Beruflich Dokumente
Kultur Dokumente
Peter Van den Bergh, Belgium; Pierre Bouche, France; David R. Cornblath, USA; Eileen
Evers, UK; Robert D. Hadden, UK; Angelika F. Hahn, Canada; Richard A.C. Hughes, UK;
Isabel Illa, Spain; Carol L. Koski, USA; Jean-Marc Léger, France; Eduardo Nobile-Orazio,
Italy; John D. Pollard, Australia; Claudia Sommer, Germany; Pieter A. van Doorn,
Netherlands; Ivo N. van Schaik, Netherlands
Introduction
CIDP is an acquired demyelinating neuropathy of presumed auto-immune origin. The
disease course is chronically progressive, stepwise, or recurrent. The typical clinical picture
comprises symmetric proximal and distal weakness, sensory loss, and hypo- or areflexia.
However, the total clinical spectrum is much wider, including predominantly distal or
proximal weakness, pure motor or sensory forms, and asymmetric or focal presentations.
Cranial nerve, central nervous system, and autonomic involvement can occur. The
diagnosis of CIDP is based on a combination of clinical features, nerve conduction studies,
spinal fluid analysis, and, in selected cases, nerve biopsy. As there is no definitive biologic
diagnostic marker and as clinical and laboratory features are heterogeneous, recognition of
CIDP may not be straightforward in some cases.
detect all the clinically diagnosed cases of CIDP). Thus, new criteria for clinical practice
may be needed. Criteria for CIDP are closely linked to criteria for detection of peripheral
nerve demyelination. Various sets of published electrodiagnostic criteria seem to lack
specificity or sensitivity (Bromberg, 1991; Wilson, 2000; Molenaar, 2002; Nicolas et al.,
2002; Thaisetthawatkul et al., 2002; Van den Bergh and Piéret, 2004). Therefore, although
aware that scientifically valid methods are being used to create research and clinical
criteria for CIDP, diagnostic criteria based on the best available current scientific and
clinical evidence are urgently needed for clinicians to be able to recognize and treat most
patients with CIDP. In this document, we present a new set of CIDP criteria based on
expert consensus (Level D recommendation).
Background
The first set of diagnostic clinical criteria was published by Dyck et al. (1975; 1982) and
included progressive course at 6 months, usually slowed nerve conduction velocities (and
occurrence of conduction block), spinal fluid cyto-albumenic dissociation, and nerve biopsy
demonstrating segmental de- and remyelination, subperineurial or endoneurial edema, and
perivascular inflammation. Exclusion criteria were associated diseases, monoclonal
gammopathy, and evidence of hereditary neuropathy. This descriptive set was the basis for
a formalized set of criteria, proposed by Barohn et al. (1989). Mandatory inclusion and
exclusion criteria reduced the required disease progression time to 2 months. Major
laboratory criteria consisted of nerve biopsy abnormalities, motor conduction slowing to <
70% in 2 nerves, and spinal fluid protein > 45 mg/dl. Fulfillment of all criteria was
necessary for a definite diagnosis; fulfillment of only 2 and 1 laboratory criteria led to the
diagnostic categories of probable and possible, respectively. Of 60 patients with a clinical
diagnosis of CIDP by the authors, 30% had all 3 laboratory abnormalities, 48% had 2, and
22% had 1; however, 95% responded to treatment, mainly prednisone.
Research criteria for CIDP were proposed by an Ad Hoc Subcommittee of the AAN (1991).
Fulfillment of clinical, physiological, pathological, and spinal fluid criteria led to 3 diagnostic
categories (definite, probable, possible). Fulfillment of pathological criteria was necessary
for a definite diagnosis. Physiological criteria for primary demyelination were very detailed,
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but restrictive when applied clinically as 3 of 4 nerve conduction parameters were required
to be abnormal, even for the diagnosis of possible CIDP. On the other hand, the criteria for
partial motor conduction block and abnormal temporal dispersion were probably not
restrictive enough, as suggested by AAEM consensus criteria for the diagnosis of partial
conduction block (Olney et al., 1999). Patients who meet AAN research criteria certainly
have CIDP, but many patients who clinicians diagnose as CIDP do not meet these criteria.
