that reduces B-lym- insight into the underlying mechanisms of nerve
phocyte counts.117,118 However, no data that have damage and may facilitate the development of more
been collected on the basis of randomized, con- effective treatments.
trolled studies with a sufficient number of patients We are indebted to Marinos C. Dalakas, of Bethesda, Md., David
R. Cornblath, of Baltimore, and John Pollard, of Sydney, for their
are available to allow conclusive recommendations critical review of the manuscript and many helpful suggestions.
about treatment with any of these agents. Further-

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