To increase sensitivity, Saperstein et al. (2001) proposed a modified criteria set based on
the AAN criteria (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task
Force, 1991) and Barohn et al. (1989) criteria. The differences were that (1) nerve biopsy
was not mandatory for a definite diagnosis, (2) spinal fluid protein > 45 mg/dl was
mandatory, and (3) modification of AAN physiological criteria such that abnormality of 2 of
4 nerve conduction parameters was sufficient and a change in criteria for conduction block
to match the AAEM consensus.
Electrodiagnostic criteria
At least 12 sets of electrodiagnostic criteria for primary demyelination have been published,
not only to identify CIDP but also demyelinating GBS (for review, see Van den Bergh and
Piéret, 2004). Bromberg (1991) compared 3 sets (Albers and Kelly, 1989; Barohn et al.,
1989; Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,
1991) and found maximal sensitivity of 50% (66% after modification) with 100% specificity
with regard to ALS and diabetic neuropathy. Van den Bergh and Piéret (2004) (and
unpublished observations) confirmed 100% specificity of these 3 sets for ALS and diabetic
neuropathy with sensitivity levels of 43% (Albers and Kelly, 1989), 29% (Barohn et al.,
1989), and 39% (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task
Force, 1991). A fourth fully specific set had 68% sensitivity (Meulstee et al., 1995). They
found lack of specificity (44-97%) with regard to diabetic neuropathy of 8 other sets. They
proposed a 100% specific new set with 75% sensitivity. Dispersion of the distal CMAP as
an additional parameter appears to be a promising tool that may significantly enhance
sensitivity. Thaisetthawatkul et al. (2002) reported 78% sensitivity with 94% specificity for
ALS and diabetic neuropathy by using only this parameter. Combination of the distal CMAP
dispersion parameter with criteria proposed by Nicolas et al. (2001) increased sensitivity
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from 61 to 87% but specificity decreased from 91 to 85% for ALS and from 100 to 94% for
diabetic polyneuropathy (Thaisetthawatkul et al., 2002). The results of combination with the
Van den Bergh and Piéret (2004) criteria are pending. It is expected that this combination
under appropriate conditions will significantly increase sensitivity without affecting
specificity.
Pathological criteria
Nerve biopsy, usually the sural sensory nerve, is considered useful for confirming the
diagnosis, but is a mandatory criterion for a definite diagnosis of CIDP only in the AAN
criteria (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force,
1991). Demyelinating lesions were found retrospectively on nerve teasing in 48%, 50%,
and 72% of cases by Barohn et al. (1989), Haq et al. (2000), and Bouchard et al. (1999),
respectively, and in ultrastructural studies 79% of cases (Haq et al., 2000). Haq et al.
(2000) found 83% (teasing) and 91% (ultrastructure) specificity with regard to diabetic
neuropathy. Interestingly, lack of agreement between electrodiagnostic and histological
criteria was observed. Vallat et al. (2003) found histological evidence of de- and
remyelination and/or cellular infiltrates in 8 of 44 patients with CIDP who did not meet
electrophysiologic criteria. In a prospective study, Gabriel et al. (2000) showed an
alteration of the diagnosis in 14% of the patients after sural nerve biopsy. These
observations are indicative of the added value of nerve biopsy in reaching a final diagnosis.
However, when Krendel et al. (1989) compared histological features of sural nerve biopsies
of patients with CIDP and patients with other neuropathies, no abnormalities were specific,
but cellular infiltrates and onion bulbs appeared to be diagnostically helpful when
considered together with clinical information. Retrospective studies have shown that sural
nerve biopsy is of limited value (Molenaar et al., 1998; Bosboom et al., 1999; 2001).
Bosboom et al. (1999; 2001) compared sural nerve biopsies from patients with CIDP and
chronic idiopathic axonal polyneuropathy (CIAP) and from normal controls. Although
significant differences of features of demyelination, axonal degeneration, and inflammation
were found, there was a considerable overlap of abnormalities in CIDP and CIAP. Attempts
to identify more specific diagnostic signs of inflammation (upregulation of matrix
metalloproteinases 2 and 9 [Leppert et al., 1999; Jann et al., 2003] and of specific
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CLINICAL CRITERIA
I Inclusion criteria
A Typical CIDP
• Chronically progressive, stepwise, or recurrent symmetric proximal and distal
weakness and sensory dysfunction of all extremities, developing over at least 2
months; cranial nerves may be affected
• Absent or reduced tendon reflexes in all extremities
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B Atypical CIDP
One of the following, but otherwise as in A (tendon reflexes may be normal in unaffected
limbs)
• Predominantly distal weakness (distal acquired demyelinating symmetric, DADS)
• Pure motor or sensory presentations (and possibly autonomic)
• Asymmetric presentations (multifocal acquired demyelinating sensory and motor,
MADSAM, Lewis-Sumner syndrome)
• Focal presentations (e.g., involvement of the brachial plexus or of one or more
peripheral nerves in one upper limb)
• Central nervous system involvement (may occur in otherwise typical CIDP)
II Exclusion criteria
ELECTRODIAGNOSTIC CRITERIA
I Definite
A. At least 50% prolongation of motor distal latency above the upper limit of normal
values in 2 nerves, or
B. At least 30% reduction of motor conduction velocity below the lower limit of normal
values in 2 nerves, or
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C. At least 20% prolongation of F-wave latency above the upper limit of normal values
in 2 nerves (> 50% if amplitude of distal negative peak CMAP < 80% of lower limit of
normal values), or
D. Absence of F-waves in 2 nerves if amplitude of distal negative peak CMAP at least
20% of lower limit of normal values + at least one other demyelinating parameter in
at least one other nerve, or
E. Partial motor conduction block: at least 50% amplitude reduction of the proximal
negative peak CMAP if distal negative peak CMAP at least 20% of lower limit of
normal values in 2 nerves or in 1 nerve + at least one other demyelinating
parameter in at least one other nerve, or
F. Abnormal temporal dispersion (> 30% duration increase between the proximal and
distal negative peak CMAP) in at least 2 nerves, or
G. Distal CMAP duration (interval between onset of the first negative peak and return to
baseline of the last negative peak) of at least 9 msec in at least 1 nerve + at least
one other demyelinating parameter in at least one other nerve
II Probable: At least 30% amplitude reduction of the proximal negative peak CMAP,
excluding the posterior tibial nerve, if distal negative peak CMAP at least 20% of lower limit
of normal values in 2 nerves or in 1 nerve + at least one other demyelinating parameter in
at least one other nerve
SUPPORTIVE CRITERIA
A. Elevated cerebrospinal fluid protein with cell counts < 10/mm3 (Level A
recommendation)
B. Magnetic Resonance Imaging showing gadolinium enhancement and/or hypertrophy
of the cauda equina, lumbosacral or cervical nerve roots, or the brachial or
lumbosacral plexuses (Level C recommendation)
C. Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination
in > 5 fibres by electron microscopy or in > 6 of 50 teased fibres
D. Clinical improvement following immunomodulatory treatment (Level A
recommendation)
• Osteosclerotic myeloma
• Others (vasculitis, hematologic and non-hematologic malignancies, including
Waldenström’s macroglobulinemia and Castleman’s disease)
The following minimal set of investigations should be considered to search for associated
diseases that may require treatment independently from CIDP: serum and urine
immunoglobulin electrophoresis by immunofixation; fasting blood glucose; oral glucose
tolerance test; complete blood count; blood urea nitrogen and serum creatinine; liver
function tests; HIV, hepatitis B and C, and Borrelia burgdorferi serology, CRP, ANA, ENA,
thyroid function tests
DIAGNOSTIC CATEGORIES
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